EP4608981A1

EP4608981A1 - Gene therapy treatment of mtres1 related diseases and disorders

Info

Publication number: EP4608981A1
Application number: EP23883600.1A
Authority: EP
Inventors: Omri GOTTESMAN; Emma BRANDT; Shannon BRUSE; Paul BUSKE; Brian CAJES; David JAKUBOSKY; David Lewis; Gregory Mcinnes; David Rozema; John VEKICH
Original assignee: Empirico Inc
Current assignee: Empirico Inc
Priority date: 2022-10-25
Filing date: 2023-10-23
Publication date: 2025-09-03
Also published as: WO2024091874A1

Abstract

Disclosed herein are compositions comprising a MTRES1 gene therapy. Also provided herein are methods of treating conditions associated with MTRES1 gene mutations that include providing a MTRES1 gene therapy.

Description

GENE THERAPY TREATMENT OF MTRES1 RELATED DISEASES AND DISORDERS

CROSS REFERENCE

[001] This application claims the benefit of U.S. Provisional Application No. 63/419,211 filed on October 25, 2022, which is incorporated herein by reference in its entirety.

INCORPORATION BY REFERENCE OF A SEQUENCE LISTING

[002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 54462-745.601.xml, created October 19, 2023, which is 25,341 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.

BACKGROUND

[003] Neurological disorders are a common problem, particularly in the older population.

Improved therapeutics are needed for treating these disorders.

SUMMARY

[004] Disclosed herein, in some embodiments, are compositions comprising an MTRES1 gene therapy and when administered to a subject in an effective amount modulates central nervous system (CNS) MTRES1. In some embodiments, the CNS MTRES1 is decreased. In some embodiments, the CNS MTRES1 is decreased by about 10% or more, as compared to prior to administration. Disclosed herein, in some embodiments, are compositions comprising an MTRES 1 gene therapy and when administered to a subject in an effective amount increases cognitive function or slows cognitive decline. In some embodiments, the cognitive function is increased by about 10% or more, as compared to prior to administration. In some embodiments, the cognitive decline is slowed by about 10% or more, as compared to prior to administration. Disclosed herein, in some embodiments, are compositions comprising an MTRES 1 gene therapy and when administered to a subject in an effective amount decreases a marker of neurodegeneration. In some embodiments, the marker of neurodegeneration comprises a central nervous system (CNS) or cerebrospinal fluid (CSF) marker of neurodegeneration. In some embodiments, the marker of neurodegeneration comprises a measurement of central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) beta-amyloid 42, CSF tau, CSF phospho-tau, CSF or plasma neurofilament light chain (NfL), Lewy bodies, or CSF alpha-synuclein. In some embodiments, the marker of neurodegeneration is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the MTRES 1 gene therapy comprises gene delivery. In some embodiments, the MTRES1 gene therapy comprises delivering a nucleic acid comprising SEQ ID NO: 1. In some embodiments, the MTRES 1 gene therapy comprises delivering a nucleic acid comprising an inactivated MTRES 1 sequence. In some embodiments, the MTRES 1 gene therapy comprises altering the native sequence of at least one copy of a MTRES1 gene. In some embodiments, at least one copy of the MTRES1 gene is inactivated. In some embodiments, at least one copy of the MTRES1 gene is edited to comprise SEQ ID NO: 1. In some embodiments, the MTRES1 gene therapy comprises a programmable nuclease. In some embodiments, the MTRES1 gene therapy comprises RNA editing. In some embodiments, the composition comprises an ADAR enzyme. In some embodiments, the gene therapy is delivered in a vector. Disclosed herein, in some embodiments, are methods of treating a subject having a neurological disorder, comprising administering an effective amount of a composition described herein to the subj ect. In some embodiments, the neurological disorder comprises dementia, Alzheimer’s disease, delirium, cognitive decline, vascular dementia, or Parkinson’s disease.

[005] In certain aspects, disclosed herein is a method of treating a subject having a neurological disorder, comprising administering an effective amount of the composition disclosed herein to the subject. In some embodiments, disclosed herein is a method of treating a subject having a neurological disorder or who is at risk for developing the neurological disorder, the method comprising evaluating a subject’s risk for developing a neurological disorder and administering an effective amount of the composition disclosed herein to the subject. In some embodiments, the subject has a genotype at risk for developing Alzheimer’s disease or dementia. In some embodiments, the subject is a heterozygous or homozygous carrier of APOE4. In some embodiments, the subject is a heterozygous or homozygous carrier of MTRES1 rsl 17058816-G (c.3+lG). In some embodiments, evaluating a subject’s risk for developing a neurological disorder comprises calculating a polygenic risk score for developing Alzheimer’s disease or dementia. In some embodiments, the subject has a polygenic risk score in the 40^th percentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia. In some embodiments, the subject has a polygenic risk score in the 20^th percentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia. In some embodiments, calculating a polygenic risk score comprises providing genomic data comprising one or more genotypes of the subject, wherein the one or more genotypes is associated with a high risk for developing Alzheimer’s disease or dementia.

BRIEF DESCRIPTION OF THE DRAWINGS

[006] FIG. 1A is an image of a western blot of MTRES1 protein in the wildtype and MTRES1 c.3+lG>A mmigene expression constructs. Lane 1 : ladder (bands for 38, 31, 24, and 17 kDa are indicated); lane 2: Empty vector; lane 3: wild type (WT); lane 4: c.3+lG>A.

[007] FIG. IB is a plot quantifying MTRES1 western blot data in the wildtype and MTRES1 c.3+lG>A minigene expression constructs. Left bar: wild type (WT); right bar: c.3+lG>A. The y- axis is labeled normalized to total protein from 0 to 4 at 1 unit intervals. [008] FIG. 2 is a plot oiMTRESl mRNA qPCR data in the wildtype and MTRES1 c.3+lG>A minigene expression constructs. Left bar: wild type (WT); right bar: c.3+lG>A. The y-axis is labeled fold change from empty vector from 0 to 100 at 20 unit intervals.

[009] FIG. 3 is an image of a western blot of MTRES1 protein in the CRISPR-engineered wildtype, MTRES1 c.3+lG>A knock-in cells, and MTRES1 knock-out cell lines. Left column: whole cell lysate; right column: Mito fraction. Rows (top to bottom): wild type (WT); c.3+lG>A; KO.

[0010] FIG. 4 is a plot o MTRESl mRNA qPCR data in the CRISPR-engineered wildtype, MTRES1 c.3+lG>A knock-in cells, and MTRES1 knock-out cell lines. Left bar: wild type (WT); middle bar: c.3+lG>A; right bar: KO. The y-axis is labeled fold change from 0.0 to 1.5 at 0.5 unit intervals.

DETAILED DESCRIPTION

[0011] Large-scale human genetic data can improve the success rate of pharmaceutical discovery and development. A Genome Wide Association Study (GWAS) may detect associations between genetic variants and traits in a population sample. A GWAS may enable better understanding of the biology of disease, and provide applicable treatments. A GWAS can utilize genotyping and/or sequencing data, and often involves an evaluation of millions of genetic variants that are relatively evenly distributed across the genome. The most common GWAS design is the case-control study, which involves comparing variant frequencies in cases versus controls. If a variant has a significantly different frequency in cases versus controls, that variant is said to be associated with disease. Association statistics that may be used in a GWAS are p-values, as a measure of statistical significance; odds ratios (OR), as a measure of effect size; or beta coefficients (beta), as a measure of effect size. Researchers often assume an additive genetic model and calculate an allelic odds ratio, which is the increased (or decreased) risk of disease conferred by each additional copy of an allele (compared to carrying no copies of that allele). An additional concept in design and interpretation of GWAS is that of linkage disequilibrium, which is the non-random association of alleles. The presence of linkage disequilibrium can obfuscate which variant is “causal.”

[0012] Functional annotation of variants and/or wet lab experimentation can identify the causal genetic variant identified via GWAS, and in many cases may lead to the identification of diseasecausing genes. In particular, understanding the functional effect of a causal genetic variant (for example, loss of protein function, gain of protein function, increase in gene expression, or decrease in gene expression) may allow that variant to be used as a proxy for therapeutic modulation of the target gene, or to gain insight into potential therapeutic efficacy and safety of a therapeutic that modulates that target.

[0013] Identification of such gene-disease associations has provided insights into disease biology and may be used to identify novel therapeutic targets for the pharmaceutical industry. In order to translate the therapeutic insights derived from human genetics, disease biology in patients may be exogenously ‘programmed’ into replicating the observation from human genetics. There are several potential options for therapeutic modalities that may be brought to bear in translating therapeutic targets identified via human genetics into novel medicines. These may include well established therapeutic modalities such as small molecules and monoclonal antibodies, maturing modalities such as oligonucleotides, and emerging modalities such as gene therapy and gene editing. The choice of therapeutic modality can depend on several factors including the location of a target (for example, intracellular, extracellular, or secreted), a relevant tissue (for example, brain) and a relevant indication.

[0014] The MTRES 1 gene is located on chromosome 6, and encodes mitochondrial transcription rescue factor 1 (MTRES1), also known as chromosome 6 open reading frame 203 (C6orf203). The MTRES1 gene may also be referred to as the C6orf203 gene. MTRES1 may include 240 amino acids. MTRES 1 may include 245 amino acids. MTRES 1 may be expressed in neural cells. MTRES1 may be cytoplasmic or intracellular. MTRES1 may be localized in mitochondria within the cell. MTRES1 may be involved in mitochondrial transcription regulation. MTRES 1 may be involved in mitochondrial translation regulation. An example of an MTRES 1 amino acid sequence, and further description of MTRES1 is included at uniprot.org under accession no. Q9P0P8 (last modified October 1, 2000).

[0015] Here it is shown that loss of function MTRES 1 variants may protect against neurological diseases. For example, a loss of function MTRES 1 variant was associated with protective associations against Alzheimer’s disease, family history of Alzheimer’s disease, dementia, vascular dementia, anticholinesterase medication use, and delirium. Therefore, targeting MTRES 1 may serve as a therapeutic for treatment of a neurological disorder such as dementia, Alzheimer’s disease, delirium, cognitive decline, vascular dementia, or Parkinson’s disease.

[0016] Disclosed herein are methods and compositions for targeting MTRES 1 with gene therapy. Also provided herein are methods of treating a neurological disorder by providing an MTRES 1 gene therapy to a subject in need thereof.

I. COMPOSITIONS

[0017] Disclosed herein, in some embodiments, are compositions comprising an MTRES1 gene therapy. In some embodiments, the composition comprises an MTRES 1 gene therapy. In some embodiments, the composition consists of an MTRES 1 gene therapy. In some embodiments, the MTRES 1 gene therapy modulates MTRES 1 mRNA expression in the subject. In some embodiments, the MTRES 1 gene therapy reduces MTRES 1 mRNA expression in the subject. In some embodiments, the MTRES1 gene therapy alters the sequence of MTRES1 mRNA in the subject. In some embodiments, the MTRES 1 gene therapy alters the function, binding, or activity of MTRES 1 mRNA in the subject. In some embodiments, the MTRES 1 gene therapy modulates MTRES 1 protein expression in the subject. In some embodiments, the MTRES 1 gene therapy reduces MTRES 1 protein expression in the subject. In some embodiments, the MTRES1 gene therapy alters the sequence of MTRES1 protein in the subject. In some embodiments, the MTRES1 gene therapy alters the function, binding, or activity of MTRES 1 protein in the subject. In some embodiments, a composition described herein is used in a method of treating a disorder in a subject in need thereof. Some embodiments relate to a composition comprising an nucleic acid encoding a gene therapy for use in a method of treating a disorder as described herein. Some embodiments relate to use of a composition comprising an nucleic acid encoding a gene therapy, in a method of treating a disorder as described herein.

[0018] Some embodiments include a composition comprising an MTRES 1 gene therapy and when administered to a subject in an effective amount modulates MTRES1 mRNA or protein levels in a cell, fluid or tissue. In some embodiments, the gene therapy decreases MTRES1 mRNA or protein levels in a cell, fluid, or tissue. In some embodiments, the composition comprises an MTRES 1 gene therapy and when administered to a subject in an effective amount decreases MTRES 1 mRNA levels in a cell or tissue. In some embodiments, the cell is a neural cell such as a central nervous system (CNS) cell. Some examples of CNS cells include neurons, glia, microglia, astrocytes, or oligodendrocytes. In some embodiments, the tissue is CNS or brain tissue. In some embodiments, the MTRES1 mRNA levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the MTRES 1 mRNA levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the MTRES 1 mRNA levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the MTRES 1 mRNA levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the MTRES 1 mRNA levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the MTRES 1 mRNA levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the MTRES1 mRNA levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0019] Some embodiments include a composition comprising an MTRES 1 gene therapy and when administered to a subject in an effective amount changes the sequence of an MTRES 1 mRNA or protein in a cell, fluid or tissue. In some embodiments, the composition comprises an MTRES 1 gene therapy and when administered to a subject in an effective amount changes the sequence of MTRES 1 mRNA or protein in a cell or tissue. In some embodiments, the composition comprises an MTRES 1 gene therapy and when administered to a subject in an effective amount alters the function, binding, or activity of MTRES1 mRNA or protein in in a cell or tissue. In some embodiments, the cell is a neural cell such as a central nervous system (CNS) cell. Some examples of CNS cells include neurons, glia, microglia, astrocytes, or oligodendrocytes. In some embodiments, the tissue is CNS or brain tissue.

[0020] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount modulates MTRES1 protein levels in a cell, fluid or tissue. In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount decreases MTRES1 protein levels in a cell, fluid or tissue. In some embodiments, the cell is a neural cell such as a central nervous system (CNS) cell. Some examples of CNS cells include neurons, glia, microglia, astrocytes, or oligodendrocytes. In some embodiments, the tissue is CNS or brain tissue. In some embodiments, the MTRES1 protein levels are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the MTRES 1 protein levels are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the MTRES 1 protein levels are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the MTRES1 protein levels are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0021] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount alters MTRES 1 function, activity or binding in a cell, fluid or tissue. In some embodiments, the composition comprises an MTRES 1 gene therapy and when administered to a subject in an effective amount decreases MTRES 1 function, activity or binding in a cell, fluid or tissue. In some embodiments, the cell is a neural cell such as a central nervous system (CNS) cell. Some examples of CNS cells include neurons, glia, microglia, astrocytes, or oligodendrocytes. In some embodiments, the tissue is CNS or brain tissue. In some embodiments, the MTRES 1 protein function, activity or binding are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the MTRES 1 protein function, activity or binding are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the MTRES 1 protein function, activity or binding are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the MTRES 1 protein function, activity or binding are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the MTRES1 protein function, activity or binding are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the MTRES 1 protein function, activity or binding are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the MTRES 1 protein function, activity or binding are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0022] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount diminishes a neurological disorder phenotype. The neurological disorder disease may include dementia, Alzheimer’s disease, delirium, cognitive decline, vascular dementia, or Parkinson’s disease. In some embodiments, the neurological disorder phenotype is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the neurological disorder phenotype is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0023] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount enhances a protective phenotype against a neurological disorder in the subject. The neurological disorder may include dementia, Alzheimer’s disease, delirium, cognitive decline, vascular dementia, or Parkinson’s disease. In some embodiments, the protective phenotype is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the protective phenotype is increased by about 10% or more, as compared to prior to administration In some embodiments, the protective phenotype is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the protective phenotype is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the protective phenotype is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[0024] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount decreases a marker of neurodegeneration in the subject. Some example markers of neurodegeneration may include central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) beta-amyloid 42, CSF tau, CSF phospho-tau, CSF or plasma neurofilament light chain (NfL), Lewy bodies, or CSF alpha-synuclein. In some embodiments, the marker of neurodegeneration is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the marker of neurodegeneration is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0025] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount decreases central nervous system (CNS) amyloid plaques in the subject. In some embodiments, the CNS amyloid plaques are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CNS amyloid plaques are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0026] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount decreases central nervous system (CNS) tau accumulation in the subject. In some embodiments, the CNS tau accumulation is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CNS tau accumulation is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0027] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) beta-amyloid 42 in the subject. In some embodiments, the CSF beta-amyloid 42 is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF beta-amyloid 42 is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF beta-amyloid 42 is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF beta-amyloid 42 is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF beta-amyloid 42 is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF beta-amyloid 42 is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF beta-amyloid 42 is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0028] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) tau in the subject. In some embodiments, the CSF tau is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF tau is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF tau is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF tau is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF tau is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF tau is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF tau is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0029] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) tau in the subject. In some embodiments, the CSF phospho-tau is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF phospho-tau is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF phospho-tau is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF phospho-tau is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF phospho-tau is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF phospho-tau is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF phospho-tau is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0030] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount decreases cerebrospinal fluid (CSF) alpha-synuclein in the subject. In some embodiments, the CSF alpha-synuclein is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by about 10% or more, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the CSF alpha-synuclein is decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages. [0031] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount decreases Lewy bodies in the subject. In some embodiments, the Lewy bodies are decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by about 10% or more, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by no more than about 10%, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, or no more than about 90%, as compared to prior to administration. In some embodiments, the Lewy bodies are decreased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, or by a range defined by any of the two aforementioned percentages.

[0032] In some embodiments, the composition comprises an MTRES1 gene therapy and when administered to a subject in an effective amount increases cognitive function. In some embodiments, the cognitive function is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, as compared to prior to administration. In some embodiments, the cognitive function is increased by about 10% or more, as compared to pnor to administration. In some embodiments, the cognitive function is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more, as compared to prior to administration. In some embodiments, the cognitive function is increased by about 200% or more, about 300% or more, about 400% or more, about 500% or more, about 600% or more, about 700% or more, about 800% or more, about 900% or more, or about 1000% or more, as compared to prior to administration. In some embodiments, the cognitive function is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, as compared to prior to administration. In some embodiments, the cognitive function is increased by no more than about 10%, as compared to prior to administration. In some embodiments, the cognitive function is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, as compared to prior to administration. In some embodiments, the cognitive function is increased by no more than about 200%, no more than about 300%, no more than about 400%, no more than about 500%, no more than about 600%, no more than about 700%, no more than about 800%, no more than about 900%, or no more than about 1000%, as compared to prior to administration. In some embodiments, the cognitive function is increased by 2.5%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%, or by a range defined by any of the two aforementioned percentages.

A. Gene therapy

[0033] Described herein are compositions for use in gene therapy. There are different methods of gene therapy, including gene delivery, gene editing, and RNA editing. As used herein, “gene delivery” comprises a system that delivers a therapeutic gene to a subject. The therapeutic gene may comprise a gene which is overexpressed. The therapeutic gene may suppress a relevant target or phenotype. The therapeutic gene may be integrated into the genome. The therapeutic gene may remain in the cell as an episome. As used herein, “gene editing” comprises altering a sequence of the target gene within the genome. Gene editing may refer to replacing a sequence with a different sequence. Gene editing may refer to inducing mutations in a genomic sequence. Gene editing may refer to producing a knock-out version of a genomic sequence. As used herein, “RNA editing” comprises altering a sequence of an RNA within in an organism.

[0034] In some embodiments, the compositions comprise a nucleic acid encoding a gene therapy. In some embodiments, the gene therapy comprises gene delivery. In some embodiments, the gene therapy comprises gene editing. In some embodiments, the methods further comprise delivering a protein (e.g. a programmable nuclease). In some embodiments, the methods comprise delivering a nucleic acid encoding a gene therapy and a protein for use in a gene therapy (e.g. a Cas9 protein and a gRNA).

(i) Gene delivery

[0035] In some embodiments, the gene therapy comprises a gene delivery system. In some embodiments, the gene delivery system comprises a nucleic acid. In some embodiments, the gene delivery system comprises a nucleic acid encoding MTRES1. In some embodiments, the MTRES1 comprises a MTRES1 c.3+lG>A variant (SEQ ID NO: 1). In some embodiments, the compositions comprise a nucleic acid comprising the MTRES1 c.3+lG>A variant gene. In some embodiments, the compositions comprise a nucleic acid comprising a nonfunctional variant of the MTRES1 gene. [0036] In some embodiments, the gene delivery system comprises a sequence that inhibits the native MTRES 1 expression. In some embodiments, the gene delivery system comprises a sequence that decreases the activity of the native MTRES 1. In some embodiments, the gene delivery system comprises a sequence comprises at least a portion of SEQ ID NO: 1. In some embodiments, the gene delivery sequence comprises a sequence that can block RNA binding.

[0037] In some embodiments, the nucleic acid is delivered to a cell. In some embodiments, the nucleic acid is retained within the cell. In some embodiments, the nucleic acid is integrated into the cell’s genome. In some embodiments, the nucleic acid is maintained as an episome.

(ii) Gene editing [0038] In some embodiments, the methods comprise editing the sequence of at least one MTRES1 gene within the genome. In some embodiments, the methods comprise inactivating an MTRES1 gene within the genome In some embodiments, the methods comprise changing the sequence of an MTRES1 gene within the genome.

[0039] In some embodiments, the compositions comprise a programmable nuclease. In some embodiments, the programmable nuclease is programmed to bind to a target sequence. In some embodiments, the programmable nuclease is configured to cut a target sequence. In some embodiments, the composition is configured to inactivate the target sequence. In some embodiments, the composition further comprises a donor nucleotide. In some embodiments, the donor nucleotide is used to replace the native MTRES1 sequence in the genome with the MTRES1 c.3+lG>A variant (SEQ ID NO: 1).

[0040] In some embodiments, the target sequence comprises an MTRES1 gene. In some embodiments, the target sequence comprises a coding sequence within the MTRES1 gene. In some embodiments, the target sequence comprises a regulatory sequence within the MTRES1 gene. In some embodiments, the regulatory sequence comprises a promoter, an enhancer, an intron, or an intron splicing site. In some embodiments, the target sequence comprises an untranslated region (UTR). In some embodiments, the untranslated region comprises a 3’ UTR. In some embodiments, the untranslated region comprises a 5 ’ UTR.

[0041] In some embodiments, described herein is a programmable nuclease. Programmable nucleases for gene editing include zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs), and the RNA-guide clustered regulatory interspaced short palindromic repeats (CRISPR) and CRISPR associated nucleases (CRISPR/Cas). In some embodiments, the programmable nuclease binds to the genome at a target sequence. In some embodiments, the programmable nuclease cleaves the genome at the target sequence. In some embodiments, the programmable nuclease cleaves the genome near the target sequence. In some embodiments, the programmable nuclease cleaves the genome within about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, or 100 basepairs of the target sequence.

[0042] In some embodiments, the compositions described herein comprise a ZFN. ZFNs comprise a DNA binding domain and a nuclease. The DNA binding domain comprises three to six zinc finger repeats that recognize specific basepair sequences In some embodiments, the ZFN binds to the target sequence. In some embodiments, the ZFN cleaves the genome near the target sequence. [0043] In some embodiments, the compositions described herein comprise a TALEN. TALENs comprise a non-specific FokI nuclease domain fused to a customizable DNA-binding domain. This DNA-binding domain is composed of highly conserved repeats derived from transcription activator- hke effectors (TALEs). The TALE domains can be designed to target a specific target sequence. In some embodiments, the TALEN binds to the target sequence. In some embodiments, the TALEN cleaves the genome near the target sequence. [0044] In some embodiments, the compositions described herein comprise a CRISPR/Cas system. In some embodiments, the composition comprises a Cas endonuclease that cleaves the genomic DNA at a target sequence. In some embodiments, the Cas endonuclease comprises a Cas endonuclease selected from the group consisting of: Cpfl, Casl, CaslB, Cas2, Cas3, Cas4, Cas5, Cash, Cas7, Cas8, Cas9 (also known as Csnl and Csxl2), CaslO, Csyl, Csy2, Csy3, Csel, Cse2, Cscl, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Csxl7, Csxl4, CsxlO, Csxl6, CsaX, Csx3, Csxl, Csxl5, Csfl, Csf2, Csf3, and Csf4. In some embodiments, the compositions comprise a guide RNA (gRNA) that guides the Cas endonuclease to the target site.

[0045] In some embodiments, the programmable nuclease cleaves the genomic DNA at the target sequence. Without being limited by theory, the double-stranded break may be repaired via the non- homologous end joining mechanisms of the cell, resulting in random insertions or deletions (“indels”) at the repair site. These indels may results in lack of gene function.

[0046] In some embodiments, the compositions described herein comprise a donor template. In some embodiments, the donor template is used to replace the endogenous genomic sequence with a sequence in the donor template. In some embodiments, the donor template comprises at least one homology arm. In some embodiments, the homology arms comprises a homology sequence comprising at least 10, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides. In some embodiments, the homology sequence comprises at least 70%, 80%, 90%, 95%, 97.5%, 98%, 99%, or 99.5% homology with a genomic sequence.

(iii) RNA editing

[0047] In some embodiments, the compositions described herein comprise RNA editing. In some embodiments, the methods comprise editing the sequence of at least one MTRES1 transcript. In some embodiments, the methods comprise inactivating a MTRES 1 transcript. In some embodiments, the methods comprising changing the sequence of an MTRES1 transcript. In some embodiments, the methods comprise changing the sequence of an MTRES 1 transcript to a sequence corresponding with the MTRES 1 c.3+lG>A variant.

[0048] In some embodiments, the compositions for RNA editing comprise an ADAR enzyme. ADARs are RNA editing enzymes that target double-stranded regions of RNA. In some embodiments, the ADAR deaminates at least one adenosine to produce inosine, which is translated as guanosine.

B. Vectors

[0049] The compositions described herein can be encoded by a nucleic acid. A nucleic acid is a type of polynucleotide comprising two or more nucleotide bases. In certain embodiments, the nucleic acid is a component of a vector that can be used to transfer the polypeptide encoding polynucleotide into a cell. As used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. [0050] One type of vector is a genomic integrated vector, or “integrated vector,” which can become integrated into the chromosomal DNA of the host cell. Another type of vector is an “episomal” vector, e g., a nucleic acid capable of extra-chromosomal replication. Vectors capable of directing the expression of genes to which they are operatively linked are referred to herein as “expression vectors.” In the expression vectors, regulatory elements such as promoters, enhancers, polyadenylation signals for use in controlling transcription can be derived from mammalian, microbial, viral or insect genes. The ability to replicate in a host, usually conferred by an origin of replication, and a selection gene to facilitate recognition of transformants may additionally be incorporated.

[0051] A vector may be a viral vector or a non-viral vector. Non-limiting examples of viral vectors include vaccinia, measles, vesicular stomatitis virus (VSV), polio, reo virus, adenovirus, lentivirus, g-retrovirus, herpes simplex virus (HSV) and adeno-associated virus (AAV). In some embodiments, the viral vector comprises AAV. In some embodiments, the AAV comprises a serotype selected from the group consisting of AAV1, AAV2, AAAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10 and AAV11. In some embodiments, the serotype is selected from the group consisting of AAV1, AAV2, AAV4, AAV5, AAV8, and AAV9.

[0052] The vector may be non-viral. Non-viral methods of delivery include, without limitations, inj ection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

C. Formulations

[0053] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0054] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises a saline solution. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or a saline solution. In some embodiments, the composition comprises a liposome. In some embodiments, the pharmaceutically acceptable carrier comprises liposomes, lipids, nanoparticles, proteins, protein-antibody complexes, peptides, cellulose, nanogel, or a combination thereof.

[0055] In some embodiments, the composition is formulated to cross the blood brain barrier. In some embodiments, the composition is formulated for central nervous system (CNS) delivery. In some embodiments, the composition includes a lipophilic compound. The lipophilic compound may be useful for crossing the blood brain barrier or for CNS delivery. II. METHODS AND USES

[0056] Disclosed herein, in some embodiments, are methods of administering a composition described herein to a subject. Some embodiments relate to use a composition described herein, such as administering the composition to a subject.

[0057] Some embodiments relate to a method of treating a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of treatment. Some embodiments include administering a composition described herein to a subj ect with the disorder. In some embodiments, the administration treats the disorder in the subj ect. In some embodiments, the composition treats the disorder in the subject.

[0058] In some embodiments, the treatment comprises prevention, inhibition, or reversion of the disorder in the subj ect. Some embodiments relate to use of a composition described herein in the method of preventing, inhibiting, or reversing the disorder. Some embodiments relate to a method of preventing, inhibiting, or reversing a disorder a disorder in a subj ect in need thereof. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents, inhibits, or reverses the disorder in the subject. In some embodiments, the composition prevents, inhibits, or reverses the disorder in the subj ect.

[0059] Some embodiments relate to a method of preventing a disorder a disorder in a subj ect in need thereof. Some embodiments relate to use of a composition described herein in the method of preventing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration prevents the disorder in the subject. In some embodiments, the composition prevents the disorder in the subject.

[0060] Some embodiments relate to a method of inhibiting a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of inhibiting the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration inhibits the disorder in the subject. In some embodiments, the composition inhibits the disorder in the subject.

[0061] Some embodiments relate to a method of reversing a disorder a disorder in a subject in need thereof. Some embodiments relate to use of a composition described herein in the method of reversing the disorder. Some embodiments include administering a composition described herein to a subject with the disorder. In some embodiments, the administration reverses the disorder in the subject. In some embodiments, the composition reverses the disorder in the subject.

[0062] In some embodiments, the administration is systemic. In some embodiments, the administration is intravenous. In some embodiments, the administration is by injection.

A. Disorders

[0063] Some embodiments of the methods described herein include treating a disorder in a subject in need thereof. In some embodiments, the disorder is a neurological disorder. Non-limiting examples of neurological disorders include dementia, Alzheimer’s disease, delirium, cognitive decline, vascular dementia, or Parkinson’s disease. In some embodiments, the neurological disorder includes cognitive decline. In some embodiments, the neurological disorder includes delirium. In some embodiments, the neurological disorder includes dementia. In some embodiments, the neurological disorder includes vascular dementia. In some embodiments, the neurological disorder includes Alzheimer’s disease. In some embodiments, the neurological disorder includes Parkinson’s disease. The neurological disorder may include a neurodegenerative disease. The neurological disorder may be characterized by protein aggregation.

B. Subjects

[0064] Some embodiments of the methods described herein include treatment of a subject. Nonlimiting examples of subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a vertebrate. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a cattle. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is an animal, a mammal, a dog, a cat, cattle, a rodent, a mouse, a rat, a primate, or a monkey. In some embodiments, the subject is a human.

[0065] In some embodiments, the subject is male. In some embodiments, the subject is female.

[0066] In some embodiments, the subject is an adult (e.g. at least 18 years old). In some embodiments, the subject is > 90 years of age. In some embodiments, the subject is > 85 years of age. In some embodiments, the subject is > 80 years of age. In some embodiments, the subject is > 70 years of age. In some embodiments, the subject is > 60 years of age In some embodiments, the subject is > 50 years of age. In some embodiments, the subject is > 40 years of age. In some embodiments, the subject is > 30 years of age. In some embodiments, the subject is > 20 years of age. In some embodiments, the subject is > 10 years of age. In some embodiments, the subject is > 1 years of age. In some embodiments, the subject is > 0 years of age.

[0067] In some embodiments, the subject is < 100 years of age. In some embodiments, the subject is < 90 years of age. In some embodiments, the subject is < 85 years of age. In some embodiments, the subject is < 80 years of age In some embodiments, the subject is < 70 years of age. In some embodiments, the subject is < 60 years of age. In some embodiments, the subject is < 50 years of age. In some embodiments, the subject is < 40 years of age. In some embodiments, the subject is < 30 years of age. In some embodiments, the subject is < 20 years of age. In some embodiments, the subject is < 10 years of age. In some embodiments, the subject is < 1 years of age. [0068] In some embodiments, the subject is between 0 and 100 years of age. In some embodiments, the subject is between 20 and 90 years of age. In some embodiments, the subject is between 30 and 80 years of age. In some embodiments, the subject is between 40 and 75 years of age. In some embodiments, the subject is between 50 and 70 years of age. In some embodiments, the subject is between 40 and 85 years of age.

C. Genotyping

[0069] Disclosed herein, in some embodiments, are systems, methods and kits for detecting one or more genotypes. In some embodiments, the genotypes described herein are detected using suitable genotyping devices (e.g., array, sequencing). In some instances, a sample is obtained from the subject or patient indirectly or directly. In some instances, the sample may be obtained by the subject. In other instances, the sample may be obtained by a healthcare professional, such as a nurse or physician. The sample may be derived from virtually any biological fluid or tissue containing genetic information, such as blood. Methods disclosed herein for detecting a genotype in a sample from a subject comprise analyzing the genetic material in the sample to detect at least one of a presence, an absence, and a quantity of a nucleic acid sequence encompassing the genotype of interest.

[0070] In some embodiments, the genotype is a genotype at risk for developing Alzheimer’s disease or dementia. In some embodiments, the subject is a heterozygous carrier of APOE4. In some embodiments, the subject is a homozygous carrier of APOE4. In some embodiments, the subject is a heterozygous carrier of MTRES1 rsl 17058816-G (c.3+lG). In some embodiments, the subject is a homozygous carrier of MTRES1 rsl 17058816-G (c.3+lG).

[0071] In some embodiments, a polygenic risk score is calculated. In some embodiments, the polygenic risk score includes APOE. In some embodiments, the polygenic risk score does not include APOE. In some embodiments, the polygenic risk score includes at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 variants. In some embodiments, the polygenic risk score includes at least about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000 or more variants. In some embodiments, the polygenic risk score includes at least 1000, 10,000, 100,000, 1,000,000 or more variants.

[0072] In some embodiments, the steps of calculating a polygenic risk score comprise providing a sample from a subject, optionally purifying DNA from the sample by processing the sample, assaying the optionally processed sample to detect genotypes of at least two genetic loci in the sample, processing the genotypes to produce a polygenic risk score (PRS), calculating the percentile risk of the subject by comparing the PRS to a reference population and selecting a therapy to treat a disease or disorder of the subj ect based on the percentile.

[0073] In some embodiments, a subject is at risk for developing Alzheimer’s disease or dementia if the subject has a polygenic risk scope in the upper 50th percentile, 40th percentile, 30th percentile, 20th percentile, 10th percentile, 5th percentile, 4th percentile, 3rd percentile, 2nd percentile, or 1st percentile. In some embodiments, a subject is at risk for developing Alzheimer’s disease or dementia if the subject has a polygenic risk score in the upper 20th percentile. In some embodiments, a subject is at risk for developing Alzheimer’s disease or dementia if the subject has a polygenic risk score in the upper 40th percentile.

[0074] Nucleic acid-based detection techniques that may be useful for the methods herein include quantitative polymerase chain reaction (qPCR), gel electrophoresis, immunochemistry, in situ hybridization such as fluorescent in situ hybridization (FISH), cytochemistry, and next generation sequencing. In some embodiments, the methods involve TaqMan™ qPCR, which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acids with a hydrolysable probe specific to a target nucleic acid.

[0075] In some instances, the methods involve hybridization and/or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses, and probe arrays. Non-limiting amplification reactions include, but are not limited to, qPCR, selfsustained sequence replication, transcriptional amplification system, Q-Beta Replicase, rolling circle replication, or any other nucleic acid amplification known in the art. As discussed, reference to qPCR herein includes use of TaqMan™ methods. An additional exemplary hybridization assay includes the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence of a genotype provided herein. A non-limiting method is one employed in Anal Chem. 2013 Feb 5; 85(3): 1932-9.

[0076] In some embodiments, detecting the presence or absence of a genotype comprises sequencing genetic material from the subject. Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis. Sequencing methods also include next-generation sequencing, e.g., modem sequencing technologies such as Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.

[0077] In one aspect, the methods provided herein for determining the presence, absence, and/or quantity of a nucleic acid sequence from a particular genotype comprise an amplification reaction such as qPCR. In an exemplary method, genetic material is obtained from a sample of a subject, e.g., a sample of blood or serum. In certain embodiments where nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In certain embodiments, this technique uses alcohol precipitation using ethanol, methanol, or isopropyl alcohol. In certain embodiments, this technique uses phenol, chloroform, or any combination thereof. In certain embodiments, this technique uses cesium chloride. In certain embodiments, this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA. In certain embodiments, this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis. In an exemplary embodiment, the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification.

D. Baseline measurements

[0078] Some embodiments of the methods described herein include obtaining a baseline measurement from a subject. For example, in some embodiments, a baseline measurement is obtained from the subject prior to treating the subject. Non-limiting examples of baseline measurements include a baseline cognitive function measurement, a baseline central nervous system (CNS) amyloid plaque measurement, a baseline CNS tau accumulation measurement, a baseline cerebrospinal fluid (CSF) beta-amyloid 42 measurement, a baseline CSF tau measurement, a baseline CSF phospho-tau measurement, a baseline neurofilament light (NfL) measurement, a baseline CSF alpha-synuclein measurement, a baseline Lewy body measurement, a baseline MTRES 1 protein measurement, or a baseline MTRES 1 mRNA measurement.

[0079] In some embodiments, the baseline measurement is obtained directly from the subject. In some embodiments, the baseline measurement is obtained by observation, for example by observation of the subject or of the subject’s tissue. In some embodiments, the baseline measurement is obtained nonmvasively using an imaging device.

[0080] In some embodiments, the baseline measurement is obtained in a sample from the subject. In some embodiments, the baseline measurement is obtained in one or more histological tissue sections In some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay, on the sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g. HPLC) assay. In some embodiments, the baseline measurement is obtained by PCR.

[0081] In some embodiments, the baseline measurement is a baseline cognitive function measurement. The baseline cognitive function measurement may be obtained directly from the subject. For example, the subject may be administered a test The test may include a cognitive test such as the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), or MiniCog. The test may include assessment of basic cognitive functions such as memory, language, executive frontal lobe function, apraxia, visuospatial ability, behavior, mood, orientation, or attention. The baseline cognitive function measurement may include a score. The baseline cognitive function measurement may be indicative of mild cognitive impairment, or of severe cognitive impairment. The baseline cognitive function measurement may be indicative of a neurological disorder. [0082] The baseline measurement may include a baseline In some embodiments, the marker of neurodegeneration measurement. Examples of marker of neurodegeneration may include central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) betaamyloid 42, CSF tau, CSF phospho-tau, CSF or plasma neurofilament light chain (NfL), Lewy bodies, or CSF alpha-synuclein. Any of these measurements may be reduced in relation to the baseline measurement. Some examples of ways to measure these may include an assay such as a immunoassay, colorimetric assay, or microscopy.

[0083] In some embodiments, the baseline measurement is a baseline amyloid plaque measurement. The baseline amyloid plaque measurement may include a central nervous system (CNS) amyloid plaque measurement. In some embodiments, the baseline amyloid plaque measurement includes a baseline concentration or amount. The baseline amyloid plaque measurement may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. The baseline amyloid plaque measurement may be performed on a biopsy. The baseline amyloid plaque measurement may be performed using a spinal tap (for example, when the baseline amyloid plaque measurement includes a baseline cerebrospinal fluid (CSF) amyloid plaque measurement). In some embodiments, the baseline amyloid plaque measurement is obtained by an assay such as an immunoassay. The baseline beta amyloid plaque measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease.

[0084] In some embodiments, the baseline measurement is a baseline beta-amyloid 42 measurement. The baseline beta-amyloid 42 measurement may include a cerebrospinal fluid (CSF) beta-amyloid 42 measurement. In some embodiments, the baseline beta-amyloid 42 measurement includes a baseline concentration or amount. The baseline beta-amyloid 42 measurement may be performed on a biopsy. The baseline beta-amyloid 42 measurement may be performed using a spinal tap (for example, when the baseline beta-amyloid 42 measurement includes a baseline CSF betaamyloid 42 measurement). In some embodiments, the baseline beta-amyloid 42 measurement is obtained by an assay such as an immunoassay. The baseline beta-amyloid 42 measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease.

[0085] In some embodiments, the baseline measurement is a baseline tau measurement. In some embodiments, the baseline tau measurement includes a baseline concentration or amount. The baseline tau measurement may be performed on a biopsy. In some embodiments, the baseline tau measurement is obtained by an assay such as an immunoassay. The baseline beta tau measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease. [0086] In some embodiments, the baseline tau measurement is a baseline central nervous system (CNS) tau measurement. The baseline tau measurement may include a baseline total tau measurement. The baseline tau measurement may include a baseline unphosphorylated tau measurement. The baseline tau measurement may include a baseline phosphorylated tau (phospho- tau) measurement. In some embodiments, the baseline tau measurement is a baseline tau accumulation measurement. In some embodiments, the baseline tau measurement is a baseline CNS tau accumulation measurement. The baseline CNS tau accumulation measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.

[0087] The baseline tau measurement may include a cerebrospinal fluid (CSF) tau measurement. The baseline CSF tau measurement may be performed after use of a spinal tap. The baseline CSF tau measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.

[0088] The baseline CSF tau measurement may include a baseline CSF phospho-tau measurement. The baseline CSF phospho-tau measurement may include an amount of phospho-tau in relation to total tau or unphosphorylated tau. For example, the baseline CSF phospho-tau measurement may include a phospho-tau/tau ratio. The baseline CSF phospho-tau measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease. [0089] In some embodiments, the baseline neurofilament light chain (NfL) measurement includes a baseline CSF or plasma NfL measurement. The baseline NfL measurement may be a baseline CSF NfL measurement. The baseline NfL measurement may be a baseline plasma NfL measurement. The NfL measurement may include a concentration or an amount. The baseline NfL measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.

[0090] In some embodiments, the baseline measurement is a baseline alpha-synuclein measurement. The baseline alpha-synuclem measurement may include a cerebrospinal fluid (CSF) alpha-synuclein measurement. In some embodiments, the baseline alpha-synuclein measurement includes a baseline concentration or amount. The baseline alpha-synuclein measurement may be performed on a biopsy. The baseline alpha-synuclein measurement may be performed using a spinal tap (for example, when the baseline alpha-synuclein measurement includes a baseline CSF alpha- synuclein measurement). In some embodiments, the baseline alpha-synuclein measurement is obtained by an assay such as an immunoassay. The baseline alpha-synuclein measurement may be indicative of a neurodegenerative disease such as Parkinson’s disease. The baseline alpha-synuclem measurement may be indicative of dementia.

[0091] In some embodiments, the baseline measurement is a baseline Lewy body measurement. The baseline Lewy body measurement may include a central nervous system (CNS) Lewy body measurement. In some embodiments, the baseline Lewy body measurement includes a baseline concentration or amount. The baseline Lewy body measurement may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. The baseline beta Lewy body measurement may be indicative of dementia.

[0092] In some embodiments, the baseline measurement is a baseline MTRES1 protein measurement. In some embodiments, the baseline MTRES1 protein measurement comprises a baseline MTRES1 protein level. In some embodiments, the baseline MTRES1 protein level is indicated as a mass or percentage of MTRES1 protein per sample weight. In some embodiments, the baseline MTRES1 protein level is indicated as a mass or percentage of MTRES1 protein per sample volume. In some embodiments, the baseline MTRES1 protein level is indicated as a mass or percentage of MTRES 1 protein per total protein within the sample. In some embodiments, the baseline MTRES 1 protein measurement is a baseline CNS or CSF MTRES 1 protein measurement. In some embodiments, the baseline MTRES 1 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay.

[0093] In some embodiments, the baseline measurement is a baseline MTRES 1 mRNA measurement. In some embodiments, the baseline MTRES 1 mRNA measurement comprises a baseline MTRES 1 mRNA level. In some embodiments, the baseline MTRES 1 mRNA level is indicated as an amount or percentage of MTRES 1 mRNA per sample weight. In some embodiments, the baseline MTRES1 mRNA level is indicated as an amount or percentage of MTRES1 mRNA per sample volume. In some embodiments, the baseline MTRES 1 mRNA level is indicated as an amount or percentage of MTRES 1 mRNA per total mRNA within the sample. In some embodiments, the baseline MTRES 1 mRNA level is indicated as an amount or percentage of MTRES 1 mRNA per total nucleic acids within the sample. In some embodiments, the baseline MTRES 1 mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the baseline MTRES1 mRNA measurement is a baseline CNS or CSF MTRES 1 mRNA measurement. In some embodiments, the baseline MTRES 1 mRNA measurement is obtained by an assay such as a polymerase chain reaction (PCR) assay. In some embodiments, the PCR comprises quantitative PCR (qPCR). In some embodiments, the PCR comprises reverse transcription of the MTRES 1 mRNA.

[0094] Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, the baseline measurement is obtained in a sample obtained from the subject. In some embodiments, the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein. In some embodiments, a baseline measurement is obtained in a sample obtained from the subject prior to administering the composition to the subject.

[0095] In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the fluid sample is a CSF sample In some embodiments, the fluid sample includes a central nervous system (CNS) fluid sample. The CNS fluid may include cerebrospinal fluid (CSF). In some embodiments, the fluid sample includes a CSF sample. In In some embodiments, the sample is a blood, plasma, or serum sample. In some embodiments, the sample comprises blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole-blood sample. In some embodiments, the blood is fractionated or centrifuged. In some embodiments, the sample comprises plasma. In some embodiments, the sample is a plasma sample. A blood sample may be a plasma sample. In some embodiments, the sample comprises serum. In some embodiments, the sample is a serum sample. A blood sample may be a serum sample. [0096] In some embodiments, the sample comprises a tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the tissue comprises central nervous system (CNS) tissue. For example, the baseline MTRES1 mRNA measurement, or the baseline MTRES1 protein measurement, may be obtained in a CNS tissue sample obtained from the patient. The CNS tissue may include brain tissue. The CNS tissue may include nerve tissue. The CNS tissue may include neurons, glia, microglia, astrocytes, or oligodendrocytes, or a combination thereof. The CNS tissue may include neurons. The CNS tissue may include glia. The CNS tissue may include microglia. The CNS tissue may include astrocytes. The CNS tissue may include oligodendrocytes.

[0097] In some embodiments, the sample includes cells. In some embodiments, the sample comprises a cell. In some embodiments, the cell comprises a CNS cell. The CNS cell may include a brain cell. The CNS cell may include a nerve cell. The CNS cell may be a neuron, glial cell, microglial cell, astrocyte, or oligodendrocyte. The CNS cell may be a neuron. The CNS cell may be a glial cell. The CNS cell may be a microglial cell. The CNS cell may be an astrocyte. The CNS cell may be an oligodendrocyte.

E. Effects

[0098] In some embodiments, the composition or administration of the composition affects a measurement such as a cognitive function measurement, a central nervous system (CNS) amyloid plaque measurement, a CNS tau accumulation measurement, a cerebrospinal fluid (CSF) betaamyloid 42 measurement, a CSF tau measurement, a CSF phospho-tau measurement, a NfL measurement, a CSF alpha-synuclein measurement, a Lewy body measurement, an MTRES1 protein measurement, or an MTRES 1 mRNA measurement, relative to the baseline measurement.

[0099] Some embodiments of the methods described herein include obtaining the measurement from a subject. For example, the measurement may be obtained from the subject after treating the subject. In some embodiments, the measurement is obtained in a second sample (such as a fluid or tissue sample described herein) obtained from the subject after the composition is administered to the subject. In some embodiments, the measurement is an indication that the disorder has been treated. [00100] In some embodiments, the measurement is obtained directly from the subject. In some embodiments, the measurement is obtained nonmvasively using an imaging device. In some embodiments, the measurement is obtained in a second sample from the subject. In some embodiments, the measurement is obtained in one or more histological tissue sections. In some embodiments, the measurement is obtained by performing an assay on the second sample obtained from the subject. In some embodiments, the measurement is obtained by an assay, such as an assay described herein. In some embodiments, the assay is an immunoassay, a colorimetric assay, a fluorescence assay, a chromatography (e.g., HPLC) assay, or a PCR assay. In some embodiments, the measurement is obtained by an assay such as an immunoassay, a colorimetric assay, a fluorescence assay, or a chromatography (e.g., HPLC) assay. In some embodiments, the measurement is obtained by PCR. In some embodiments, the measurement is obtained by histology. In some embodiments, the measurement is obtained by observation. In some embodiments, additional measurements are made, such as in a 3rd sample, a 4th sample, or a fifth sample.

[00101] In some embodiments, the measurement is obtained within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 12 hours, within 18 hours, or within 24 hours after the administration of the composition. In some embodiments, the measurement is obtained within 1 day, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, or within 7 days after the administration of the composition. In some embodiments, the measurement is obtained within 1 week, within 2 weeks, within 3 weeks, within 1 month, within 2 months, within 3 months, within 6 months, within 1 year, within 2 years, within 3 years, within 4 years, or within 5 years after the administration of the composition. In some embodiments, the measurement is obtained after 1 hour, after 2 hours, after 3 hours, after 4 hours, after 5 hours, after 6 hours, after 12 hours, after 18 hours, or after 24 hours after the administration of the composition. In some embodiments, the measurement is obtained after 1 day, after 2 days, after 3 days, after 4 days, after 5 days, after 6 days, or after 7 days after the administration of the composition. In some embodiments, the measurement is obtained after 1 week, after 2 weeks, after 3 weeks, after 1 month, after 2 months, after 3 months, after 6 months, after 1 year, after 2 years, after 3 years, after 4 years, or after 5 years, following the administration of the composition.

[00102] In some embodiments, the composition reduces the measurement relative to the baseline measurement. For example, an adverse phenotype of a neurological disorder may be reduced upon administration of the composition. The neurological disorder may include dementia, Alzheimer’s disease, delirium, cognitive decline, vascular dementia, or Parkinson’s disease. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subj ect. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[00103] In some embodiments, the composition increases the measurement relative to the baseline measurement. For example, a protective phenotype of a neurological disorder may be increased upon administration of the composition. The neurological disorder may include dementia, Alzheimer’s disease, delirium, cognitive decline, vascular dementia, or Parkinson’s disease. In some embodiments, the increase is measured in a second sample obtained from the subject after administering the composition to the subj ect. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 10% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by about 100% or more, increased by about 250% or more, increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 10%, relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline measurement. In some embodiments, the measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline measurement. In some embodiments, the measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[00104] In some embodiments, the measurement is a cognitive function measurement. The cognitive function measurement may be obtained directly from the subject. For example, the subject may be administered a test. The test may include a cognitive test such as the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), or Mini-Cog. The test may include assessment of basic cognitive functions such as memory, language, executive frontal lobe function, apraxia, visuospatial ability, behavior, mood, orientation, or attention. The cognitive function measurement may include a score. The cognitive function measurement may be indicative of a lack of cognitive impairment. In some embodiments, the cognitive function measurement is indicative of mild cognitive impairment, and the baseline cognitive function measurement is indicative of severe cognitive impairment. The cognitive function measurement may be indicative of a neurological disorder.

[00105] In some embodiments, the composition increases the cognitive function measurement relative to the baseline cognitive function measurement. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the cognitive function measurement is increased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by about 10% or more, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by about 100% or more, increased by about 250% or more, increased by about 500% or more, increased by about 750% or more, or increased by about 1000% or more, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by no more than about 10%, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by no more than about 100%, increased by no more than about 250%, increased by no more than about 500%, increased by no more than about 750%, or increased by no more than about 1000%, relative to the baseline cognitive function measurement. In some embodiments, the cognitive function measurement is increased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or by a range defined by any of the two aforementioned percentages.

[00106] In some embodiments, the measurement is an amyloid plaque measurement. The amyloid plaque measurement may include a central nervous system (CNS) amyloid plaque measurement. In some embodiments, the amyloid plaque measurement includes a concentration or amount. The amyloid plaque measurement may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. The amyloid plaque measurement may be performed on a biopsy. The amyloid plaque measurement may be performed using a spinal tap (for example, when the amyloid plaque measurement includes a cerebrospinal fluid (CSF) amyloid plaque measurement). In some embodiments, the amyloid plaque measurement is obtained by an assay such as an immunoassay. The beta amyloid plaque measurement may be indicative of a treatment effect of the MTRES1 gene therapy on a neurodegenerative disease such as Alzheimer’s disease.

[00107] In some embodiments, the composition reduces the amyloid plaque measurement relative to the baseline amyloid plaque measurement. In some embodiments, the reduction is measured in a second sample obtained from the subj ect after administering the composition to the subj ect. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the amyloid plaque measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by about 10% or more, relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by no more than about 10%, relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline amyloid plaque measurement. In some embodiments, the amyloid plaque measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[00108] In some embodiments, the measurement is a beta-amyloid 42 measurement. The betaamyloid 42 measurement may include a cerebrospinal fluid (CSF) beta-amyloid 42 measurement. In some embodiments, the beta-amyloid 42 measurement includes a concentration or amount. The betaamyloid 42 measurement may be performed on a biopsy. The beta-amyloid 42 measurement may be performed using a spinal tap (for example, when the beta-amyloid 42 measurement includes a CSF beta-amyloid 42 measurement). In some embodiments, the beta-amyloid 42 measurement is obtained by an assay such as an immunoassay. The beta-amyloid 42 measurement may be indicative of a treatment effect of the gene therapy on a neurodegenerative disease such as Alzheimer’s disease. [00109] In some embodiments, the composition reduces the CSF beta-amyloid 42 measurement relative to the baseline beta-amyloid 42 measurement. In some embodiments, the reduction is measured in a second sample (for example, a CSF sample) obtained from the subject after administering the composition to the subject. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by about 10% or more, relative to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by no more than about 10%, relative to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline CSF beta-amyloid 42 measurement. In some embodiments, the CSF beta-amyloid 42 measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages. [00110] In some embodiments, the measurement is a tau measurement. In some embodiments, the tau measurement includes a concentration or amount. The tau measurement may be performed on a biopsy. In some embodiments, the tau measurement is obtained by an assay such as an immunoassay. The beta tau measurement may be indicative of a treatment effect of the gene therapy on a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.

[00111] In some embodiments, the tau measurement is a central nervous system (CNS) tau measurement. The tau measurement may include a total tau measurement. The tau measurement may include a unphosphorylated tau measurement. The tau measurement may include a phosphorylated tau measurement. In some embodiments, the tau measurement is a tau accumulation measurement. In some embodiments, the tau measurement is a CNS tau accumulation measurement. The CNS tau accumulation measurement may be indicative of a treatment effect of the gene therapy on a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.

[00112] In some embodiments, the composition reduces the CNS tau accumulation measurement relative to the baseline CNS tau accumulation measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the CNS tau accumulation measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by about 10% or more, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by no more than about 10%, relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline CNS tau accumulation measurement. In some embodiments, the CNS tau accumulation measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[00113] The tau measurement may include a cerebrospinal fluid (CSF) tau measurement. The CSF tau measurement may be performed after use of a spinal tap. The CSF tau measurement may be indicative of a treatment effect of the gene therapy on a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.

[00114] In some embodiments, the composition reduces the CSF tau measurement relative to the baseline CSF tau measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured in a second CSF sample obtained from the subject after administering the composition to the subj ect. In some embodiments, the CSF tau measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by about 10% or more, relative to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by no more than about 10%, relative to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline CSF tau measurement. In some embodiments, the CSF tau measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[00115] The CSF tau measurement may include a CSF phospho-tau measurement. The CSF phospho-tau measurement may include an amount of phospho-tau in relation to total tau or unphosphorylated tau. For example, the CSF phospho-tau measurement may include a phospho- tau/tau ratio. The CSF phospho-tau measurement may be indicative of a treatment effect of the gene therapy on a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.

[00116] In some embodiments, the composition reduces the CSF phospho-tau measurement relative to the baseline CSF phospho-tau measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured in a second CSF sample obtained from the subject after administering the composition to the subject. In some embodiments, the CSF phospho- tau measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by about 10% or more, relative to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by no more than about 10%, relative to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline CSF phospho-tau measurement. In some embodiments, the CSF phospho-tau measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[00117] In some embodiments, the neurofilament light chain (NfL) measurement includes a CSF or plasma NfL measurement. The NfL measurement may be a CSF NfL measurement. The NfL measurement may be a plasma NfL measurement. The NfL measurement may include a concentration or an amount. The NfL measurement may be indicative of a neurodegenerative disease such as Alzheimer’s disease or Parkinson’s disease.

[00118] In some embodiments, the composition reduces the NfL measurement relative to the baseline NfL measurement. In some embodiments, the reduction is measured in a second sample obtained from the subj ect after administering the composition to the subj ect. In some embodiments, the NfL measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by about 10% or more, relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by no more than about 10%, relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline NfL measurement. In some embodiments, the NfL measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[00119] In some embodiments, the measurement is a alpha-synuclein measurement. The alpha- synuclein measurement may include a cerebrospinal fluid (CSF) alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement includes a concentration or amount. The alpha- synuclein measurement may be performed on a biopsy. The alpha-synuclein measurement may be performed using a spinal tap (for example, when the alpha-synuclein measurement includes a CSF alpha-synuclein measurement). In some embodiments, the alpha-synuclein measurement is obtained by an assay such as an immunoassay. The alpha-synuclein measurement may be indicative of a treatment effect of the gene therapy on a neurodegenerative disease such as Parkinson’s disease. The alpha-synuclein measurement may be indicative of a treatment effect of the gene therapy on dementia.

[00120] In some embodiments, the composition reduces the alpha-synuclem measurement relative to the baseline alpha-synuclein measurement. In some embodiments, the reduction is measured in a second sample obtained from the subj ect after administering the composition to the subj ect. In some embodiments, the alpha-synuclein measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by about 10% or more, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by no more than about 10%, relative to the baseline alpha-synuclein measurement. In some embodiments, the alpha-synuclein measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline alpha-synuclem measurement. In some embodiments, the alpha- synuclein measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[00121] In some embodiments, the measurement is a Lewy body measurement. The Lewy body measurement may include a central nervous system (CNS) Lewy body measurement. In some embodiments, the Lewy body measurement includes a concentration or amount. The Lewy body measurement may be performed using an imaging device. The imaging device may include a positron emission tomography (PET) device. The beta Lewy body measurement may be indicative of a treatment effect of the gene therapy on dementia.

[00122] In some embodiments, the composition reduces the Lewy body measurement relative to the baseline Lewy body measurement. In some embodiments, the reduction is measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the Lewy body measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by about 10% or more, relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by no more than about 10%, relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline Lewy body measurement. In some embodiments, the Lewy body measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[00123] In some embodiments, the measurement is an MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement comprises an MTRES1 protein level. In some embodiments, the MTRES1 protein level is indicated as a mass or percentage of MTRES1 protein per sample weight. In some embodiments, the MTRES1 protein level is indicated as a mass or percentage of MTRES1 protein per sample volume. In some embodiments, the MTRES1 protein level is indicated as a mass or percentage of MTRES1 protein per total protein within the sample. In some embodiments, the MTRES1 protein measurement is a CNS tissue or fluid MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay. [00124] In some embodiments, the composition reduces the MTRES1 protein measurement relative to the baseline MTRES1 protein measurement. In some embodiments, the composition reduces CNS tissue or fluid MTRES1 protein levels relative to the baseline MTRES1 protein measurement. In some embodiments, the reduced MTRES1 protein levels are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the MTRES1 protein measurement is decreased by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by about 10% or more, relative to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline MIRES 1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by no more than about 10%, relative to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100% relative to the baseline MTRES1 protein measurement. In some embodiments, the MTRES1 protein measurement is decreased by 2.5%, 5%, 7.5%, 19%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or by a range defined by any of the two aforementioned percentages.

[00125] In some embodiments, the measurement is an MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement comprises an MTRES1 mRNA level. In some embodiments, the MTRES1 mRNA measurement is a measurement of MIRES 1 mRNA sequences. In some embodiments, the MTRES1 mRNA measurement is a measurement of a variant MTRES1 mRNA sequence. In some embodiments, the MTRES1 mRNA measurement is a ratio of the native MTRES1 mRNA sequence to the variant MTRES1 mRNA sequence. In some embodiments, the MTRES1 mRNA level is indicated as an amount or percentage of MTRES1 mRNA per sample weight. In some embodiments, the MTRES1 mRNA level is indicated as an amount or percentage of MTRES1 mRNA per sample volume. In some embodiments, the MTRES1 mRNA level is indicated as an amount or percentage of MIRES 1 mRNA per total mRNA within the sample. In some embodiments, the MTRES1 mRNA level is indicated as an amount or percentage of MTRES1 mRNA per total nucleic acids within the sample. In some embodiments, the MTRES1 mRNA level is indicated relative to another mRNA level, such as an mRNA level of a housekeeping gene, within the sample. In some embodiments, the MTRES1 mRNA measurement is a CNS tissue or fluid MTRES1 mRNA measurement. In some embodiments, the MTRES 1 mRNA measurement is obtained by an assay such as a PCR assay. In some embodiments, the PCR comprises qPCR. In some embodiments, the PCR comprises reverse transcription of the MTRES1 mRNA.

[00126] In some embodiments, the composition reduces the MTRES1 mRNA measurement relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is obtained in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the composition reduces MTRES1 mRNA levels relative to the baseline MTRES1 mRNA levels. In some embodiments, the reduced MTRES1 mRNA levels are measured in a second sample obtained from the subject after administering the composition to the subject. In some embodiments, the second sample is a CNS sample. In some embodiments, the MTRES1 mRNA measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more, relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by about 10% or more, relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by no more than about 2.5%, no more than about 5%, or no more than about 7.5%, relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by no more than about 10%, relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by no more than about 20%, no more than about 30%, no more than about 40%, no more than about 50%, no more than about 60%, no more than about 70%, no more than about 80%, no more than about 90%, or no more than about 100%, relative to the baseline MTRES1 mRNA measurement. In some embodiments, the MTRES1 mRNA measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or by a range defined by any of the two aforementioned percentages.

III. DEFINITIONS

[00127] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subj ect matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[00128] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc , as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[00129] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[00130] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[00131] The terms “subject,” and “patient” may be used interchangeably herein. A “subject” can be a biological entity containing expressed genetic materials. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. The subject can be a mammal. The mammal can be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.

[00132] As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

[00133] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subj ect reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

[00134] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. VI. EXAMPLES

Example 1; A Splice Donor Variant in MTRES1 Demonstrates Protective Associations for Dementia and Alzheimer’s Disease Related Traits

[00135] Variants m MIRES 1 were evaluated for associations with dementia, Alzheimer’s disease and related traits in approximately 452,000 individuals with genotype data from the UK Biobank cohort, rsl 17058816 is a rare (AAF=0.006) splice donor variant (c.3+lG>A) in MTRES1. This variant is considered to be a loss of function variant that results in a loss or change in the abundance or activity of the MTRES1 gene product.

[00136] The analyses resulted in identification of dementia and Alzheimer’s disease-related associations for the MTRES1 c.3+lG>A variant. For example, c.3+lG>A was associated with decreased risk of Alzheimer’s disease, dementia, delirium, and vascular dementia, c. 3+lG>A was also associated with decreased risk of family history of Alzheimer’s disease and decreased risk of dementia medication use (Table 1A and IB)

Table 1A. MTRES1 Dementia, Alzheimer’s and related trait associations

Table IB. MTRES1 Dementia, Alzheimer’s and related trait associations

[00137] These results indicate that loss or change of function of MTRES1 results in protection from dementia and Alzheimer’s disease and related diseases. These results further indicate that therapeutic modulation of MTRES1 may result in similar disease-protective effects.

[00138] Minigene constructs expressing protective variants in MTRES1 result in a reduction of MTRES1 mRNA and MTRES1 protein Minigene expression constructs encoding for wild type and rsl 17058816 (c.3+lG>A) MTRES1 proteins were generated. Minigene constructs (<10kb) are easier to synthesize and have greater transfection efficiency in downstream experiments than constructs that exceed lOkb in length. The minigene constructs have a portion of internal, intronic sequence removed, but retain all exons and UTRs. Therefore, the pre-mRNA of the exons, reduced introns, and 5’ and 3’ UTRs of the protein coding transcript (ENST00000625458) of MTRES1 was cloned into a pcDNA3. 1(+) vector driven by a CMV promoter. Empty vector was used as control. For rsl 17058816 expression constructs, the A allele replaced the G allele at DNA sequence position chr6: 107030108 (human genome build 38). This leads to the loss of a splice donor site (c.3+lG>A). [00139] Transfections of HEK-293 cells were optimized. HEK-293 cells were plated in a 6-well plate in complete growth media and grown for 48 hours followed by a media change. Cells were then transfected with 2 pg of plasmid DNA and 7 pl of TransIT-2020. Cells were incubated for 48 hours, and then harvested.

[00140] Cell lysates from transfected cells were assayed to evaluate intracellular MTRES1 protein by western blot (FIG. 1A). In empty vector transfected HEK-293 cells, a faint band representing endogenous MTRES1 expression was detected by western blot as a band at 24 kDa. In cells transfected with the wild type construct, significant expression of MTRES1 was detected by western blot as a band 24 kDa. In cells transfected with the rsl 17058816 construct, reduced MTRES1 protein compared with wild type was detected by western blot as a band between 24 kDa. When normalizing to total protein, cells transfected with the rsl 17058816 construct express approximately 75% less MTRES1 protein compared with cells transfected with the wild type construct (FIG. IB). Cell lysates from transfected cells were also assayed to evaluate MTRES1 mRNA by qPCR. Cells transfected with the rsl 17058816 construct express approximately 70% lessMTRESl mRNA compared with cells transfected with the wild type construct (FIG. 2).

[00141] These data provide experimental verification that MTRES1 gene variants associated with protection from dementia and Alzheimer’s disease result in a change or loss of MTRES1 protein and MTRES1 mRNA abundance or function. Accordingly, in some cases therapeutic modulation or inhibition of MTRES1 may be an effective genetically -informed method of treatment for these diseases.

CRISPR-Engineered Cell Lines Expressing Protective variants in MTRES1 result in a reduction of MTRES1 mRNA and MTRES1 protein

[00142] Sanger- verified CRISPR cell lines on a HEK-293 clonal background were generated including a rsl l7058816-A (c.3+lA) homozygous knock-in (KI), a homozygous knock-out (KO) and a mock-transfected wild type (WT) cell line.

[00143] Cells were grown, fractionated, and whole cell lysates and mitochondrial fractions harvested. Whole cell and mitochondrial fraction lysates from CRISPR cell lines were assayed to evaluate intracellular MTRES1 protein by western blot (FIG. 3). In WT cells, significant MTRES1 expression was detected by western blot as a band at 24 kDa in both whole cell lysates and mitochondrial fractions. In CRISPR KI cells, reduced MTRES1 protein compared with WT was detected by western blot in both whole cell lysates and mitochondrial fractions. In CRISPR KO cells, no MTRES1 protein was detected by western blot in either whole cell lysates or mitochondrial fractions.

[00144] Whole cell lysates from CRISPR cell lines were also assayed to evaluate MTRES1 mRNA by qPCR (FIG. 4). In CRISPR KI cells, approximately 70% iessMTRESl mRNA expression is observed compared with cells transfected with the wild type construct. In CRISPR KO cells, no MTRES1 mRNA expression was detected by qPCR. [00145] These data provide further experimental verification that MTRES1 gene variants associated with protection from dementia and Alzheimer’s disease result in change or loss of MTRES1 protein and MTRES1 mRNA abundance or function. Accordingly, in some cases therapeutic modulation or inhibition of MTRES1 may be an effective genetically-informed method of treatment for these diseases.

Example 2; Modulation of MTRES1 in a Mouse Model for Alzheimer’s Disease Using MTRES1 gene therapy

[00146] In this experiment, a mouse model of Alzheimer’s Disease (AD) will be used to evaluate effects of MTRES1 gene therapy. The model includes Tg2576 mice which express human amyloid beta precursor protein (APP) and presenilin-1 (PSEN1) transgenes with five AD-linked mutations. Cognitive function is measured using a forced swimming test (FST). In some embodiments, the gene therapy is a method of gene delivery (e.g., delivery with a viral vector or with a non-viral vector). In some embodiments, the gene therapy is a method of gene editing. In some embodiments, the gene therapy uses a programmable nuclease (e.g. ZFN, TALENs, CRISP/Cas). In some embodiments, the gene therapy is a method of RNA editing (e.g. editing with an ADAR enzyme).

[00147] Seven-month-old mice are divided into two groups: Group 1— a group treated with the MTRES1 gene therapy, Group 2 - a group treated with vehicle.

[00148] Mice are administered the treatment or the vehicle on day 0 of treatment. The behavioral tests are performed 8 weeks after the injection.

[00149] To rule out nonspecific motor effects that could influence the FST results, the potential effect of treatment on locomotor activity is assessed. Mice are evaluated using the openfield paradigm (44x44x40 cm) in a sound-attenuated room. The total distance (cm) traveled by each mouse is recorded for 5 min by a video surveillance system (SMART; Panlab SL, Barcelona, Spain) and is used to quantify activity levels. The floor of the open-field apparatus is cleaned with 10% ethanol between tests.

[00150] The FST includes a behavioral test useful for screening potential drugs that influence cognition and assessing other manipulations that are expected to affect cognitive related behaviors. On the first day, mice are placed individually in the water and allowed to swim for 15 mm. The next day, mice are placed again in the water to observe the duration of immobility for 6 min using a camera. Following a l-min session of acclimation to the apparatus, all behaviors are recorded for 5 min by a video surveillance system (SMART 2.5.21; Panlab SL). Immobility is defined as motionless floating in the water, only allowing movements necessary for the animal to keep its head above the water. The total immobility time in the FST is recorded as an index of cognitive ability.

[00151] Twenty four hours after the behavioral assessment, the mice are sacrificed by cervical dislocation following an intraperitoneal injection of 0.3 ml Nembutal (5 mg/ml) (Sigma Cat. No. 1507002). Brain and spinal cord tissues are removed and placed in RNAlater for mRNA isolation. [00152] mRNA is isolated from tissue placed in RNAlater solution using the PureLink kit according to the manufacturer’s protocol (ThermoFisher Cat. No. 12183020). The reverse transcriptase reaction is performed according to the manufacturer’s protocol. Samples are stored at -80 °C until real-time qPCR was performed in triplicate using TaqMan Gene Expression Assays (Applied Biosystems FAM/MTRES1 using a BioRad CFX96 Cat. No. 1855195). A decrease in MTRES1 mRNA expression in the cortical tissue from mice dosed with the MTRES1 siRNAl or ASO1 is expected compared to MTRES1 mRNA levels in the cortical tissue from mice dosed with the non-specific controls. There is an expected decrease in the total immobility time in the FST in mice that receive the MTRES1 siRNA or ASO compared to the total immobility time in the FST in mice that receive the non-specific control along with no change between treatment groups in the locomotor activity test. These results will show that the MTRES1 siRNA or ASO elicit knockdown of MTRES1 mRNA in cortical tissue, and that the decrease in MTRES1 expression is correlated with a decrease in total immobility time in the FST along with no change in locomotor activity. These results will indicate that administration of a gene therapy to a mammalian subject may be used to treat neurological disorder that includes cognitive decline.

Example 3: Protective variants in MTRES1 modulate APOE E4-mediated risk of Alzheimer’s disease and dementia

[00153] The major common genetic risk factor for Alzheimer’s disease is the A OE haplotype, with permutations of 2 genetic variants, rs429358 (p.Cysl 12Arg) and rs7412 (p.Argl58Cys) defining 3 major APOE haplotypes - E2, E3 and E4 (Table 2). The APOE2 haplotype is considered protective, APOE3 haplotype is considered ‘neutral’ and APOE4 haplotype is considered risk for Alzheimer’s disease and dementia.

Table 2. APOE alleles and haplotypes

[00154] Stratified genetic analyses were performed to evaluate the effect of the MTRES1 rsl 17058816 splice donor variant (c.3+lG>A) on wAPOE4 risk background in 452,401 individuals with genotype data from the UK Biobank cohort. All stratified analyses were performed under the assumption that the APOE3 haplotype and the MTRES1 rsl l7058816 (c.3+lG>A) reference (G) alleles are ‘neutral’, therefore the reference group in these analyses consists of individuals who are MTRES1 rsl 17058816 (c.3+lG>A) G/G and APOE E3/E3.

[00155] In addition to replicating the well-known association between APOE4 and significantly increased risk of dementia, the analyses indicate that APOE4 homozygous individuals that carry a single copy of MTRES1 rsl 17058816-A (c.3+lA) alternative (A) allele have approximately half the relative risk of dementia compared with .4 ( E-/ homozygous individuals that are homozygous for the MTRES1 rsl l7058816-G (c.3+lG) reference (G) allele (Table 3).

Table 3.APOE4 and MTRES1 rs!17058816 (c.3+lG>A) stratified analyses

[00156] These results indicate that change or loss of function of MTRES1 results in protection from dementia even in the context of the exceptionally high genetic risk conferred by APOE4 homozygosity. These results further indicate that therapeutic modulation or inhibition of MTRES1 may result in similar disease-protective effects m ' AP0E4 heterozygous and homozygous carriers at increased genetic risk of Alzheimer’s disease and dementia.

Example 4: Protective variants in MTRES1 modulate polygenic risk of Alzheimer’s disease and dementia

[00157] Polygenic risk scores (PRS) are increasingly being utilized in the screening, diagnosis and treatment of disease. PRS aggregate the effects (or weights) of a large number of genetic variants on a given disease to estimate an individual’s risk for that disease Those individuals within the highest percentiles of the score tend to have a higher incidence of the disease as compared to individuals in the percentiles below, and this information can be utilized in both clinical and research settings to select individuals most likely to benefit from a diagnostic test or therapeutic intervention.

[00158] A PRS score was generated using publicly-available weights from 37 independent genetic variants, with a p value less than le-5 within a meta-analysis of Alzheimer’s disease (PGS catalogue- PGS000898). Notably, this set of variants did not include the APOE locus, allowing examination of 4 /YlE-i independent polygenic risk for Alzheimer’s The PRS score was calculated for 452,401 individuals with genotype data from the UK Biobank cohort, multiplying weights by the number of alternative alleles, and summing across all variants per individual. Examining model performance, individuals in the upper 20^th percentile of PRS scores were 1.68 times more likely to have all cause dementia as compared to those in the remaining 80% of samples.

[00159] Genetic analyses were performed to evaluate the effect of the MTRES1 rsl 17058816 splice donor variant (c.3+lG>A) on the risk of dementia in the full sample of 452,401 UK Biobank participants and in subsetted strata comprising the upper 20^th and 40^th percentiles of the Alzheimer’s disease PRS (90,492 participants and 158,331 participants respectively). [00160] The analyses indicate that theMTRESl rsl 17058816 splice donor variant (c.3+lG>A) is associated with protection from dementia in all individuals and in individuals at high polygenic risk of Alzheimer’s disease, with a notable increase in the already large protective effect size as the polygenic risk increases (allelic odds ratios of 0.489, 0.337, and 0.291 among all individuals and individuals in the top 40^th and 20^th percentiles for PRS risk respectively) (Table 4).

Table 4. MTRES1 rs!17058816 (c.3+lG>A) associations within Alzheimer’s Disease PRS strata

[00161] These results indicate that in the context of 4 /Vl/'-i independent, high polygenic risk for Alzheimer’s disease, MTRES1 change or loss of function confers protection from dementia. These results further indicate that therapeutic modulation or inhibition of MTRES1 may result in similar disease-protective effects in individuals with high polygenic risk for Alzheimer’s disease and dementia.

[00162] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and compositions within the scope of these claims and their equivalents be covered thereby.

SEQUENCES CCACTGCATTCCAGCCTGGGCAACAGAGGAAGACCCTGTCTCAAAAAAAAAAAAAAGAA

AAAAAAAGAAAAAAGGAGAAGAGAAGGAGGCAGCAAAGGAGTCTTTTCTTTTTTTTTTTT

TTGAGATAGAGTTTCGCTCCTGTTGCCCAGGCTGGAGTGCAATGGCTTCGGCTCACTGCAG

CCTCCGCCTCCCAGGTTCAAGTGATTCTCCTGCCTCAACCTCCTGAGTAGCTAGGATTACA

GATGCCTGCCATCGTGCCCAGCTATTTTTTTTTTTTGAGACGTCTCACTCTTGTTGTCCAGG

CTGGAGTGCAATGGCGCAATCTCAGCTCACTGCAACCTCTGCCTCCCGGGTTCAAGCGGTT

CTCGTGCCTCATCCTACTGAGTAGCTGGGATTACAGGCACGTGCCACCACATTCAGCTAAT

TTTTGTATTAGTAGTAGAGACAGGGTTTCTCCATGTTGGTCAGGCTGGTCTCGAACTCCCG

ACCTCAGGTGATCCACCCACCTCGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCAC

CGTGTCCGGCCAGCAGAGGAGTCTTGAGAAGCAGCAGCCACAGGAGAGACAGGAAGAAA

ACCAAGAGTAAGGTGTCTTGGCGACCAAGTGAAGAAGAGAGGCGTGATCGGTTTTTTCAA

GTGCTGCTGAGGAGTCAATTAAGATGAGGACTAACATGACCTTTTGGATTTAGAAAATGA

AAGGAGTGGAATTGAGGAGAGTTAGACAACTGTTTTGAGAAGTTTTATGGTAAAGAGGA

GCAAGAAAAGAGGTGGTAGCTGGGGAGGAGTGGAGGCAAGAGGTTTGTGTAATTGCTTG

CTTTTGAATGAGACAAAAGTAACAGCATCCTCTCCTTTACTATAGCCACCCCCACGTTGAT

TCATTTCCTCACATATGCCAAGTGCCTGGCTAGGCCTTGGTAAAACACGCAATTCTTGTCA

TCAGGGAACTGCCATTTAAGTGGAATGTGGGCAAGTAAACTGACTGCCAGGGCACACATG

TAAAAGCAGGTCCAGGGGAGGTTGAACCCTGCATCAGCTGGAGCTCAGAGCAAGAATGC

CTGAGCTGGGTGCAGTGGATCACGCCTGTAATTCCAGCACTTTGGGAGGCCGAGGCAGGC

GGATTACAAGGTTAGGAGTTCGAGACCAGCCTGGCCAACATAGTGAAACCCCATCTCTGC

TAAAGATGCAAAAATTAGCCAGGCGTGGTGCCGTGTGCCTGTAGTCCCAGTTACTGGGGA

GGCTGAGGCGGGAGAATTGCTTGAACCCAGGAGGCGGAGGTTGCAGTGAGCTGAGCACT

GCACACCAGCCCGGGTGACAGTGCAAGACTCCATCTCAAAAAAATAAAAAAATGCCTGA

GCATCCTTGAATGCTCATCCTCATTCATCCTTGAATGAGAGAAAAATAACAGCATGCCAA

TGGACTGGTCCATTATCAAGCAAAAAAATCACTGTTGTAACTTGATATTTCCCCATAGCTC

GGTTTCAGGCCACCTTTGCTCTCAGAACTTTGTAGGCATCCTTGCTCTGCGCTCCAGCTGG

TGCAGGGTTCAGCCTCCCCGGACCTGCTTTCACATCTGTGCCCTGGCAGTCAGTTTACTTG

TCCACATTCCACTTAAATGGCAGTTCCCTGGTGACAAGGACTGTGTGTTTTATACCAAGGC

CTACCCAGGAACTTGGCATATGTGGGCGAACGAGTGATTGTAGGGGTGGCTATAGTAATG

GGCAGGATGCTCATTTCATTTCTAGAAATTGAATCTGCAACCATTCACTGGTTTTGGTATG

TCCTGAGCAGAGGAGTGAAGAACAGGGCACTGTGTAGTCCCTATCACTACACTTAGAGTT

TGGGAGATAATTTGTGACTTAATTCAAAAGTAACAAAAAAATGTGTAGTGTTGGTGCAAC

CAGAGTATGGAAAAGGGCATGTGGGGCATGGCTTGGTAGAGGAGGATGTGACTCGTGTG

GAGTCTGGAGGAAGAGGAGACCATGACAAAGGGACAGGAATTTTTCAGTAGTAGATTTTT

_TTTTTTTTTCAAG_TG_AGC_TATAAGG_AACCCAG_TATTCTCCAG_TGCTGC_TTTGG_CTTG_AGAG

GAGCTGGGTGCCTGGTTAGCTTTCTTCTCTGGCACCCCCACTTCCAACTCAGGGCTCCCCT

GACCAGTTTCAAAGTCCTGAGGCAGGGCCGGGCACGGTGGCTCACGCCTGTAATCCCAGC

ACTTTGGGAGGCTGAGCTGGGCAGATCACGAGGTCAGGAGATCAAGACCATCCTAGCTAA

CATGGTGAAACCCCGTCTCTACCAAAGATACAAAAAATTAGCCGGGCGTGGTGGCGGGTG

CCTGTACTCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATGGCAGGAACCTGGGAGGCA

GAGCTTGCAGTGAGCTGAGATTGTACCAATGCACTCCAGCCTGGGCGACAGAACAAGACT

CCGTCTCAAAAATAATAATAATAATAACAAAGTTCTGAGGCAGAATCTGGGTCCTCCCTT

GTGACCCTGAGTGCCCACTGCTAACAACTACAAATGGTCATCATCTCCAGCAAGAATTAG

CTTAATGTGTTTCCTCAATTTTATGTTTTTAATGAATTTTATCTAAGCTTCCAACATTTGCC

AATGTTTGCCTGCTAGAAAGTTAAGCTGATCACAATGAGAGGTAGTGAGTAGCTAATAAA

CACAAGGGAATACGTGGCTTGACATTTTGGTATGTTTGTTGAATTTACAAGTGCACCTGAT

TCTAAATAGTTATTTTCTGCAAGGAAAGGTTTCCTAATGCAGGTAGCAGAGAGCCACATC

ATATCTAGGCATTCCTCAAAGTAAACAACGGTACGGTATAAAGCTAGGACTTTTCTCAAA

GTCAGGAAAAGAGTGTAAAAAAGATACTGAAAAACATAAAAATAGAACTTATGGATGGG

GAGTGTGGGCACCCAGGGTCTGACACAGAAACAGGACTACTTCCCTTCCCTAGGTGTCTC

CTCTTAGGATATTTTCTAAGTTGGGGCAACAGTTCCTCCCACTCTTCTACCCCTGAAAACT

ATCTGTTCTCTCTGGTATTGCACTGGTTGGTGAGTTTTTATTCCAGAAAAAAAAAAGGAAA

ATAGATGTCAGGGTGTGGAAGAAAGAGTGCTTAACTTGGAGTCAGAACACTGATGGACA

GTTCAGCATGGTAGTAATGAGTCTAGGCTTTGCAGCTCGGATGCCTAGATTTGAAGAGTA

TCTGTGTGACCCTATAACTGAGATGGGCTTGTCGCAAGGAACAAATGAGTTAACGTGTAG AGCAATGCCTGGCCCACGGTGAAAACAATGAGCTTTAAGGAGACTTGACCTTGGTCGGGT GCGTTGGCTCATGCCTGTAATCCTAGCACTTTGGGAGGCCAAGGTGGGCAGATCACCTGA GGTCGGGAGTTCAAGACCAGCCTGACCAACATGGAGAAACCCCGTCTCTACTAAAAATAC AAAATTAGCCAGGCGTGGTGGCACATGCCTGTAATCCCAGCTACTAGGGAGGCTGAGGCA GGAGAATCACTTGAACCTGGAAGGCGGAGGTTGCAGTGAACCGAGATCACACCATTGCA CTCCAACCTGGGCAACAAGAGTGAATCTCCGTCTTAAAAAAAAAGAAGACTTGACCTTGG GATCCTAGCCCTGTCATTTACTAGCTGTGCCACTTAGCGTATTCTTAAATTGCTTCAACTTT TGTTTGTACTCATCTGCAAAATGAGGGAACTGCACAAGGTCATCCCTCAGAGGGTGCTTTT TTTTTTCTTATTTTTGAGATGGAGTTTCACTCTTGTTGCCCAGGCTGGAGTGCAATGACACA ATCTCGGCTCACCGCAACCTCCGCCTCCCAGGTTCAAGCAATTCTCCTGCCGCAGCTTCCC AAGTAGCTGGGATTACAGGCACGCACCACCATGCCCAGCTAATTTTGTATTTTTAGCAGA GACCGGGTTTCTCCATGTTAGGCTGGTCTCAAACTCCCAAACTCAGGTCATCAGTCCACCT CAGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACCTAAGTAAAACTTTGAATAATG ACTCTAGGACTTAAGACCAACACAGACTTCCTGGGGATGATGTTAGAGAGCTCTGGCCAC CTATGGCTAAACCTTCCTGTGTGTTTTGGGTGGTTGGGAGAGTATGAGAGGCTGTGCTTAT GAGTTAATTATTTTTCTTCAGATTTTACATTGTGAAGGATCTATGCCAAAATCTTACAGTG GTTAACATAGAGTGGAGTATGGCTGGTTTTAATTTTCTTTTTTTGAGATGGAGTTTCGCTCT TGTTGCCCAGGCTGGAGTGCAATGGCACAATCTTGGCTCACTGCAACCTCAACCTCCTGG GTTCAAGCGATTCTCCTGCCTCAGCCTCCCGAGTAGCTGAGATAACAGGCACCCACCACC ATGCCTGGCTAATTTTTGTGTTTTTAGTAGAGATGGGGTTTCACCATGTTGGCCAGGCTGG TCTCAAACTCCTGACCTCAGGTTATCTGCCAGCCTTGGCCTCCCAAAGTGCTGGGATTACA GGTGTGAACCACCACACCCGTCCAGTTTTCTTCATATTTTTTCAAATTTTCTACATGAAAAT TTATTTTATATACATATAATCAGAAATTTTATGAAAAAATATTATTGCATATAGGGGGTAT ACTCAACCTTTCCTAGTTATGACTTTTGGGGGGGCATCTAATTTAAATGTATTATTAATGC CCCGATATTCAAATATACTACTGTTGGCAACACTGGGCCGTGGCTATACAAACCTGTGAC AAAGTTTTCCTAGACCCACAGTGAGAAAAATAAATGACAATAGTTGATTTCTTATAATGC AAAATTTATTCATCTTAAAGAAGTTTAATTCTGGCCGGGCACTGTGGCTCACACCTATAAT CTCAGCACTTTGGGAGGCTGAGGCGGACAGATCACCTGAGGTCAGGAGTTCCAGACGAGC CTGACCAATATGGAGAAACCCCATCTCTACTAAAAATACAAAATTAGCCAGACGTGGTAG CGCATGCCTGTAATCGCAGCTGCTCAGGAGGCTGAGGCAGGAGAATCACTTGAACCCAGG AGGCAGAGGCAGTGAGCCGAGATCGAGCCGTTTCACTCCAGCCTGGGCAAACAAGAGCG AAACTCCATCTCAAAAAAAGTTGTTTAATTCTGGCTGGGTGCGGTGACTCACGCCTCTAAT CCCAGCACTTTGGGAGGCCGACGCAGGCAGATCACGAGGTCAGGAGATCGAGACCATCC TGTCTAACACGGTGAAACCCGTCTCTACTAAAAATACAAAAAAATTAGTTGGGCGTGGTG GTGGGCACCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATGGCGAATGGCGT GAACCCAGGAGGCGGAGCTTGCAGTGAGCTGAGATCGCGCCACTGTACTCCAGCCTGGGC GACAGAGTGAGACTCCGTCTCAAAAAAAAAAAAAAAAAGTGGTTCAATTCTGAGATTAT GTCCTTCCTACTCTTTTGGCATGAAATCTTTCTTGGAGTCCACCATGAGGTATCTTTCTCAA TTTTGTTTTTTCTGTAGAGATAGAGTCTTACTGTTGCCCAGGCTGGTCTCAAACTCCTGGGC TCAAGCAGTCCTCCTGCCTCAGCTTCCCAAAGTGCTGGGATACAGGCGTGAGCCACTGCG CCTAGCCTAGTTACCTTTAAAAAAAAAGTTTTTTTAATTGTACTAATCAATGAAATATACA GCCTGGGAAATGCTGAAATCCCAGACTGGAGTGCAGTGACACGATCTCAGCTCACTGCAA CCTCTGCCTCCCAGGTTCAAGCACCCGCCACCACACCTGGCTAATTTTTGTATTTTGAGTA GAGATGGGGTTTCACCATGTTGGCCAGGATGGTCTCAAGCACCTGACCTCAAGTGATCTG CCCGCCTCAGCCTCCCAAAGTGTTGGGATTACCGGCATGAGCCACCATGCCTGGCTCCAG CTAATTTTCGTACTAAAAGTAGAGATGGGGTTTCACCACGTTGGCCAGGCTGGTCTTGAAC TCCTCACCTCAAGTGATCCTCCCTCCTTGGACTCCAAAGTGGTGGGATTACAGGCGTGAGC CTGTACCCAGCCTGATTATGTAAAATTTAAAATTAGCGAGACCTCATCTCTACTAAATAAA TTAAATCTAAAAAATTTAAAGGCATTTTTATGAATGGGTATTATTCATTCTCTATTACGCT AGAATATGTGTAAAAGTAATTATTGGCAACATTTCTCTTGAAGGTACTTCAGGTAGTTTCT AGTCATTATTTTAGAGTACTCTGGATTATATAGCATTTTATTTATTTATTTTATTTTTGAGA CAGAGTCTCACTCTATCGCCCAGGCTGGAGTGCAGTGGTGCAATCTCAGCTCACTGCAAC CTTTACCTCCCAGGTTCTAGCAATTTTCCTGCCTTAGCCTCCTGAGTAGCTGGGATTATAG GCGTATGCCACCACACCCGGCTAATTTTTGTATTTTTAGTAGAGATGGGGTTTCATCATGT TGGCCAGGCTGGTCTTGAACTCCTGACCTCAGGAGATCCACCCGCCTCAGCCTCCCAAAG TGCTGGGATTACAGGCATGAGCCACCATGCCCACCCTAGCATTTTAAAATTATTCCAAATT

ATAGTTATGTTGAAACAGAGTCTTTACATTCAGTCTGCTTTATTTCCCTTTTAAGACTTAGA

TTGGAGTCCCAAGAGTGGTGGATTAATAGAGTTGAGACTGGGTCGTATGCTCATCCATGC

CAGGGAAATAAGGCCCAAAATGTTAAATATAAATTGGAAGTAGCTAGCTCCATGTTTTTG

AGTGAGCCATAATCAGAGGTATCAATCCTAAGGTACAATCTAGGCACAAAGGAAAGTCAT

TTGCAGACTCACGGTACAAGGATGTTAACCATATGGAAACCCTTCCCTCATTACCAAATC

ATGGTCTCTAAAACCTTCTTGATATACTTGCAGGGGTGGGGGTGAGTGTGAGTCTGCCACC

ATCATAAGATGGTTTCTGCTACATTTGAAGTAACTGTAGGAGTTGATTGCCCTCTGACATG

TCACAAGCACTTGTTGCAGTTCCCTAGTTTGTGGATCTCTAGACCCCTTCCTTGTCTGCTAG

TTAATGCCTCTGTTAAACATTGGGAAGGAGATGTAAAAGGAGTTAAAATGCAGGTCTGTC

CAATTTGCTCACCCTTACCTCTGATTTGCTGGGGCTGGAGGTTGAAATAAAGTTTAGAGAT

TCACTCTGGATTTTATGAAGTCATGATCTGGTGTCCTTCCTTGGCAAAGTCAATGTTGTAA

GGATGTAATGTATGTCAGTCAACAGTCTTTCTCTCCAAATTTTCCTTTAAAAACAAAACCA

GGGCAGGCGTGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCAAGGCAGGCGG

ATCACCTGAGGTTGGGAGTTCAAGACCAGCCTGACCACCGTGTAGAAACCCCATCTCTAC

TAAAAATACAAAATTAGCTGGACGTGGTGGTGCATGCCTGTAATTACAGCTACTGGGGAG

GCTGAGGCAGGAAAATAGCTTGAACCCAGGAGGCGGAGGTTGCAGTGAGCCGAGATCAC

GCCATTGCACTCCAGCCTGGGCAACAAGAGCAAAACTCCATCTCAAAAAAAATAATAATA

AATAAAAAAACAAACATAATTGAGAACTATTGTTAGTATTTTTTTTAGGAGCAATCAGTA

CCCAAAGCTAATTTGTGGGAGGGAGAAGAGTAGAACCAGTGCTTTCACATATACTCATAT

CACATTGGACCTTCCTGACAATCCTATGAGCTAAGCACATTAGTTGCAGCTAGAAGATTC

ACTGTGCTGTGGTATATGGCCCTTAGTACATGCAGATTGATATGACCCTGTTTTTGTTTTTT

TGTTTTTTGGTTTTTTTTAATTTTGGGATGTGGTTTCTCTCTTGTTGCCTGGGCTGGAGTGC

AGTGGCGTGATCTCAGCTCACTGCAACCTCTGCCTCCTGGGTTCAAGTGATTCTCCTGCCT

CAGCCTCCCGAGTAGCTGGGATTACAGGCGCCTGCCACCACACCCGGCTAATTTTTGTATT

TTTAGTAGAGATGGGGTTTTGCCATGTTGGCCAGGCTGGTCTTGTACTCCTGACCTCAGGT

GATCCACCCACCTCAGCCTCCCAAAGTGCTGAGATTACAGGCGTGAACCACTGCGCCAGG

CCCAATAGGACTTTTTAGGGGCGAATACGTATAGTACTGTACATAAAGCGTTCATAGTGC

ATATGGTTTATGTTGTAATAATGTCATGACACTGCACTTGTGAGATAAAACTGATTTATTA

TCTGTTTCAGATTATAAGCGCCATGGCTATGGCTAGTGTTAAATTGCTTGCCGGTGTTTTA

AGAAAGCCAGATGCCTGGATTGGACTCTGGGGTGTTCTCCGAGGGACACCTTCATCATAC

AAACTCTGTACTTCCTGGAATCGATACTTGTATTTTTCTAGTACCAAGTTACGTGCACCAA

ATTATAAAACACTTTTTTATAATATTTTCTCACTGAGACTCCCAGGGCTTTTACTATCTCCA

GAATGTATTTTTCCTTTTTCCGTAAGACTCAAAAGTAATATAAGGTCTACAAAATCTACTA

AAAAGTCTCTGCAAAAAGTAGATGAAGAGGACTCTGATGAAGAAAGCCATCATGATGAG

ATGAGTGAGCAGGAAGAGGAGCTTGAGGATGATCCTACTGTAGTCAAAAACTATAAAGA

CCTGGAAAAAGCAGTTCAGTCTTTTCGGTATGATGTTGTCCTGAAGACGGGGCTAGATATT

GGGAGAAAGTGAGTATGATACGCATTTCATTATAAACTCGCTCGTAGTCATGTTATTTTAA

TATAGCATTACAAATCACTTGGCCCATATTATGGTGAAGAATAACCACAATAAAAGGACC

TTTGTAGGTAACCTGTTTCAATTATTTCATTTTATAGATGAGCAAACTGATTTCCAAAGAA

GTCAAGTGACTGCCTGCAAATCCTATGTGCCATATTTGAATCTAAGACACAGTTGACTGTA

AGATGAACCATTGATTTAAAAACAGCTTCTTGAGGAGAAAATGAATCACCATATTAGATG

TATGTAGCAAACGTAAAATGTACCTGGATATTTCACAAATGCTATAATGTGAGACGGTAC

CTCAGCTGGGCATGGTGACTCATGCCTGTAATCCCAGCACTTTGAGAGGCTGAGCTGGGC

GGATCACAAGGTCAGGAGTTCAAGACCAGCTTGGCCAATATGGTGAAACCCTGTCTCTAC

TAAAAATACAAAAATTAGCCGGGCGAGGTGGCAGGCGCCTGTAGTCCCAGCTGCTTGAGA

GGCTGAGGCAGGAGAGTCACTTGAACCCGGGAGGCAGAGGTTGCAGTGAGCCGAGATCG

CGCCACTGCACTCCAGCCTGGGTAACAGAGTGAGACTCCATCTGAAAAAAAAAAAAAGA

GGTACCTCTTAGAATTAACAGCATGATGTATACTAAGATGTTGGTTAAGAATGCACGCTTT

GGCTGGGCGCAGTGGCTCATGTCTGTAATCCGAGCACTTTGGGAGGCCAAGGCGGGCGGA

TCACAAGGTCAGGAGATCGAGACCATCCTGGCTAGCACGGTGAAACTCCGTCTCTACTAA

AAATACAAAAAATTAGCCAGGCGTGGTGGCAGGCGCCTGTAGTCCCAGCTACTCGGAGGC

TGAGGCAGGAGAATGGTGGGAACCCGGGAGGCGGAGCTTGCAGTGAGCCGAGATCACGC

CATTGCACTCCAGCCTGGGCGACAGAGCAAGACTCCGTCTCAAAAAAAAAAAAAAAAAA

GAATGCAGGCTTTGGAGTGAGATTACTGGGGTTTCAATCCTGGTTCTGTGTGACCTTGGGC AAGTTACTTAAACTTTCTGACCCTCAGTTTTCTCATCTGTAAAATGAAGATGACAGAACCT AGTTTAGAGAGTGGTTGCTAGGATTGAGTGACTATATATTTATGTCAAACACTTATTACAG TGTCTGGCACATAGTAAGTACTCAACATATGTTGGCTATTTTGAAGAAAATACTACATATG TTCATATATAATAGAGGTATTTCTGGGTTTTTTTGTTTTTTGTTTTTTGCTTTTTTTGAGACG GAGTCTTGCTCTGTTGCCCAGGCTGGAGTGCCATGGCACGATCTCGGCTCACTGCAAGCTC CGCCTCCCGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCGAGTAGTTGGGAATACAGGCG CCCACCACCACGCCTGGCTAATTTTTTTGTATTTTTTTAGTAGAGACGGGATTTCACTGTGT TAGCCAGGATGGTCTCGATCTCCTGACCTCGTGATCCACCCACCTCCGCTCCCAAAGTGCT GGGATTACAGGCGTGAGCCACCGCGCCTGGCGAAGATTTCTTTAGTATTCTGATTCCCTCT CTGCTAGATTAATTATATAAGAATAGTGGCCTTCATTGTTCATTTATTCCCTTAGGAATGA TTGCATGCATATTGTATACAATGTAAGAATTGTGATATGAATAAATGCAGCAAAACTTCTT GTGTAATTTGTACCTTTATGACCTAATGTAATGGCATAGTTTAATTTTTTAATCCCTGAAGC TTAAGAGATTCATAAAAAGGGCCGGGTGTGGTGGCTCACGCCTGTAGTCCCAGCACTTTG GGAGGCCAAGGCAGGTGTATCACGAGGTCAGGTGATCGATAGCATCCTGGCTAACATAGT GAAACCCTGTCTCTACTAAAAATACAAAAAATTGGCCGGGCGTGGTGGCAGGCGCCTGTG GTTCCAGCTACTTGGGAGGCTGAGGCAGGAGAATGATGTGAACCCAGGAGGCAGAGCTT GCAGTGAGCTGAGATCGCACCACTGCACTCCAGCCTGGGCAACAAAGTGGGACTCCGTCT CAAAAAAAAAAAAAAAAAAGGTTCATAAAAATGAGCCAGCCCACAGGCCCCACCCTTGG CATTCTGATCAGGGTGCCATTAGAGAATGTTCTCTAAACTCTGGCAAACAAATAAGGGGG CCTCTCCTCTCCCAGAGTAGTAACTCCTGCTGTTGTTATTAAGCCAAGCTCCACATGTCAG TCACCTGGAATCAGATATCAAAAAAAGGTGTACTGATTTTTAGCTGCTTCCTCCCCCGGTC TGGTTGCCCTAGTGCGTTAAGTTCAGAGAGATCAGCAGCTGTCAGATTGGAATCTCCCCA GCCTCAGTACAAACTGGCAGAGGGTTTCTTAATGGCCTTGCCATACATGTGGTGCCTGGTT TTTCTCTCAGTGTACAGAGCAGGTGTCTGAGGGGAAGGAAGTGCCCACTCACTTTGGCTG TTGTGAATCACCAGAGCTGCAGCCTGGCCATGTAGTCTCTGCACTGGGAGTCAGGTGGAG TACCCCAGGCCCCTGTCCAGAATGGAGCTTGACATCTATGCTAAAACCTTTCTTAAGGCTC CAATTAACTGCCTAAGAGCACTAGCAAATCTTTGCAGCAGTTCAACATCTATTTAGAAAT GCCCTTTGGTCTCCCTGTTTCAGATACACATCAGAGCAGGTGACTTTCACTTTCCCAGGAC TCAAAATGGAGACTGGGGAATCCTTGTCAGAATAAACATTAATGGAGGGCCGGGTGCGGT GGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCTGAGGTGGGCGGATCATGAGGTCAGG AGATCGAGACCATCCTGGCTAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAAAA AATTACCCAGGCGTGGTGGCGGGCGCCTGTAGTCCCAGCTACTCAGGAGGCTGAGGCAGG AGAATGGCGTGAACTTGGGAGGTGGAAGCTGCAGTGAGCCGAGACCACACCACCGCACT CCAGCCTGGGCAATGGAGCGAGACTCCATCTCAAAAAAAAAAAAAAAGTAATGGCAAGT GTTTATCTCAAACTTGTATACAGTTGATGCTTGAACAGTGTGGGGGTTAGGGGTGCCAACC CCCATGCAGTTGAAAAGCCACATATAACTTTTGACACTCAGAAAACTTAACTACTAATATT TTGACACTCAGAAAACTTAACTACTAATATAGCCTACTGTTGACCAAAGGCCTTACTGATA CACAGTTACAATAAAGTAAGCTAGAGAAAAGAAAATGTTATTAAGAAAATCATAAGGAA GTGAAAATATATTTACTATTTATTAAGTGGAAGTGGATCATCATGAAGGTCTTCATCCTGG CTGAGGAAGAGGAGGAAGAGGAGGCGTTGGACTTGCTGTCTCAGAGGTGGCAGAGGCTA AAGGAAATCCACATATAAGTGGATCTGCACAGTTTGGACCCGTGCTGGCCAAGGGTCAAC TGCAATTGTTTTGAGTATATTTCTATATTTTAAAGCACTTTACCTTTAAAAAAAATAGATTT GAGGCCGGACGCGGTGGTTCACGCCTGTAATCCCAGCACTTTGGGAGGCCAAGGCGGGCG GATCACGAGGTCAGGAGTTCAAGACCAGCCTGGCCGACATAGTGAAACCCTGTCTCTACT AAAAATACAAAAGTTAGGCATGTTGATGTGTGCCTGTAGTCCCAGCTACTGGGAGGCTGA GGCAGGAGAATCACTTGAACCCAGGAGGTGGAGGTTGCAGTGAGCCGAGATGGCGCCAC TGCACTCCAGCTTGGGCAACAGAGTGAGACTTTGTCTCAAAAAACAAACAAAAAAAATA

GATTTGAGGGTACAAGTGTAGTTTTGTTACGTGGATATACTGTATAGTGATGAAGTCTGGG CTTGAGTGTACCCATCACCCAAATTGTGTACATTGTTGCTTTTTTTTGTTTTGTAGCAAAGT GGAAGATGCTTTCTACAAAGGTGAACTCAGGCTGAATGAGGAAAAATTATGGAAGAAAA GCAGAACGGTGAGATACTAACCTAAAATGACAGCCAGATGTTTTCGTCTCTTACTCTGCTA GTAACTCAATTAATGCTGTCCCAAATTTTCCCTCTGGCTCCTCTTCTTTCTCTGAGGTCCTT TGTGGTCCTCCACGTCAAGCTGGTGGGAATCAGCTACAGGCTTCAGACACACAGGCACTT TCACTTTTGCAGCCTTAATGATCTTCTGATGAAGCTTCTCCCTTTTAAAATTTTAGAATACA CCACTGTTAGAACTGGCAGAAATCCATTAATTAAACTTCCAGGTCATTAATGTTAGCCCTC ATGGAATCCTCATAATCAGATTTCAAAGAAACATTTGATCCACGTAGAATTGTTCTTTGGC

CAGTGGTATCTGAGCAGATGTGTAATTCTATACAGCTCAGCAGTACCCAGTGAGTGCTTG

CTGGATGCACGGCTTTGTGTGCAGAGCAGTTATAGAAAAGGATGTGTTCTGTATTTTCTGA

CAAGTCCATATCAATACTGTTGTTAAGTGAAAGTCAGTTACAAGAAAATGTGTTTCCAGTC

TCCACTTTTCTAACAATAAATCATATATAAAAATTCTGGGGCACAGTGGCTCATGCTTGTA

ATCCCAGCACTTTGGGAGCTGAGGCCAGCAGATCGCTTGAGCCCAGGAGTTGAAGACCAG

CCTGGGCAACATGGCAAAACTGTCTCTACAAAAAATACAAAAAATTAGCCAGGCGTGGTG

GCAGGCGCTTGTCCCAGCTACTCAGGAGGCTGAGACGGGAGGATTATCTGAGCCTAGGAG

GTCAAGGCTGCAGTGAGCCATAATCATGCCAATGCACTCCAGTTTGGGTGACAGAGTGAG

ACCCTGTCTCAAAAAAAAAAATTCTGGCTGGGCGCAGTGACTCACACCTGTAATCCCAGC

ACTTTGGGAGGCCGAGTCAGGTGGATCACGAGGTCAGGAGATCGAGACCATCCTGGCTAG

CACAGTGAAACCCCATCTCTACTAAAAATACAAAAAAAAATTAGCCGGGTGTGGTGGTGG

GCGCCTGTAGTCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATGGCATGAACCTGGGAG

GCGGAGCTTGCAGTGAGCCGAGATCGTGCCACTGCACTCCAGCCTGGGCGACAGAGCGA

GACTTCGTCTCAAAAAAAAAAAAAAAATTCTGTTAGAAAATATTTTTTTGTAAAAGTAAG

TTACGTATATATATACATCTGGAATTAAAATACTGCTGTTACTAGCATTTATCTTTAATTG

AAGCATTATGGGTTATGTTAATTTCATAGTTTTTATTTTCTGAATTTTTTTACCATGAGTAT

GTATCACTTTCATAATGGAAAAAACAATACTGATAATAAAAGTTAACAAAACACAATAAA

AAGTTATGACAGAGACCCTTAAAAAGTGTGGAAGACACAAGACACGAGGTATTGGAAGA

CATAATCTAACTCAGTGTTCAGGGAACAAAGGTTCCAGAGAAGTTAGACATACTTTGGAG

ATTGTTTTCATTTCATCTTTCATATTTCAAAATACCCCTGGGGTTGGAGGATCCGAACTAC

ATCCGGTTGCCCTAGGACATGGGAAATTGAGGCTGTCGGCTGTCAGCCGTGCATTTGGGT

GAGCACTGAGGCTTCCTGCAGTCCTTGCTAACTGGGATCATGCAGGTTCTTGTAGCTCTGT

GGGCAGAAGGAGGGAAAACTCCCCCAAGCTGTCTCAGCCCCCAAGTCCCAGGGCCCTGGT

GATGCCCCTGACTTGAACCGGCAGGCTGGGACTGTGGCTGGCTGTCAGCAGCTATTGCTC

AGTGAGCTACATGCAGTCATAAGCCCTTCTCATCTCTGAATAGCTTTTTCCTGCTGTAGCC

TGCCCTCCTTCTAAGCTGCAGTATTCCAAAAACAAGATGTATTCTTGGAGTAAAGAATGAT

TACTCCCTGAACACCCTGTCTCTGTGCTGGGGCCTCATTTACAAACCCCACTAGACTATTT

TTCCTCACACCCCTCCCACCCGCCCCCGTTTTGTGATGTTGTTAACTACAGCCTAATTGCTG

CTGCTTCATTCTGCCTTGGGTGTTCTGTTGTCTCAGCTGCCTTCCATGTTTCTTGTGAGGGT

CAGCAAAGGAAGGGGGCATTATTAACGCTCAGCTGTCTTGTTACTAGGAGGCCTGGTAGC

CATAGAAACTGCAGCTAACTAGAGATTTGAAATGTAGATATTTGGAACAGCTCCTAATCC

CAGCCAGTTTTGCTTTGTGTCTGCTGAGGGACAGGGGCCGTGGAGGGGAATAAAGAATGC

CTCGCCTTCCCTGGTCTGCTCTGTGGAGCCTGTGCCTGGCTGCTGACCCCGAAGGGTCAGG

TGCTTGTCTGATGCTGCAGCTCTAACCCTGGCTGTCTGCGATTCAGCAAAGCTTTTCTTTG

AGCTGAAAACCAGGTGAAGCCCAGGGTGTGGTAGGTGTTGGGTAACTGTTGATTAAACAG

TGGGTGTGTGGTGTCCAAGTATGGGGATTGAATCCTTCCTAAACTCATCTCTTCCTGGGAT

CAGTTGGGTAAAGGAGGAGCACCCCTTCTCTGTGCTACAAGGAAGCTCCAAAGGGATTCA

TTCTTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTATTTTTAGTAG

AGACGGGGTTTCACTGTGTTAGCCAGGATGGTCTCGATCTCCTGACCTTGTGATCCACCTG

CCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCACACCCCGCCAAAGGGAT

TCATTCTTTAGCCACACACTAGCCTTCTCTATCCAGAGGCAGACATCATGCACAGTATCTC

TATGAAAGGATATACACAGAGTATCCTTTTCTTTGTATATTTTTTTTTTCTTTTTCTTTATTT

TATTTTGGAGACAGTGTCTTGCTCGGTTACCCAGGCTGGAGTGCGGTGGTGCAGCCACAG

CTCATTGCAACCTTGACCTTCTGGGCTCAAGTGATCTTCCCACCTCAGCCTCCCGAGTAGC

TGGTATGACAGGCACACCACCACGTCTGGTTAATTTTTTATTTTTTATAGAGACAGGGTCT

CACTGTGTGGTCCAGGCTGGTCTTAAACTCCTGACCTCAAGTGATCTACCCACCTTGGCCT

CCCAAAATTCTGAGATTGCAGGCATGAGACACCACACCTGGCCTATACACCTTTTCTTTGT

CTACCCTTTTGTATCTTCTAAATTTTGTATCATATGCATATATTACTTATTAAAAATGAATT

GTAGGCCGGGCACAGTGGCTCACACCTGTAATCCCAGCACTTTGGGAGGTCAAGGCAGGT

GGAACACTTGAGGCCAGGAGTTTGAGACCAGCCTGGCCAACATGGTGAAACCCCATCTCT

ACTAAAAATACAGAAAGTTACCCGGGCATGGTGGCAGGCTCCTGTAATTCCAGCTATTCA

GGAGGCTGAGGCAGGAGAATCGTTTGAATCCAGGAGGTGGAGCTTGCAGTGAGCCAAGA

TCGCGCCATTGCACTCCAGCCTGGGCAGCAGAGCGAGACTCCATCTCAAAAAAAGAAAAC

AAACAAAAAAAGAATTTTAGCTGAGCAAGTTGGTGTGTGTCTGTAGTCGCAGCCACTTGG GAGGCTGAGGAGGGAGTGTCGTTGAGCCCAGGAGTTTGAGGCTACAGTACACTATGATTA

TGCCTATGAATAGCCACTGCATTCCAGCCTGAGCAACATGTGAGACCTCATCTCTTTAAAA

ATAGTAATTTGAATGAAATAAGGTTATACCAAAAAGGTAAAGCAGAGTTCCCAAGCCTTG TATTTCTTTTTTTTGAGACAGCCTTGCTCTTGTTGCCCAGGCTGGAGTGCAATGGCACGAT CTCGGCTCACTGCAACCTCTGCCTCCCAGGTTCAAGCGATTCTCTTGCTTCAGCCTCCAGA GTACCTGGGATTACAGGCACCTACCATCACGTTCTGATAATTTTTGTATTTTTAGTAGAGA

CGGGGTTTCGCCATGTTGGCCAGGCTGGTCTTGAACTCCTGACCTCGTGATCCACCCTCAG CCTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACCACGCCTGGCCTGTATTTCTAGACG

GATTTTTTAAAATGTCCACATAGGCTGAAGTAGTCATTTTAAAAAATTGAACCCAGGGTTG

GGCGCGGTGGCTCACACTTGTAATCCCAGCACTTTGGGAGGCCAAGGCAGGTGGATCATG

AGGTCAAGAGATCAAGACCATTCTGGCCAACATGATGAAACCCTGTCTCTACTAAAAATA

CAAAAATTAGCTGGGTGTGGTGGCACATCCCTGTAGTCCCAGCTACTTGGGAGGCTGAGG

CAGGAGAATCACTTGAAACTGGGAGGTGGAGGTTGCAGTGAGCCGAGATCACACCACTG

CACTCCAGCCTGGTGACACGGTGAGACTCCATGTCAAAAAAAAAAAAAAAAGAAAAAAA

AAATTGAACCAGCAGAACTACAGAAGGGTGGAACCCCCCCACCCCTGCCCAGGTACCTGT GTTGTCCTATCCCTCAAACCCAAGGGGAGAAACAGTCTTGACAATAGCTGTGGTATGAGC

CTTTCTGCTTCTCAGCCCACAGGAGAGGAAGTTAATGGTTTAAAATCTGCCCCTCTGTGAG

TTTTATATCCAGCTATTGTGGGTTTCCTGGATTGGCCAGTATACTGTTGTGGCAAGCAGGT

GCGCATGCCCATGTTGTGGACTGACTGTTGGGCCTGCAGAGGTCTTGAGTGGGTGGGAGA ATAGACATGGGCTTGTTCTGGGGAGGTTGAAAGGTTTCAGAGTCTGAAGTTGTATCTGCCT TAAAGAACATTAATTGTAAAATAAGATAAAAGTCAGCATTTGACACCATACTTCTTAAAC AGAAGCCCTCTAGTAGCCTTATAAATGGCAATGTGTGCCCACTTACTGTCAGTGGTCCACA

CATGGGCTTGCTCACCCCCTACTGGAAGCAGTGGTGAGGGGTATGAGATGGCTCCCAGTC ATCCCTGGCTTATGTTTTAGTAGAAGCAGCAGCATGTGGCTCCTGGGTCTGTATGGCCCTT

_{C TTTTTTTTTTTTTTTTTTTTTTGGAGACGGAGTCTCGCTCTGTCGCCCAGGCTGGAGTGCA}

GTGGCGAGATCTCGGCTCACTGCAAGCTCCGCCTCCCGGATTCATGCCATTCTTCTGTCTC

AGCCTCCCGAGTAGCTAGAACTACAGGCGCCCGCCACCACACCCAGCTAATTTTTTGTATT

TTTAGTAGAGACGGGGTTTCACCGTGTTAGCCAGGATGGTCTCGATCTCCTGACCTTATGA TCTGCCCACCTCAGCCTCCCAAAGTACTGGGATTACAGGCTTGAGCCACCGTGCCCAGCC GGCCCTTCTTTTTTTTTTTTTTTTTTGAGACAGAGCTTTGCTCTTGTCGCCCAGGCTGGAGT GCAATGGCGCCATCTTGGTTCACCGCAACCTCTGCCTCCTGGGTTCAAGTGATTCTCCTGC

CTCAGCCTCTCAAGTAGCTGGGATTACAGGTGTGTGCCACCATGCTCAGCTAATTTTGTAT TTTTAGTAGAGACGGGGTTTCACCATGTTGGTCAGGCCAGTCTTGAACTCCTGACCTCAGG TGGTCCACCCACCTTGGCCTCCCAAAGTGCTGGGATTACAGGTGTGAACCACTGTGCTCG GCCCTGTTTGGCCCTTCTTGAGTGTCTGGAAAGATCCCTTGAGATCCTGAGCTGCCTGGAC

CCGGTATCTGTCTTGGGCTGTCCATACCTTCAGCACAGACCAGTGTCCTTGACCTTGGAGC TGACATAACTGCCCCAGGGCATGCATTGCACTGTCTCAACTGAAGCTGCTTTCTGTGCAAA AATGGGTTTGACCTCAGCCTTTTAACCCATTGAATCAGCATCCAACTCTGCTTTCTGTGGC ATTCTACCTTTGTGAGTGAGTTGAGGCAAGTGTTGCACTGGAAATTGTCTTCACTGTGCAT

GTAGTAATTACTGTGCACACAGTCTCTAAGACTGCCCCCACTTTCTTTGTCTTTTGCCAGTG

TTACCAAGATAAATGTGTCCATTCAAATATTTCCTTAAGTCACCCAATAGATGTGAGTATT

TGAGCTACTCTGCGCAGGGACTATCCACAGCCAGCCAGTTGTCTAGTTCTGAAGGAAGGA

CACTGGCTGATATTGAGGCCCTTGTATTTGAGGCACTCTCCCTTTCTTTTTTTTTTTTTTTTT _TTTTTTTTCGT_TTTTTTCG_TTTTTTTGAGA_TGG_AGTCTCCCTCTGT_CGC_CCGGGC_TGGC_ATGC AGTGACATGATCTTGGCTCACTGCAACCTCTACTTCCCGGGTCCAAGCGATTCTCCTGCCA CAGCCTTCCGAGTATTTGGGATCACAGGCACCCACCACCACACACAGCTAATTTTTTTATT

TTTAGTAGAGACGGGATTTCACCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGT

GATCCACCGAGCTTGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCACCTGA

CCTTTCACCCTCCCTTTCACGCTGAGGCACTGGGATAGGTGACAGTGACTAAGGTCAGGG

CCTTTACTCACCTGCCCCTCCTCTGGGTCATGATCATGTGGTGAAAACTCAGAGCAGTAAT

GTTTGCATTGGCCTGGATTTCCCGAAGTGTAACCAAGCCTCTGTTTTCTTTTAATTTTCAGG TGAAAGTGGGAGATACATTGGATCTTCTCATTGGAGAGGATAAAGAAGCAGGAACAGAG ACAGTTATGCGGATTCTCTTGAAAAAAGTGTTTGAAGAGAAGACTGAAAGTGAAAAATAC AGAGTGGTGTTACGGCGGTGGAAAAGTTTAAAGTTGCCTAAGAAGAGAATGTCTAAATAA

ATGGATTGCTTTTTAGCAATAGAGCTGCTTTCTAGTGGTAAAGGAAGGGGTCACCTGAAA

Claims

CLAIMS What is claimed is:

1. A composition comprising an MTRES1 gene therapy and when administered to a subject in an effective amount modulates central nervous system (CNS) MTRES1.

2. The composition of claim 2, wherein the CNS MTRES1 is decreased.

3. The composition of claim 2, wherein the CNS MTRES1 is decreased by about 10% or more, as compared to prior to administration.

4. A composition comprising an MTRES1 gene therapy and when administered to a subject in an effective amount increases cognitive function or slows cognitive decline.

5. The composition of claim 4, wherein the cognitive function is increased by about 10% or more, as compared to prior to administration.

6. The composition of claim 4, wherein the cognitive decline is slowed by about 10% or more, as compared to prior to administration.

7. A composition comprising an MTRES1 gene therapy and when administered to a subject in an effective amount decreases a marker of neurodegeneration.

8. The composition of claim 7, wherein the marker of neurodegeneration comprises a central nervous system (CNS) or cerebrospinal fluid (CSF) marker of neurodegeneration.

9. The composition of claim 7, wherein the marker of neurodegeneration comprises a measurement of central nervous system (CNS) amyloid plaques, CNS tau accumulation, cerebrospinal fluid (CSF) beta-amyloid 42, CSF tau, CSF phospho-tau, CSF or plasma neurofilament light chain (NfL), Lewy bodies, or CSF alpha-synuclein.

10. The composition of any one of claims 7-9, wherein the marker of neurodegeneration is decreased by about 10% or more, as compared to prior to administration.

11. The composition of any one of claims 1-10, wherein the MTRES1 gene therapy comprises gene delivery.

12. The composition of claim 11, wherein the MTRES1 gene therapy comprises delivering a nucleic acid comprising SEQ ID NO: 1.

13. The composition of claim 11, wherein the MTRES1 gene therapy comprises delivering a nucleic acid comprising an inactivated MTRES1 sequence.

14. The composition of any one of claims 1-10, wherein the MTRES1 gene therapy comprises altering the native sequence of at least one copy of a MTRES1 gene.

15. The composition of claim 14, wherein at least one copy of the MTRES1 gene is inactivated.

16. The composition of claim 14, wherein at least one copy of the MTRES1 gene is edited to comprise SEQ ID NO: 1.

17. The composition of claim 14, wherein the MTRES1 gene therapy comprises a programmable nuclease.

18. The composition of any one of claims 1-10, wherein the MTRES1 gene therapy comprises RNA editing.

19. The composition of claim 18, wherein the composition comprises an ADAR enzyme.

20. The composition of any one of claims 1-19, wherein the gene therapy is delivered in a vector.

21. The composition of any one of claims 1-20, further comprising a pharmaceutically acceptable carrier.

22. The composition of claim 21, wherein the composition is formulated for administration to a central nervous system.

23. The composition of claim 21 or 22, wherein the composition is formulated for delivery to a neural cell.

24. A method of treating a subject having a neurological disorder, comprising administering an effective amount of the composition of any one of claims 1-23 to the subject.

25. The method of claim 24, wherein the neurological disorder comprises dementia, Alzheimer’s disease, delirium, cognitive decline, vascular dementia, or Parkinson’s disease.

26. A method of treating a subject having a neurological disorder or who is at risk for developing the neurological disorder, the method comprising evaluating a subject’s risk for developing a neurological disorder and administering an effective amount of the composition of claim 23 to the subject.

27. The method of claim 25 or 26, wherein the subject has a genotype at risk for developing Alzheimer’s disease or dementia.

28. The method of claim 27, wherein the subject is a heterozygous or homozygous carrier of APOE4.

29. The method of claim 27, wherein the subject is a heterozygous or homozygous carrier of MTRES1 rsl 17058816-G (c.3+lG).

30. The method of claim 25 or 26, wherein evaluating a subject’s risk for developing a neurological disorder comprises calculating a polygenic risk score for developing Alzheimer’s disease or dementia.

31. The method of claim 30, wherein the subject has a polygenic risk score in the 40^th percentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia.

32. The method of claim 30, wherein the subject has a polygenic risk score in the 20^th percentile or higher, which is indicative of a high risk for developing Alzheimer’s disease or dementia.

33. The method of claim 30, wherein calculating a polygenic risk score comprises providing genomic data comprising one or more genotypes of the subject, wherein the one or more genotypes is associated with a high risk for developing Alzheimer’s disease or dementia.