AU2018101460A4

AU2018101460A4 - Compositions and method for maintaining/improving cognitive function

Info

Publication number: AU2018101460A4
Application number: AU2018101460A
Authority: AU
Inventors: Christopher Oliver; Attila Pataki
Original assignee: Blackmores Ltd
Current assignee: Blackmores Ltd
Priority date: 2012-12-11
Filing date: 2018-09-28
Publication date: 2018-10-25
Anticipated expiration: 2021-12-11
Also published as: CN104981244A; AU2013360021A1; MY187748A; WO2014089620A1

Abstract

The present invention provides compositions comprising a combination of: (i) one or more B vitamins or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and (ii) phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof, and/or methods of using the same combination for maintaining/improving cognitive function of adults including elderly adults and/or for maintaining/improving mood in ageing subjects and/or reducing risk markers of cardiovascular disease and/or genetic markers and/or biochemical markers associated with ageing. The compositions include, but are not limited to, dietary supplements e.g., nutritional supplements.

Description

2018101460 28 Sep 2018

Compositions and method for maintaining/improving cognitive function [0000] The present application is a divisional application of Australian Application No. 2013360021, which is incorporated in its entirety herein by reference.

Field of the Invention [0001] The present invention relates to compositions comprising a combination of one or more B vitamins and a phospholipid and/or a lipoic acid and/or methods of using the same combination for maintaining/improving cognitive function of adults including elderly adults and/or for maintaining/improving mood in ageing subjects and/or reducing risk markers of cardiovascular disease and/or genetic markers and/or biochemical markers associated with ageing. The compositions include, but are not limited to, dietary supplements e.g., nutritional supplements.

Background of the Invention [0002] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

[0003] A decline in cognitive function is often considered a natural part of ageing. However, given the increase in general health and life expectancy of people, coupled with increasing demands in the work place, there is a desire to maintain a high degree of cognitive function in addition to maintaining physical ability of the ageing population.

[0004] Individuals with a decline in cognitive function can be subdivided into those with memory loss that is age-related, and in that sense benign, and those whose memory or other cognitive symptoms are the first clinical manifestations of Alzheimer’s or another dementia i.e. mild cognitive impairment (MCI).

[0005] Therapeutic treatments for MCI are important, since MCI is considered the prodromal phase of Alzheimer’s disease. Data suggest that conversion from MCI to dementia occurs at a rate of 10% to 15% per year with -80% conversion by the sixth year of follow-up; although -5% of MCI subjects remain stable or convert back to normal (Lovell MA. J Alzheimers Dis. 2010; 19:219).

2018101460 28 Sep 2018 [0006] The prevalence and incidence of Alzheimer’s disease (AD) is expected to increase dramatically over the next three decades. In 2010 Alzheimer’s disease affected more than five million patients in the U.S. and is predicted to rise to 16 million by 2050, costing the U.S. economy more than $140 billion/yr. Globally, an estimated 35.6 million people have dementia which is expected to reach 65.7 million in 2030 and 115.4 million in 2050 (Weiner MW et al. Alzheimers Dement. 2010;6:202-211). In Australia, there will be 75,000 so-called baby boomers with dementia by 2020 and dementia will be the third largest source of health and residential care costs by 2030; in the absence of new medications to treat dementia, it is predicted that almost 950,000 people will be living with dementia by 2050 (Access Economics report - ‘Dementia across Australia: 2011-2050’, September 09 2011). Thus, not only is there a large economic and social burden from the current state of AD and dementia prevalence, these burdens are also expected to increase dramatically.

[0007] The aetiology of cognitive decline, formation of MCI and progression to AD is complex, multifaceted, and not fully understood. This is evidenced by the numerous risk factors thought to play a role in the development of Alzheimer’s (see Table 1; Smith AD Food Nutr Bull. 2008;29:S143-S172).

[0008] It is thought that an accumulation of oxidative damage may start in presymptomatic phases i.e. MCI, and that progression to AD might be related to depletion of antioxidant defences (Baldeiras I et al. J Alzheimers Dis. 2010). Reactive oxygen and nitrogen species (ROS and RNS) formed during normal metabolism, and in higher fluxes under pathological conditions, can cause the oxidation of amino acid residues on proteins, forming protein carbonyls. In one study, global oxidative stress measurements revealed significantly higher levels of protein carbonyls in the MCI inferior parietal lobule (IPL) relative to PCAD (and controls), despite equal levels of neuropathology (Aluise CD, et al. J Alzheimers Dis. 2010).

[0009] Population-based studies have also shown that those with type 2 diabetes mellitus have an increased risk of cognitive impairment, dementia, and neurodegeneration (23) and even in persons without diabetes, glucose dysregulation is seen as predictor for cognitive impairment (e.g., Whitmer RA. Curr Neurol Neurosci Rep. 2007;7:373-380). Aberrant glucose or insulin metabolism may be reflected in the formation of glycation end products that may physically affect the brain. Insulin, a hormone with potent effects in the brain, may also provide a potential beneficial and protective role in cognitive function. Insulin resistance, which refers to the reduced sensitivity of target tissues to the favourable effects of insulin, is related to multiple chronic conditions which may impact cognition and increase dementia risk. With insulin resistance-associated conditions reaching epidemic proportions, the prevalence of Alzheimer's disease and other cognitive disorders will continue to rise exponentially.

2018101460 28 Sep 2018

TABLE 1. Some of the postulated nongenetic risk factors for Alzheimer’s disease

Risk factor⁰	Evidence base^⁷	Key references’⁷
Age	Prospective, pathology	Braak[199]
Myocardial infarction	Prospective	Luchsinger [200]
Hypertension (midlife)	Prospective	Kivipelto [201], Qiu [120]
Hypertension	Clinical trials of antihypertensive drugs	Qiu [120]
Low blood pressure	Prospective	Qiu [120\|
Cholesterol: blood and dietary	Prospective	Shobab [202]
Atherosclerosis	Prospective, pathology	Roher [203], Honig [204]
Atrial fibrillation	Community, cross-sectional	Ott [205]
Diabetes	Prospective	Biessels [206]
Obesity	Prospective	Kivipelto [201], Whitmer [207]
Smoking (midlife)	Prospective	Tyas[208]
Lack of alcohol consumption	Prospective	Mukamal [209], Luchsinger [210]
Low physical activity (midlife)	Prospective, pathology	Yoshitake [211], Fratiglioni [212], Rovio [213], Larson [214], Powdewils [215]
Lack of fish in diet	Prospective	Morris [216], Huang [217]
Rate of decline in body-mass index	Prospective	Buchman [2I8],but see Stewart [219]
Lack of social and mental activities	Prospective	Fratiglioni [212]
Low education	Prospective	Karp [220]
Low intake of antioxidants	Prospective	Engelhart [221], Morris [222], but see Luchsinger [223], Engelhart [224]
Raised blood markers of inflammation	Prospective	Engelhart [225], van Oijen [226]
Raised plasma total homocysteine	Case control pathology, prospective	See tables 2 4
Low intake or pl asma concentrations of folate and vitamin B₁₂	Case-control pathology, prospective	See tables 2, 3, and 5
Low testosterone in men	Case-control and prospective	Hogervorst [227], Moffatt [228], Henderson [229]
Use of hormone replacement therapy in women > 65 yr	Randomized trial	Craig [230]
Lack of use of NSAIDs	Prospective	Szekely [231]
Low TSH	Case-control, pathology	Kalmijn [232], van Osch [233]
Head injury in men	Prospective	Fieminger [234]'
Depression	Prospective	Green [235], Porno [236]
Poor self-perceived health	Prospective	Larson [214], Yip [237]

ii. Risk factor is defined in relation to observational epidemiology unless otherwise indicated, and is included in the list if studies have shown an association with dementia of the Alzheimer type (DAT) or Alzheimer’s disease that is independent of other risk factors.

b. The diagnosis is one of the standard clinical operational procedures unless otherwise stated.

c. The references given are not necessarily the first reports but are intended to provide entry points into the literature.

[0010] Despite studies attempting to identify underlying causes for the formation of MCI and progression to AD, currently there are very few treatment options available for persons with AD and the treatment options that are available are only short-lived and not overly effective. Such therapies have focused on narrow therapeutic targets such as, anticholinesterase inhibitors e.g., donepezil. These medications are very expensive and in Australia, available only after medical approval. Thus, treating persons with AD or MCI is viewed as difficult with the current technology.

2018101460 28 Sep 2018 [0011] Improving cognitive ability or slowing the decline of cognitive function in healthy elderly people, or ageing individuals is desirable for increasing quality of life and perhaps to delay the onset of MCI and AD. Use of nutritional supplements or compositions that may be taken as dietary supplements would also represent attractive cost-effective alternatives.

[0012] A number of clinical studies have attempted to use B vitamins to slow a decline in cognitive function. One reason why researchers have pursued this line of investigation is that blood homocysteine (Hey) can be lowered cheaply by the administration of B vitamins (namely folic acid, vitamin B6 and vitamin B12).

[0013] It has been estimated there have been, as of 2008, as many as 77 cross-sectional studies on more than 34,000 subjects and 33 prospective studies on more than 12,000 subjects showing associations between cognitive deficit or dementia and Hey and/or B vitamin status (Smith AD Food Nutr Bull. 2008;29:S143-S172).

[0014] Despite the link between elevated homocysteine (Hey) levels and various disease states (e.g. stroke, heart disease, Alzheimer’s) intervention trials have been less than impressive. In 2010 a study was published from the Oxford Project to Investigate Memory and Ageing (OPTIMA) from University of Oxford showing that “The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins.” (Smith AD et al. PLoS ONE. 2010;5). In contrast, another study using 140 subjects with mild to moderate Alzheimer disease or vascular dementia randomly assigned to 1 mg of methylcobalamin and 5 mg of folic acid, or placebo once daily for 24 months, no effect on reducing global cognitive decline Kwok T et al. Clin Nutr. 2011;30:297-302.

[0015] In a systematic review and meta-analysis of randomized controlled trials of effect of homocysteine lowering treatment on cognitive function published in 2012 the authors concluded that “Supplementation of vitamins B12, B6, and folic acid alone or in combination does not appear to improve cognitive function in individuals with or without existing cognitive impairment.”(Ford AH, Almeida OP. J Alzheimers Dis. 2012;29:133-149).

[0016] There remains a need for safe, cheap and effective therapies, e.g., effective nutritional supplements or dietary supplementation to maintain or improve cognitive ability or slow the decline of cognitive function in individuals with MCI or AD or healthy elderly individuals so that the onset of MCI or AD is may be avoided.

2018101460 28 Sep 2018 [0017] It is an objective of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art treatments, or to provide a useful alternative.

Summary of the Invention [0018] In a first aspect, the present invention provides a composition comprising an effective amount of a combination of:

(i) one or more B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and (ii) phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof, to maintain/improve cognitive function and/or slow the age-related decline in cognitive function of an adult subject.

[0019] In a second aspect, the present invention provides a method for maintaining/improving cognitive function and/or slowing age-related decline in cognitive function of an adult subject comprising administering a combination of:

(i) one or more B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and (ii) phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof, in amounts and for a time sufficient to maintain/improve cognitive function and/or slow the age-related decline in cognitive function of said adult subject.

[0020] In a third aspect, the present invention provides use of an effective amount of a combination of:

(i) one or more B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and (ii) phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof,

2018101460 28 Sep 2018 to maintain/improve cognitive function and/or slow age-related decline in cognitive function of an adult subject.

[0021] In a fourth aspect, the present invention provides a use of an effective amount of a combination of:

(i) one or more B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and (ii) phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof, in the manufacture of a medicament, dietary/nutritional supplement, or nutraceutical for maintaining/improving cognitive function and/or slowing age-related decline in cognitive function of an adult subject.

[0022] A number of different adult subjects are contemplated for any aspect and/or example described herein. The age of the adult subjects may vary. Adult subjects may include biological adults, e.g., subjects that have completed puberty and may include any subjects over the age of about 10 e.g., about 10 to 95 years. Typically, an adult subject is considered to be a subject over the age of 18, e.g., 18 to 95 years. For example, adult subjects may be between the ages of about 18 to 90 years, or about 20 to 90 years, or about 25 to 90 years, or about 30 to 90 years, or about 35 to 90 years, or about 40 to 90 years, or about 45 to 90 years, or about 50 to 90 years, or about 55 to 90 years, or about 60 to 90 years, or about 65 to 90 years, or about 70 to 90 years, or about 75 to 90 years, or about 80 to 90 years, or about 85 to 90 years, or about 18 to 85 years, or about 18 to 80 years, or about 18 to 75 years, or about 18 to 70 years, or about 18 to 65 years, or about 18 to 60 years, or about 18 to 55 years, or about 18 to 50 years, or about 18 to 45 years, or about 18 to 40 years, or about 18 to 30 years, about 18 to 25 years, or about 25 to 30 years, or about 30 to 35 years, or about 35 to 40 years or about 40 to 45 years, or about 45 to 50 years, or about 50 to 55 years, or about 55 to 60 years, or about 60 to 65 years, or about 65 to 70 years, or about 70 to 75 years, or about 75 to 80 years, or about 80 to 85 years, or about 85 to 90 years, or about 90 to 95 years, or about 30 to 40 years, or about 40 to 50 years, or about 50 to 60 years, or about 60 to 70 years, or about 70 to 80 years, or about 80 to 90 years. In another example, the adult subjects may be elderly subjects between the ages of about 50 to 65 years, or about 60 to 75 years, or about 70 to 85 years, or about 80 to 95 years.

2018101460 28 Sep 2018 [0023] The adult subject of any aspect and/or example described herein may also include patients that have Alzheimer’s disease, MCI, dementia or other similar neurological impairments. The adult subject of any aspect and/or example described herein may also include those subjects that have a pre-disposition and/or at risk of developing to Alzheimer’s disease, MCI, dementia or other similar neurological impairments. For example, subject(s) may be tested for biochemical, genetic, or other risk factors and/or markers that indicate that the subject(s) has a pre-disposition and/or at risk of developing to Alzheimer’s disease, MCI, dementia or other similar neurological impairments. Such markers may be identified using any test or assay known in the art for such purposes e.g., as described in Stough et al. Nutrition Journal 2012, 11:11. Risk factors for Alzheimer’s disease, MCI and/or dementia include, but are not limited to those listed in Table 1. Risk markers also include, but are not limited to measuring glycated haemoglobin, insulin levels, blood glucose levels, markers of oxidative stress, markers of inflammation, C-reactive protein, F2-lsoprostanes, inflammatory cytokines including, but not limited to, TNF-alpha, IL-2, IL-4, IL-6, IL-10, and IFN-gamma, liver function, and genetic markers including detecting the presence of Single Nucleotide Polymorphism (SNPs) in DNA samples from subjects. Any known SNP in the art associated with increased risk of AD, dementia, MCI and cognitive decline in affected and/or normal elderly may also be used. For example, this includes the SNP of APOE allele, which is associated with increased risk of AD and cognitive decline in normal elderly. SNPs associated with increased risk of AD, dementia, MCI and cognitive decline in affected and/or normal elderly may also include any number of SNPs of cytokines, e.g., inflammatory cytokines.

[0024] Risk factors for Alzheimer’s disease, MCI and/or dementia include, but are not limited to measuring cerebral energy metabolism. For example, this includes, but is not limited to measuring insulin levels, insulin function, glucose uptake and metabolism, insulin resistance and downstream effectors of the insulin resistance pathway in the brain e.g., as described in Medhi and Chakrabarty, Neurol Sci (2013) 34: 1719-1725 and/or Cholerton et al., European Journal of Pharmacology (2013) 719: 170-179. For example, the level and/or activity of PI3K/Akt and/or downstream effectors, glucose uptake and metabolism in the brain including intraneuronal and/or extraneuornal glucose, UDPGLcNAc, tau-O-GIcNAc, oxidative stress, advanced glycated end products (AGE) tau phosphorylation, levels of transferrin receptors, iron influx in neurons, PgP Αβ clearance may be measured. These parameters may be measured using any test or assay known in the art for measuring energy metabolism and/or insulin resistance e.g., as described in Medhi and Chakrabarty, Neurol Sci (2013)34: 1719-1725 and/or Cholerton et al., European Journal of Pharmacology (2013)

2018101460 28 Sep 2018

719: 170-179. The levels and/or activities of each may be measured and compared to a standard known in the art. It will be apparent to a person skilled in the art whether or not a change in the level and/or activity is an indicator of risk for Alzheimer’s disease, MCI and/or dementia.

[0025] Cognitive function is measurable over any time-frame e.g., hours, days, weeks, months or years. Cognitive function which has not changed or has increased over one or more described time-frames, is considered to be maintained or improved in the adult subject, e.g., in any subject described herein. Cognitive function may also decline with increasing age in an adult subject. In this example, cognitive function is measured over longer timeframes, e.g., months or years in ageing subjects as described herein. The cognitive function is measured at two or more time points in an ageing subject. For example, the decline in cognitive function in an ageing subject may be measured between several months or several years to establish a rate of decline. The rate of decline may be compared to a standard known in the art taking into consideration the age of the subject. The rate of decline may also be compared to cognitive function that is then measured again in the same subject, after the subject has aged for a further period of months or years. Age-related decline is considered slowed if the rate of decline that is less compared to the standard or compared to a second measurement is less.

[0026] It will be apparent to the skilled artisan that since cognitive function may be measured, a time sufficient to maintain/improve cognitive function and/or slow the agerelated decline in cognitive function the adult subject may be determined as required. For example the time may be 1 month, or 2 months, or 3 months, or 4 months, or 5 months, or 6 months, or 7 months, or 8 months, or 9 months or 10 months, or 11 months, or 12 months. In another example, the time may be 1 to 2 years, or 2 to 4 years, or 4 to 6 years, or 6 to 8 years or 8 to 10 years, or greater than 10 year. It will also be apparent that the time of administration may be continued for the life of the adult subject.

[0027] Cognitive function may be measured using any test or assay known in the art for such purposes e.g., as described in Stough et al. Nutrition Journal 2012, 11:11. Cognitive function parameters include, but are not limited to, reasoning, decision making, attention span, problem solving, spatial abilities, perceptual-motor and/or cognitive speed, and/or memory. Cerebral energy metabolism is also correlated to cognitive function. Thus, a measure of cerebral energy metabolism may also be used as a parameter to indicate changes in cognitive function. For example, measuring cerebral energy metabolism

2018101460 28 Sep 2018 includes, but is not limited to measuring insulin levels, insulin function, glucose uptake and metabolism, insulin resistance and downstream effectors of the insulin resistance pathway in the brain e.g., as described in Medhi and Chakrabarty, Neurol Sci (2013) 34: 1719-1725 and/or Cholerton et al., European Journal of Pharmacology (2013) 719: 170-179. For example, the level and/or activity of PI3K/Akt and/or downstream effectors, glucose uptake and metabolism in the brain including intraneuronal and/or extraneuronal glucose, UDPGLcNAc, tau-O-GIcNAc, oxidative stress, advanced glycated end products (AGE) tau phosphorylation, levels of transferrin receptors, iron influx in neurons, PgP Αβ clearance may be measured. These parameters may be measured using any test or assay known in the art for measuring energy metabolism and/or insulin resistance e.g., as described in Medhi and Chakrabarty, Neurol Sci (2013) 34: 1719-1725 and/or Cholerton et al., European Journal of Pharmacology (2013) 719: 170-179. The levels and/or activities of a parameter described herein may be measured at a time-frame as described according to any aspect, embodiment and/or example herein. It will be apparent to a person skilled in the art whether or not a there is a significant change in the level and/or activity of any one or more parameters described according to any aspect, embodiment and/or example herein.

[0028] Positron emission tomography (PET), which is a nuclear medical imaging technique that produces a three-dimensional image or picture of functional processes in the body. PET may be used to measure cognitive function and/or a risk factor for Alzheimer’s disease, MCI and/or dementia as described according to any aspect, embodiment and/or example herein. For example, this may be achieved e.g., as described in Nasrallah and Dubroff, Semin Nucl Med 2013 November; 43(6):449-61. In one example, fluorodeoxyglucose (18-F) brain uptake is measured using PET (FDG-PET). FDG is an analogue of glucose. In FDG-PET, the concentrations of tracer imaged may be used to indicate tissue metabolic activity by virtue of the regional glucose uptake.

[0029] In a fifth aspect, the present invention provides a composition comprising an effective amount of a combination of:

2018101460 28 Sep 2018 to maintain/improve mood in an ageing subject and/or slow the age-related decline in the mood in an adult subject.

[0030] In a sixth aspect, the present invention provides a method for maintaining/improving mood in an ageing subject and/or slowing the age-related decline in mood of an adult subject comprising administering a combination of:

(i) one or more B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and (ii) phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof, in amounts and for a time sufficient to maintain/improve mood in an ageing subject and/or slow the age-related decline in the mood of an adult subject.

[0031] In a seventh aspect, the present invention provides use of an effective amount of a combination of:

(i) one or more B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and (ii) phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof, to maintain/improve mood in ageing subject and/or slow the age-related decline in the mood of an adult subject.

[0032] In an eighth aspect, the present invention provides a use of an effective amount of a combination of:

2018101460 28 Sep 2018 in the manufacture of a medicament, dietary/nutritional supplement, or nutraceutical for maintaining/improving mood in ageing subject and/or slowing the age-related decline in mood of an adult subject.

[0033] Ageing subjects includes any one or more of the described adult subjects that increase in age. Preferably, ageing subjects includes those adult subjects that are above the age of about 30 or more. Ageing subjects also includes elderly subjects. Preferably, the subjects are healthy adult subjects.

[0034] Mood may be measured using any test or assay known in the art for such purposes e.g., as described in Stough etal. Nutrition Journal 2012, 11:11. Mood parameters include, but are not limited to, depression, anxiety and general mood assessments e.g., happiness, excitement, sadness.

[0035] Mood is measurable over any time-frame e.g., hours, days, weeks, months or years. Mood which has not changed or has increased over one or more described timeframes, is considered to be maintained or improved in the adult subject. Mood may also decline with increasing age in an adult subject. In this example, mood may be measured over longer time-frames, e.g., months or years in ageing subjects as described herein. The rate of decline is measured at several time points in an ageing subject. For example, the decline in mood in an ageing subject may be measured between several months or several years to establish a rate of decline. The rate of decline may be compared to a standard known in the art taking into consideration the age of the subject. The rate of decline may also be compared to mood that is then measured again in the same subject, after the subject has aged for a further period of months or years. Age-related decline is considered slowed if the rate of decline that is less compared to the standard or compared to a second measurement is less.

[0036] It will be apparent to the skilled artisan that since mood may be measured a time sufficient to maintain/improve mood in an ageing subject and/or slow the age-related decline in the mood of an adult subject may be determined as required. For example the time may be 1 month, or 2 months, or 3 months, or 4 months, or 5 months, or 6 months, or 7 months, or 8 months, or 9 months or 10 months, or 11 months, or 12 months. In another example, the time may be 1 to 2 years, or 2 to 4 years, or 4 to 6 years, or 6 to 8 years or 8 to 10 years, or greater than 10 year. It will also be apparent that the time of administration may be continued for the life of the adult subject.

2018101460 28 Sep 2018 [0037] In a ninth aspect, the present invention provides a composition comprising an effective amount of a combination of:

(i) one or more B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and (ii) phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof, to reduce a risk marker of cardiovascular disease and/or a genetic marker and/or a biochemical marker associated with ageing in an adult subject.

[0038] In a tenth aspect, the present invention provides a method for reducing a risk marker of cardiovascular disease and/or a genetic marker and/or a biochemical marker associated with ageing in an adult subject comprising administering a combination of:

(i) one or more B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and (ii) phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof, in amounts and for a time sufficient to reduce a risk marker of cardiovascular disease and/or a genetic marker and/or a biochemical marker associated with ageing in an adult subject.

[0039] In an eleventh aspect, the present invention provides use of an effective amount of a combination of:

(i) one or more B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and (ii) phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof to reduce a risk marker of cardiovascular disease and/or a genetic marker and/or a biochemical marker associated with ageing in an adult subject.

[0040] In an twelfth aspect, the present invention provides use of an effective amount of a combination of:

2018101460 28 Sep 2018 (i) one or more B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and (ii) phosphatidylserine, alternative form(s), derivative(s), or combinations thereof, or source(s)thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof in the manufacture of a medicament, dietary/nutritional supplement, or nutraceutical for reducing a risk marker of cardiovascular disease and/or a genetic marker and/or a biochemical marker and/or a biochemical marker associated with ageing in an adult subject.

[0041] Risk markers of cardiovascular disease associated with ageing in an adult subject may be measured using any test or assay known in the art for such purposes e.g., as described in Stough et al. Nutrition Journal 2012, 11:11. Risk markers are measurable over any time-frame e.g., hours, days, weeks, months or years. A reduction in the presence of one or more risk markers, and/or a reduction in the level of one or more risk markers measured over a time-frame are considered a reduction in the risk markers. Risk markers include, but are not limited to, brachial pressures, aortic pressures and carotid-femoral Pulse Wave Velocity, cardiovascular risk markers associated with Alzheimer’s disease and/or dementia known in the art e.g., as described in Table 1.

[0042] Genetic risk markers associated with ageing in an adult subject may be measured using any test or assay known in the art for such purposes e.g., as described in Stough et al. Nutrition Journal 2012, 11:11. For example, telomere length is measurable over any timeframe e.g., hours, days, weeks, months or years. Telomere shortening is a marker of genetic damage and associated with ageing. Reduced telomere shortening measured over a timeframe is considered a reduction in a genetic risk marker.

[0043] Biochemical risk markers associated with ageing in an adult subject may be measured using any test or assay known in the art for such purposes e.g., as described in Stough et al. Nutrition Journal 2012, 11:11. Risk markers are measurable over any timeframe e.g., hours, days, weeks, months or years. A change in the presence of one or more risk markers, and/or a change in the level of one or more risk markers measured over a time-frame are considered a reduction in the risk markers, depending on the risk marker. Risk markers include, but are not limited to, glycated haemoglobin, insulin levels, blood glucose levels, markers of oxidative stress, markers of inflammation, C-reactive protein, F2Isoprostanes, inflammatory cytokines including, but not limited to, TNF-alpha, IL-2, IL-4, IL-6,

2018101460 28 Sep 2018

IL-10, and IFN-gamma, liver function tests, and biochemical risk markers associated with

Alzheimer’s disease and/or dementia known in the art e.g., as described in Table 1.

[0044] It will be apparent to the skilled artisan that since risk markers may be measured a time sufficient to a reduce risk marker of cardiovascular disease and/or a genetic marker and/or a biochemical marker associated with ageing in an adult subject may be determined as required. For example the time may be 1 month, or 2 months, or 3 months, or 4 months, or 5 months, or 6 months, or 7 months, or 8 months, or 9 months or 10 months, or 11 months, or 12 months. In another example, the time may be 1 to 2 years, or 2 to 4 years, or 4 to 6 years, or 6 to 8 years or 8 to 10 years, or greater than 10 year. It will also be apparent that the time of administration may be continued for the life of the adult subject.

[0045] The B vitamins of any aspect and/or example described herein may comprise any one or more of B vitamins including Bi, B2, B3, B₅, Ββ, B₇, Bg, B12. In one example, one or more B vitamins are combined with phosphatidylserine. In another example, one or more B vitamins are combined with lipoic acid. In another example, one or more B vitamins are combined with phosphatidylserine and lipoic acid. Preferably, the B vitamins comprise any one or more of vitamins Ββ, Bg and/or B12. In one example, vitamin Βθ is included in any aspect of the invention. In another example, vitamin Bg is included in any aspect of the invention. In another example vitamin B12 is included in any aspect of the invention. In another example, vitamins Ββ, and Bgare included in any aspect of the invention. In another example, vitamins Ββ, Bgand B^are included in any aspect of the invention.

[0046] Any alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, of the B-Vitamins that are known to the skilled artisan are also contemplated. Alternative forms include vitamers. As used herein, the alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, includes known biologically active forms and/or have measurable activity as described in any known assay used in the art to measure the function of B vitamins.

[0047] For example, any one or more vitamin Βθ may include, but is not limited to pyridoxine, pyridoxal, pyridoxamine, pyridoxine 5’-phosphate, pyridoxal 5’-phosphate, and pyridoxamine 5’-phosphate, or other alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof.

2018101460 28 Sep 2018 [0048] For example, any one or more of vitamin Bg, may include, but is not limited to folate, folic acid (folate, vitamin M, vitamin B9, vitamin Be (or folacin), pteroylglutamic acid), or dihydrofolate, tetrahydrofolate, 5-methyltetrahydrofolate (L-methylfolate) or other alternative form(s), derivative(s), or salt(s) thereof (such as the calcium salt of L-5methyltetrahydrofolate) or other alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof.

[0049] For example, any one or more form of vitamin B12 (C63H88CON14O14P) may include, but is not limited to cyanocobalamin, methylcobalamin, hydroxocobalamin, adnenosylcobalamin, or other alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof. Any one or more of the B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof used in the preparation of any aspect and/or example of the invention may be anhydrous, or non-anhydrous.

[0050] The B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof described herein may be obtained from commercially available sources and/or prepared or derived e.g., from foodstuffs according to methods known in the art. For example, B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof may be derived from unprocessed foods such as, meat, turkey and tuna, liver and meat products, kombucha, whole grains, potatoes, bananas, lentils, chili peppers, tempeh, beans, nutritional yeast, brewer's yeast, and molasses. The B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof may also be chemically synthesized. It will also be apparent to the skilled artisan that any extract or foodstuff rich in B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, may also be used.

[0051] The phosphatidylserine (Ptd-L-Ser or PS) of any aspect and/or example described herein may be used in pure or purified form from commercially available sources and/or chemically synthesized and/or prepared from PS rich sources, e.g., bovine brain and/or soy bean or combinations thereof, or it may also be provided in the form of an extract or foodstuff rich PS. Any alternative form(s), derivative(s), or salt(s) thereof, of PS that are known to the skilled artisan are also contemplated. As used herein, the alternative form(s), derivative(s), salt(s) thereof, or combinations thereof, includes known biologically active forms and/or have measurable activity as described in any known assay used in the art to measure the function and/or activity of PS. Without limitation, an example of an alternative form of PS includes conjugated phoshpatidylserine-omega-3 compound.

2018101460 28 Sep 2018 [0052] Due to the occurrence of Bovine spongiform encephalopathy (BSE) commonly known as mad-cow disease, alternative sources of PS are preferable, e.g., soy derived PS.

However, it will also be apparent to the skilled artisan that bovine derived PS may also be used, should such bovine derived PS be found risk-free from BSE pathogen and/or safe for human consumption.

[0053] The lipoic acid (5-(1,2-dithiolan-3-yl)valeric acid), includes α-lipoic acid (ALA), thioctic acid or 6,8-Dithioctanoic acid. The lipoic acid of any aspect and/or example described herein may include one or a mixture of both enantiomers (R)-(+)-lipoic acid (RLA) or (S)-(-)-lipoic acid (SLA) at various concentrations including a racemic mixture (R/S)-lipoic acid (R/S-LA). Any one or more of these forms of lipoic acid may be used in pure or purified form from commercially available sources and/or chemically synthesized and/or prepared from ALA rich sources e.g., kidney, heart, liver, spinach, broccoli, and yeast extract or combinations thereof, or lipoic acid may also be provided in the form of an extract or foodstuff rich in lipoic acid. Commercially available forms include, but are not limited to, dihydrolipoic acid and salts thereof. Any alternative form(s), derivative(s), or salt(s) thereof, of lipoic acid that are known to the skilled artisan are also contemplated. As used herein, the alternative form(s), derivative(s), salt(s) thereof, or combinations thereof, includes known biologically active forms and/or have measurable activity as described in any known assay used in the art to measure the function and/or activity of lipoic acid. Examples of biologically active forms of lipoic acid include lipoate.

[0054] Use of the (R)-(+)-lipoic acid (RLA) enantiomer and/or salts thereof in any aspect and/or example described herein is preferred.

[0055] The composition of the invention or the combination of B-vitamins and PS and/or lipoic acid according to any aspect and/or example described herein may be administered by any suitable route. The B-vitamins according to any aspect and/or example described herein may be administered separately, simultaneously or sequentially, in any order with the PS and/or lipoic acid according to any aspect and/or example described herein. The preferred route of administration is oral. The composition of the invention or the combination of Bvitamins and PS and/or lipoic acid according to any aspect and/or example described herein may be administered as a supplement in daily meals or beverages. Administration may also include in a pharmaceutical unit dosage form such as pills, tablets, caplets, tabsules or capsules, for better control of dosing and subject compliance. The composition of the invention or the combination of B-vitamins and PS and/or lipoic acid or the unit dosage form

2018101460 28 Sep 2018 according to any aspect and/or example described herein may be administered once, or twice or three times or 4 times a day. Preferably, administration is 1 or 2 times daily.

Preferably, administration is twice daily.

[0056] For example, an effective amount of the combination or an administration dosage according to the invention may include about 1 pg to about 200 mg of each B vitamin, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In one example, the effective amount or the administration dosage includes about 100 pg to about 5 mg of vitamin Bg, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 200 pg to about 5 mg of vitamin Bg, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 400 pg to about 5 mg of vitamin Bg, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 800 pg to about 5 mg of vitamin Bg, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 1.6 mg to about 5 mg of vitamin Bg, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 3.2 mg to about 5 mg of vitamin Bg, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. For example, the effective amount or the administration dosage includes about 100 pg, or about 150 pg, or about 200 pg, or about 250 pg, or about 300 pg, or about 350 pg, or about 400 pg, or about 450 pg, or about 500 pg, or about 550 pg, or about 600 pg, or about 650 pg, or about 700 pg, or about 750 pg, or about 800 pg, or about 850 pg , or about 900 pg , or about 950 pg, or about 1.0 mg, or about 1.1 mg, or about 1.3 mg, or about 1.4 mg, or about 1.5 mg, or about 1.6 mg, or about 1.7 mg, or about 1.8 mg, or about 1.9 mg, or about 2.0 mg, or about 2.2 mg, or about

2.4 mg, or about 2.8 mg, or about 3.0 mg, or about 3.2 mg, or about 3.4 mg, or about 3.8 mg, or about 4.0 mg, or about 4.2 mg, or about 4.4 mg, or about 4.8 mg, or about 5.0 mg of vitamin Bg, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof,

2018101460 28 Sep 2018 and/or source(s) thereof described in any aspect and/or example of the invention. Preferably, the effective amount or the administration dosage includes about 200 pg of vitamin Bg, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. Administration may be once, or twice or three times or 4 times a day. Preferably, administration is twice daily. The effective amount as described herein may be in the form of a single unit dosage. The effective amount, or the single unit dosage may be administered once, twice or three times or 4 times a day. Preferably, the effective amount, or the single unit dosage is administered twice daily.

[0057] In another example, an effective amount of the combination or an administration dosage according to the invention includes about 1.2 pg to about 1.5 mg of vitamin B12, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 10 pg to about 1.5 mg of vitamin B12, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 25 pg to about

1.5 mg of vitamin B12, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 50 pg to about 1.5 mg of vitamin B12, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 100 pg to about 1.5 mg of vitamin B12, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 200 pg to about 1.5 mg of vitamin B12, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 400 pg to about 1.5 mg of vitamin B12, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 800 pg to about

1.5 mg of vitamin B12, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.

2018101460 28 Sep 2018

For example, the effective amount or the administration dosage includes about 1.2 pg, or about 1.5 pg, or about 2.0 pg, or about 2.5 pg, or about 3.0 pg, or about 3.5 pg, or about 4.0 pg, or about 4.5 pg, or about 5.0 pg, or about 5.5 pg, or about 6.0 pg, or about 6.5 pg, or about 7.0 pg, or about 7.5 pg, or about 8.0 pg, or about 8.5 pg , or about 9.0 pg , or about

9.5 pg, or about 0.1 mg, or about 0.2 mg, or about 0.3 mg, or about 0.4 mg, or about 0.5 mg, or about 0.6 mg, or about 0.7 mg, or about 0.8 mg, or about 0.9 mg, or about 1.0 mg, or about 1.1 mg, or about 1.2 mg, or about 1.3 mg, or about 1.4 mg, or about 1.5 mg of vitamin Bi2, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. Preferably, the effective amount or the administration dosage includes about 250 pg of vitamin B12, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. Administration may be once, or twice or three times or 4 times a day. Preferably, administration is twice daily. The effective amount as described herein may be in the form of a single unit dosage. The effective amount, or the single unit dosage may be administered once, twice or three times or 4 times a day. Preferably, the effective amount, or the single unit dosage is administered twice daily.

[0058] In another example, an effective amount of the combination or an administration dosage according to the invention includes about 0.75 mg to about 200 mg of vitamin Ββ, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 1.5 mg to about 200 mg of vitamin Ββ, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 3 mg to about 200 mg of vitamin Ββ, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 6 mg to about 200 mg of vitamin Ββ, o_r alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 12 mg to about 200 mg of vitamin Ββ, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 25 mg to about 200 mg of vitamin Ββ, or alternative

2018101460 28 Sep 2018 form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 50 mg to about 200 mg of vitamin Ββ, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 100 mg to about 200 mg of vitamin Ββ, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. For example, the effective amount or the administration dosage includes about 0.75 mg, or about 1 mg, or about 5 mg, or about 10 mg, or about 11 mg, or about 12 mg, or about 13 mg, or about 14 mg, or about 15 mg, or about 16 mg, or about 17 mg, or about 18 mg, or about 19 mg, or about 20 mg, or about 25 mg, or about 30 mg, or about 35 mg, or about 40 mg, or about 45 mg, or about 50 mg, or about 55 mg, or about 60 mg, or about 65 mg, or about 70 mg, or about 75 mg, or about 80 mg, or about 85 mg, or about 90 mg, or about 95 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg, or about 180 mg, or about 200 mg of vitamin Ββ, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. Preferably, the effective amount or the administration dosage includes about

12.5 mg of vitamin Ββ, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. Administration may be once, or twice or three times or 4 times a day. Preferably, administration is twice daily. The effective amount as described herein may be in the form of a single unit dosage. The effective amount, or the single unit dosage may be administered once, twice or three times or 4 times a day. Preferably, the effective amount, or the single unit dosage is administered twice daily.

[0059] For example, an effective amount of the combination or an administration dosage according to the invention may include about 1 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 5 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 10 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described

2018101460 28 Sep 2018 in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 20 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 50 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 100 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 200 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 400 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 800 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. For example, the effective amount or the administration dosage includes about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 9 mg, or about 10 mg, or about 11 mg, or about 12 mg, or about 13 mg, or about 14 mg, or about 15 mg, or about 16 mg, or about 17 mg, or about 18 mg, or about 19 mg, or about 20 mg, or about 21 mg, or about 22 mg, or about 23 mg, or about 24 mg, or about 25 mg, or about 26 mg, or about 27 mg, or about 28 mg, or about 29 mg, or about 30 mg, or about 35 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg, or about 150 mg, or about 200 mg, or about 250 mg, or about 300 mg, or about 350 mg, or about 400 mg, or about 450 mg, or about 500 mg, or about 550 mg, or about 600 mg, or about 650 mg, or about 700 mg, or about 750 mg, or about 800 mg, or about 850 mg, or about 900 mg, or about 950 mg, or about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. Preferably, the effective amount or the administration dosage includes about 25 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect

2018101460 28 Sep 2018 and/or example of the invention. Administration may be once, or twice or three times or 4 times a day. Preferably, administration is twice daily. The effective amount as described herein may be in the form of a single unit dosage. The effective amount, or the single unit dosage may be administered once, twice or three times or 4 times a day. Preferably, the effective amount, or the single unit dosage is administered twice daily.

[0060] For example, an effective amount of the combination or an administration dosage according to the invention may include about 50 mg to about 1200 mg of lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 100 mg to about 1200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 150 mg to about 1200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 200 mg to about 1200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 400 mg to about 1200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 600 mg to about 1200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 800 mg to about 1200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 1000 mg to about 1200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. For example, the effective amount or the administration dosage includes about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg

2018101460 28 Sep 2018 about 400 mg, or about 425 mg, or about 450 mg, or about 475 mg, or about 500 mg, or about 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, or about 625 mg or about 650 mg, or about 675 mg, or about 700 mg, or about 725 mg, or about 750 mg, or about 775 mg, about 800 mg, or about 825 mg, or about 850 mg, or about 875 mg, or about

900 mg, or about 925 mg, or about 950 mg, or about 975 mg, or about 1000 mg of lipoic, or about 1100 mg, or about 1200 mg alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. Preferably, the effective amount or the administration dosage includes about 150 mg of lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. Administration may be once, or twice or three times or 4 times a day. Preferably, administration is twice daily. The effective amount as described herein may be in the form of a single unit dosage. The effective amount, or the single unit dosage may be administered once, twice or three times or 4 times a day. Preferably, the effective amount, or the single unit dosage is administered twice daily.

[0061] In another example, an effective amount of the combination or an administration dosage according to the invention may include the ratio of about 1:1.9:11.5 respectively of Bvitamins alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof to phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof to lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In this example, the B-vitamins are in a ratio of about 1: 1 to 2.0: 20 to 65 respectively of vitamin B9 to vitamin B12 to vitamin B6. For example, the B-vitamins are in a ratio of about 1: 1.25: 62.5 respectively of vitamin B9 to vitamin B12 to vitamin B6.

[0062] In another example, an effective amount of the combination or an administration dosage according to the invention may include the ratio of about 1:1.0 to 2.0 :10 to 20 respectively of B-vitamins alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof to phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof to lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In this example, the B-vitamins are in a ratio of about 1: 1 to 2.0: 20 to 65 respectively of vitamin B9 to

2018101460 28 Sep 2018 vitamin B12 to vitamin B6. For example, the B-vitamins are in a ratio of about 1: 1.25: 62.5 respectively of vitamin B9 to vitamin B12 to vitamin B6.

[0063] The composition of the invention or the combination of B-vitamins and PS and/or lipoic acid, or the unit dose according to any aspect and/or example described herein may be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, intrathecal, intraperitoneal, intranasal and buccal. Depending on the intended route of delivery, the compounds are preferably formulated as either oral, injectable or topical compositions. For example, oral formulation may be a conventional tablet or capsule form. In another example, the composition of the invention or the combination of B-vitamins and PS and/or lipoic acid according to any aspect and/or example described herein may be formulated e.g., as a pharmaceutical, nutraceutical, nutritional supplement and/or dietary supplement. Optionally, the formulation comprises one or more pharmaceutically acceptable carriers or excipients suitable for each formulation. It will be apparent to the person skilled in the art as to which excipients may be used for each formulation.

[0064] Unless the context clearly requires otherwise, throughout the description and the claims, the words ‘comprise’, ‘comprising’, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

[0065] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.

[0066] Each aspect of the invention described herein is to be applied mutatis mutandis to each and every aspect unless specifically stated otherwise.

[0067] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features.

2018101460 28 Sep 2018 [0068] The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionallyequivalent products, compositions and methods are clearly within the scope of the invention, as described herein.

Detailed Description of Preferred Embodiments [0069] Until the present invention, safe, cheap therapies e.g., nutritional supplements that maintain or improve cognitive ability or slow the decline of cognitive function in individuals with MCI or AD or healthy elderly individuals have not been effective. In work leading up to the present invention, the inventors reasoned that any form of therapy for AD, dementia and/or treating ageing in elderly patients should be multifaceted i.e. rely on a multiple therapeutic target approach, rather than a narrow therapeutic target as is the case with anticholinesterase inhibitors for AD. It was reasoned that a combination treatment and/or composition may be able to address the multi therapeutic approach.

[0070] Treatments directed to cognitive function had the common occurrence of at least folic acid and usually all three major vitamins that are involved in the One Carbon Cycle. Whilst the therapeutic benefits of these vitamins have been linked to aberrant homocysteine levels, the inventors reasoned that it is possible that factors within the One Carbon Cycle affected by the B vitamins are even more important and that homocysteine is a possible noncausal marker. In seeking alternative, cost-effective treatments, the inventors sought to combine B vitamins with other supplements that may enhance the effect of B vitamins and considered lipoic acid and/or PS.

[0071] Without being bound by any particular theory, the inventors reasoned that many trials have measured total homocysteine whereas blood homocysteine exists in a redox form i.e. oxidized homocysteine (HcyO) and reduced homocysteine (HycR). A high ratio of HcyO/HcyR indicates an impaired antioxidant condition. Lipoic acid is known to chelate redox-active transition metals, inhibiting the formation of hydrogen peroxide and hydroxyl radicals, to scavenge reactive oxygen species (ROS), increasing the level of reduced glutathione, down-regulating inflammatory processes, to scavenge lipid peroxidation products and to induce the enzymes of glutathione synthesis and other antioxidant protective enzymes.

2018101460 28 Sep 2018 [0072] Studies have shown that phosphatidylserine (PS) can reduce blood cortisol levels and/or to enhance cognitive function. Bovine brain is a rich source of PS and has been used in a number of trials for reducing cortisol levels. However, much of the recorded trials were halted after the occurrence of Bovine spongiform encephalopathy (BSE) commonly known as mad-cow disease, in the 1980’s and 1990’s. Thus, alternative sources of PS were sought from soybean. Soy derived PS differs considerably from Bovine PS mainly in the absence of docosahexaenoic acid (DHA). Despite a number of trials using plant-source derived PS with some positive results (Schreiber S et al. Isr J Psychiatry Relat Sci. 2000;37:302-307; KatoKataoka A et al. J Clin Biochem Nutr. 2010;47:246-255), another clinical trial of soybeanderived PS in 120 aging subjects aged > 57 years who fulfilled the more stringent criteria for age-associated memory impairment (AAMI), demonstrated no significant differences were found in any of the outcome variables between the treatment groups (Jorissen BL et al. Nutr Neurosci. 2001;4:121-134). Thus, there remains a need for safe alternative forms of PS that are effective for use in improving cognitive function.

[0073] For a better understanding of the invention and to show how it may be performed, embodiments thereof will now be described, byway of non-limiting example only.

EXAMPLE 1

By way of example, compositions of the invention according to the following formulae and dosage are prepared using standard procedures known in the art. For example, compositions of the invention are prepared as oral nutritional supplements.

Formula 1- Dosage: Two tablets per day

Active	Amount per unit dosage eg. 1 tablet
Folic acid (anhydrous)	200 pg
Vitamin B12	250 pg
Vitamin B6	12.5mg
Phosphatidylserine	25mg
RS-alphaLipoicacid	150mg

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Formula 2- Dosage: Two tablets per day

Active	Amount per unit dosage eg. 1 tablet
Folic acid (anhydrous)	200 pg
Vitamin B12	250 pg
Vitamin B6	12.5mg
Phosphatidyl serine	25mg

Formula 3- Dosage: Two tablets per day

Active	Amount Der unit dosaae ea. 1 tablet
Folic acid (anhydrous)	200 pg
Vitamin B12	250 pg
Vitamin B6	12.5mg
RS-alphaLipoicacid	150mg

Formula 4- Dosage: Two tablets per day

Active	Amount per unit dosage eg. 1 tablet
Folic acid (anhydrous)	200 pg
Vitamin B12	250 pg
Vitamin B6	12.5mg
Phosphatidyl serine	25 to 125 mg

2018101460 28 Sep 2018

Formula 5- Dosage: Two tablets per day

Active	Amount per unit dosage eg. 1 tablet
Folic acid (anhydrous)	200 pg
Vitamin B12	250 pg
Vitamin B6	12.5mg
RS-alpha Lipoic acid	150-200mg

Formula 6- Dosage: one tablet per day

Active	Amount per unit dosage eg. 1 tablet
Folic acid (anhydrous)	400 pg
Vitamin B12	500 pg
Vitamin B6	25 mg
Phosphatidylserine	50 mg
RS-alpha Lipoic acid	300 mg

Formula 7- Dosage: One tablets per day

Active	Amount per unit dosage eg. 1 tablet
Folic acid (anhydrous)	400 pg
Vitamin B12	500 pg
Vitamin B6	25 mg
Phosphatidylserine	50 mg

2018101460 28 Sep 2018

Formula 8- Dosage: One tablet per day

Active	Amount Der unit dosaae ea. 1 tablet
Folic acid (anhydrous)	400 pg
Vitamin B12	500 pg
Vitamin B6	25 mg
RS-alpha Lipoic acid	300 mg

Formula 9- Dosage: one tablet per day

Active	Amount Der unit dosaae ea. 1 tablet
Folic acid (anhydrous)	400 pg
Vitamin B12	500 pg
Vitamin B6	25 mg

EXAMPLE 2

By way of example, each active of the combination of one or more B vitamins and phosphatidylserine and/or lipoic acid as described in Example 1 is formulated for oral administration according to standard procedures in the art, wherein each active is in a single unit dosage form and whereby each single unit dosage form is administered either simultaneously or sequentially. In the case of twice daily dosage, these are administered either simultaneously, or sequentially, or once in the morning and once in the evening.

EXAMPLE 3 [0074] A four-arm clinical trial is performed by the Brain Sciences Institute (Melbourne) to determine whether 12 months, 18 months and/or 24 months administration of the composition, or a formulation comprising the same according to any aspect or example described herein, improves cognitive functioning in healthy elderly persons aged between 60

2018101460 28 Sep 2018 and 75 years. For example, any one or more of the formulae in Example 1 is administered for the described period, and/or any of the doses according to Example 2 is administered for the described period. One arm of the clinical trial comprises subjects that receive placebo. One or more further clinical trials may be performed by administering the composition, or the formulation comprising the same for any length of time and in any subject as described according to any aspect or example herein.

[0075] The following cognitive batteries and tasks are used as primary outcome measures of the clinical trials. These measures are administered at all time points (e.g., baseline, 3, 6, 9, 12, 18 and/or 24 months).

-Cognitive Drug Research Computerized Battery

-Swinburne University Computerized Cognitive Assessment Battery

-Inspection Time Task

-Cognitive Demand Battery -Mini Mental State Examination - Hick Reaction Time Paradigm

Cognitive Drug Research Computerised Battery [0076] The CDR Computerized Cognitive Assessment System is used to measure the cognitive effects of the treatments. A tailored version of the battery is used, similar to that which has previously been found to be sensitive to improved cognitive function as a consequence of ingestion of numerous nutraceuticals. The selection of computer controlled tasks from the system is administered with parallel forms of the tests being presented at each testing session. Presentation is via colour monitors on laptops, and, with the exception of written word recall tasks all responses are recorded via two-button (YES/NO) response boxes. The word recall tasks are performed with pen and paper, and the Tracking task is performed with a joystick. The entire selection of tasks takes approximately 25-30 minutes.

[0077] The tasks are presented in the following order: Immediate Word Recall, Picture Presentation, Simple Reaction Time, Digit Vigilance, Choice Reaction Time, Spatial Working Memory, Numeric Working Memory, Delayed Word Recall, Word Recognition, Picture Recognition, Rapid Visual Information Processing and the Bond-Lader VAS of Mood and Alertness (Bond and Lader, 1974).

2018101460 28 Sep 2018

Swinburne University Computerised Cognitive Assessment Battery (SUCCAB) [0078] The SUCCAB is a battery of screen-based cognitive tasks used to measure cognitive processes that have been found to most likely decline with age. As some cognitive tasks have a motor or decision time component, simple and complex reaction time tasks are also included in the test battery to control for such effects. The tasks forming the battery are described below:

Stroop Colour-Word [0079] The test consists of two congruent and two incongruent trials, presented alternately. Stimulus words are randomly presented (RED, BLUE, GREEN, and YELLOW) in either congruent or incongruent colours for 1.7-seconds, with an ISI of 0.5-seconds. Participants respond by pressing one of four buttons corresponding to the colour of the word, irrespective of what the word reads. This task is used as a measure of executive function and more specifically inhibition; participants are required to inhibit the automatic reading response.

Spatial Working Memory [0080] In each trial participants are presented with a 4 x 4 white grid on a black background, with six grid positions containing white squares. Participants are given 3 seconds to remember where the white squares are located. The grid becomes blank and a series of four white squares are sequentially displayed in various grid positions for 2seconds each. Participants respond with a yes/no response to indicate whether each square matches a position that is originally filled. In total, participants complete 14 trials, each of which is separated by a blank screen displayed for 2-seconds. Each trial is set such that two out of the four locations in the response series correspond to the original grid locations, and two do not. The task requires participants to hold spatial information in a store that has previously been described as working memory.

Contextual Memory [0081] A series of 20 everyday images are presented at the top/bottom/left/right of the screen for 3-seconds each with no ISI. On completion of the series the same images are displayed again in randomised order in the centre of the screen for 2-seconds each with no ISI. Participants respond with a top/bottom/left /right button press to indicate the original

2018101460 28 Sep 2018 location of each image. This task requires participants to recall the spatial context of the original presentation and is used as a measure of episodic memory.

Immediate/Delayed Recognition [0082] Participants are asked to study a series of 40 abstract images presented serially in the centre of the screen for 3-seconds each with no ISI. On completion, another series of images is presented, half of which are from the studied series and half are new (Immediate condition). Participants indicate with a right (yes) or left (no) button press whether or not they recognise the image from the studied series. This task is repeated at the end of the testing session with the remaining 20 images from the studied series and another 20 new images (Delayed condition). Because abstract patterns are difficult to verbalise, the task can be described as a measure of non-verbal recognition memory.

Inspection Time Task [0083] In addition, the Inspection Time task is administered to assess speed of information processing. This task assesses the presentation time that a subject requires to discriminate between two possible stimuli. The task consists of a stimulus with two vertical parallel lines joined at the top by a horizontal line. There are two versions of the stimulus; either the left line is shorter than the right or the right line is shorter than the left. Stimuli are flashed on a computer screen and the participant is instructed to press a key corresponding to the side of the symbol that is shorter. Each stimulus presentation is followed by the presentation of a backward visual mask. This prevents further processing of the stimulus in iconic memory. The speed of stimulus presentation is varied according to the accuracy of the participants’ responses. The length of presentation of the backward visual mask also varies to determine the optimal visual encoding time. The objective is to respond as accurately, rather than as quickly, as possible. The duration of stimulus presentation is varied until an 80% accuracy level is obtained by the participant. This is taken as the outcome measure for speed of visual information processing speed.

Cognitive Demand Battery

Mini-Mental State Examination (MMSE) [0084] The Mini-Mental State Examination (MMSE) (Folstein et al., 1975) is a brief 30point test that is commonly used to screen for dementia. The MMSE evaluates six areas of

2018101460 28 Sep 2018 cognitive function: orientation, attention, immediate recall, short-term recall, language, and the ability to follow simple verbal and written commands. The MMSE is divided into two sections. The first part requires vocal responses to the examiner's questions. The participant is asked to repeat a short phrase after the examiner; to count backward from 100 by 7s; to name the current season and similar brief items. It tests the participants' orientation, memory, and attention. The maximum score for this section is 21. In the second part of the examination, the participant is asked to follow verbal and written instructions, write a sentence spontaneously, and copy a geometric figure. The test is not timed but usually takes less than 10 minutes to complete.

Hick Reaction Time Paradigm [0085] An in-house version of the Hick Reaction Time Paradigm (Jensen’s Box) is administered to measure choice reaction time. The standard box has a sloping face on which 8 buttons are arrayed in a semicircle, with a 'home' key in the lower center. Above each response button lies a small led which can be illuminated, and the box contains a speaker to play alerting sounds. Several parameters can be extracted: The mean 1-choice reaction time (RT) gives simple reaction time. The slope of the function across 1,2,4, and 8 lights gives the rate of information processing; a variance or standard deviation in RTs can be extracted to give a measure of response variability within subjects.

Mood and health assessment [0086] Mood and health is assessed using the below questionnaires at all time points (e.g., baseline, 3, 6, 9, 12, 18and 24 months).

- Bond and Lader Visual Analogue Scales

-Profile of Mood Scales

-Short Form 36

- Beck Depression Inventory II

-The Spielberger State-Trait Anxiety Inventory

- Food Frequency Questionnaire

- Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire

- Chalder Fatigue Scale

- Leeds Sleep Evaluation Questionnaire

2018101460 28 Sep 2018

Bond and Lader Visual Analogue Scales [0087] Visual analogue scales is administered as part of the CDR system to assess selfreported mood. In total, 16 dimensions of mood are administered. The participant is required to mark, on a 100 mm line to what extent the described state is appropriate to him/her either at that moment in time (“right now”) or over the past week. The Bond and Lader VAS discriminates three affective dimensions: alertness, contentment, and calmness.

Profile of Mood States (POMS; McNair, Lorr, & Droppleman, 1992) [0088] The POMS is a self-report questionnaire designed to measure six dimensions of mood: tension-anxiety; depression-dejection; anger-hostility; vigour-activity; fatigue-inertia; and confusion-bewilderment. The POMS consists of 65 adjectives describing feeling and mood which is answered on a five-point Likert-type scale ranging from not at all to extremely. Respondents are asked to indicate mood reactions for the past week including today.

SF-36 (version 2) [0089] The SF-36 is a short-form health survey containing 36 questions. It yields an 8scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures and a preference-based health utility index. It will be used to assess changes in health and general well-being throughout the trial.

Beck depression Inventory-ll (BDI; Beck et al 1996) [0090] The BDI-II is a 21-item; self-report inventory designed to measure the severity of depressive symptoms. The BDI-II is one of the most widely used depression inventories in both clinical and research settings. The BDI-II asks participants to rate how they have felt over the past 2 weeks on a scale of 0 (no symptoms) to 3 (severe symptoms). Higher scores n the BDI-II indicates more severe depressive symptoms, with the maximum total score being 63. The BDI-II has adequate test-retest reliability and high internal consistency. Furthermore, the BDI-II has been demonstrated to have strong psychometric properties as an assessment tool among older adults in the general population (Segal et al 2008).

2018101460 28 Sep 2018

The Spielberger State-Trait Anxiety Inventory (STAI; Spielberger et al 1969) [0091] The STAI consists of two 20-item questionnaires, designed to measure general anxiety (Trait portion) and anxiety at the time of testing (State portion). EBm consumption has previously lead to a significant decrease in state anxiety using this measure (Stough et al 2001).

Chalder Fatigue Scale [0092] The Chalder fatigue Scale (Chalder et al., 1993) is completed by participants to assess physical and mental fatigue. The questionnaire consists of 14 items each rated on a 4-point likert scale. The Chalder Fatigue Sclae has good internal consistency.

Leeds Sleep Evaluation Questionnaire [0093] The Leeds Sleep Evaluation Questionnaire (Parrot & Hindmarch, 1978) is completed by all participants to retrospectively assess aspects of sleep including getting to sleep, quality of sleep, awake following sleep and behaviour following wakening. These four dimensions of sleep are assessed through 10 visual analogue scales.

Screening and baseline assessment [0094] Although not necessarily clinical endpoints, the following tests are used as screening instruments or to assess the participant’s baseline characteristics or function:

Mini-Mental State Examination (MMSE) [0095] The MMSE (Folstein et al., 1975) is a brief 30-point test that is used to screen for dementia. The MMSE evaluates six areas of cognitive function: orientation, attention, immediate recall, short-term recall, language, and the ability to follow simple verbal and written commands. The MMSE is divided into two sections. The first part requires vocal responses to the examiner's questions. The participant is asked to repeat a short phrase after the examiner; to count backward from 100 by 7s; to name the current season and similar brief items. It tests the participants' orientation, memory, and attention. The maximum score for this section is 21. In the second part of the examination, the participant is asked to follow verbal and written instructions, write a sentence spontaneously, and copy a geometric figure. The test is not timed but usually takes less than 10 minutes to complete.

2018101460 28 Sep 2018

Dementia Rating Scale II (DRS-II) [0096] The DRS-II is designed to assess the presence of or the progression towards dementia. Through the administration of 36 tasks and 32-stimulus cards, the DRS-II is a sensitive in differentiating levels of cognitive deficit. Consequently, the DRS-II is used to assess cognitive impairment and or dementia. The rater’s cognitive performance is evaluated with respect to scaled scores corrected for age and education as outlined in the manual. The DRS-II is a highly reliable and valid psychometric instrument. The DRS-II will be used to exclude participants with probable dementia.

Geriatric Depression Scale (GDS) [0097] The GDS (Yesavage et al. 1982) is a basic screening measure for depression suitable for elderly populations. Although the GDS cannot be used to diagnose clinical depression it provides insight into the severity of depressive symptoms experienced by the rater. The GDS sums 30 questions each of which are answered “yes” or “no”. A total score of 0-9 is considered normal, a score of 10-19 indicates mild depressive symptoms and a score of 20-30 indicates severe depressive symptoms. The GDS is a reliable and valid selfrating scale for assessing depressive symptoms in the elderly. The GDS will be used to exclude participants with severe depression.

General intelligence (IQ), Wechsler abbreviated scale of intelligence (WASI) [0098] Participants complete the vocabulary and matrix reasoning subsets of the Wechsler Abbreviated Scale of Intelligence (WASI). The vocabulary subtest is a 42-itemtask, which requires the examinee to orally define words that are presented visually and orally.

The matrix reasoning subtest shows a series of 35 incomplete grid patterns, which the examinee is asked to complete by pointing to, or stating, the correct pattern from five possible choices. The WASI is a reliable measure of intelligence for use in clinical and research settings.

Measurement of risk markers [0099] Any one or more risk markers, e.g., as described in Stough etal. Nutrition Journal 2012, 11:11 or in Table 1 herein are measured in the subjects of the trial. By way of illustrative example only, the following markers are measured.

2018101460 28 Sep 2018 [00100] Brachial pressures, aortic pressures, carotid-femoral Pulse Wave Velocity (PWV) and other cardiovascular risk markers is measured throughout the study. Measurements are conducted according to any standard method in the art. Baseline levels are determined prior to administration of the compositions or formulations to the subjects. Measurements are then repeated during the course of the trial, e.g., at 3 months, 6 months 12 months, 18 months and 24 months. A reduction in the level of one or more of these markers at each time-point relative to baseline indicates administration of the composition or formulation reduces cardiovascular risk markers.

[00101] Telomere shortening is a marker of genetic damage and associated with ageing. Telomere length is measured according to standard assays known in the art. Telomere length is assessed at baseline and at the end of the study, e.g., 12 months, 18 months or 24 months. Subjects receiving the composition or formulation are compared to controls receiving placebo. Blood is collected at baseline and at 12, 18 or 24 months. DNA is extracted and telomere length is measured according to standard protocols. Reduced telomere shortening in subjects receiving the composition or formulation compared to those receiving a placebo is considered a reduction in a genetic risk marker.

[00102] Glycated haemoglobin (HbA1c), blood glucose and insulin levels are measured prior to administration of the composition or formulation. Measurement of these markers provides an indication of glucoregulatory efficiency and control. Follow-up measurements are conducted at various time points throughout the study, e.g., weekly or monthly. Lower levels of blood glucose, insulin and HbA1c compared to baseline, or levels in the normal range are considered to be an indication of improved glucoregulatory efficiency and control, which contributes to improved age-related cognitive decline. At baseline and selected followup time-points, e.g., 3, 6, 12, 18, and 24 months, blood is collected and standard biochemical assays known in the art are performed to measure markers of oxidative stress, markers of inflammation e.g., C-reactive protein, F2-lsoprostanes, inflammatory cytokines including, but not limited to, TNF-alpha, IL-2, IL-4, IL-6, IL-10, and IFN-gamma, liver function tests. Measurements of inflammatory cytokines include a measure of cytokine levels, e.g., by ELISA or a measure of mRNA levels. A lower level of these cytokines compared to baseline indicates a lower level of inflammation in the subject after treatment.

[00103] Cerebral energy metabolism is also measured including insulin levels, insulin function, glucose uptake and metabolism, insulin resistance and downstream effectors of the insulin resistance pathway in the brain e.g., as described in Medhi and Chakrabarty, Neurol

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Sci (2013)34: 1719-1725 and/or Cholerton et al., European Journal of Pharmacology (2013) 719: 170-179. For example, the level and/or activity of PI3K/Akt and/or downstream effectors, glucose uptake and metabolism in the brain including intraneuronal and/or extraneuornal glucose, UDPGLcNAc, tau-O-GIcNAc, oxidative stress, advanced glycated end products (AGE) tau phosphorylation, levels of transferrin receptors, iron influx in neurons, PgP Αβ clearance is measured at baseline, and at 12, 18 or 24 months. These parameters are measured e.g., as described in Medhi and Chakrabarty, Neurol Sci (2013) 34: 1719-1725 and/or Cholerton et al., European Journal of Pharmacology (2013) 719: 1/ΟΙ 79.

Measurements using PET [0104] Positron emission tomography (PET), a nuclear medical imaging technique that produces a three-dimensional image or picture of functional processes in the body is used. PET is used to measure cognitive function and/or a risk factor for Alzheimer’s disease, MCI and/or dementia e.g., as described in Nasrallah and Dubroff, Semin Nucl Med 2013 November;43(6):449-61.

[0105] Glucose uptake and metabolism in the brain and metabolism is used an outcome measure of the clinical trials and may also be used to determine proof of concept early in the trial. A composition of the invention, or a formulation comprising the same according to any aspect or example described herein, is administered as described above in healthy elderly persons aged between 60 and 75 years. For example, any one or more of the formulae in Example 1 is administered for 12, 18 and/or 24 months, and/or any of the doses according to Example 2 is administered for 12, 18 and/or 24 months. One arm of the clinical trial comprises subjects that receive placebo. Glucose uptake and metabolism is measured at all time points (e.g., baseline, 3, 6, 9, 12, 18 and/or 24 months).

[0106] For example, at baseline, and selected follow-up time-points, e.g., 3, 6, 12, 18, and/or 24 months [18-F]-fluro-D-glucose is administered intravenously. Brain uptake is measured using PET (FDG-PET). Blood glucose concentration is measured before administration of the tracer to ensure that changes in glucose metabolism during FDG-PET are not due to differences in starting blood glucose levels but the intrinsic activity of the brain. At each time point, PET scanning and imaging is performed on the subject according to standard procedures e.g., as described in Nasrallah and Dubroff, Semin Nucl Med 2013 November;43(6):449-61. Brain scans are analysed to determine overall and regional areas

2018101460 28 Sep 2018 of glucose uptake and metabolism. It will be apparent to the skilled addressee where quantification of glucose metabolism in any area, or overall indicates maintenance/improvement in cognitive function or a slowing of the age-related decline in cognitive function. In particular, glucose metabolism in treated subjects is compared to baseline. Glucose metabolism in subjects receiving treatment is also compared to the placebo group. All measurements are compared and a determination is made whereby the maintenance and/or change in glucose metabolism is correlated with maintenance and/or improvement in cognitive function and/or a slowing of the age-related decline in cognitive function in the treated subjects.

Analysis [0107] The primary analysis investigates the effects of treatment on all cognitive outcomes over the course of the trial using Analysis of Variance (ANOVA) techniques. Other techniques may also be used, e.g., linear mixed modelling and intention to treat analysis. Similarly, effects of treatment on secondary outcomes are analysed. Pearson’s correlation coefficients are used to investigate whether any improvements in cognition are related to improvements in other variables e.g., biochemical, cardiovascular or mood/health factors and/or cerebral energy including glucose uptake. Correlations and regression models are used to examine baseline associations between variables. Results are considered statistically significant at p<0.05 corrected for multiple cognitive factors (primary outcome variables) or p<.05 for secondary outcome variables.

[0108] Covariates such as age, gender and baseline cognitive screening measures are adjusted for in the analyses. Results are presented as appropriate effect sizes with a measure of precision e.g., 95% confidence intervals. Compliance to treatment are determined by counting each of the trial subject’s remaining supplements after completion of the trial.

EXAMPLE 4 [0109] The Australian Research Council Longevity Intervention (ARCLI) led a research program aimed at a cohort of 60-75 year olds, measuring cognition (CDR; SUCCAB; IT, RT; Serial 3s and Serial 7s), as well as mood and well being, after intervention with a Blackmores’ micronutrient formulation (12.5 mg Vitamin B6, 200 ug Folic acid (Vitamin

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B9), 150 mg r,s-alpha Lipoic acid, 250 ug Vitamin B12 and 50 mg soy derived phosphatidylserine).

[0110] At a three month point in the research program, cognitive data for the CDR and SUCCAB batteries as well as for IT and RT scores were assessed in approximately 35 participants for CDR and around 50 for the SUCCAB and IT/RT measures.

[0111] Statistically significant or clinically relevant changes in cognition due to the Blackmores’ Micronutrient formulation over the placebo at 3 months were observed for the following cognitive processes:

Cbgnitive Measure	What does it measure?	Improvement due to Blackmores arm	P value
Immediate word recall # Correct	Long-Term Memory	Yes	.02
Immediate Word recall accuracy	Long-Term Memory	Yes	.06
Immediate word recall # errors	Long-Term Memory	Yes	.01
Simple Reaction time (ms)	Processing Sfceed	Yes	.07
Spatial WM RT	Immediate Memory	Yes	.08
Spatial WM Novel Stimulus RT	Immediate Memory	Yes	.05
Spatial WM Novel Stimulus RT	Immediate Memory	Yes	.08
Numeric WM Novel Stimulus Accuracy	Immediate Memory	Yes	.03
Numeric WM Novel Stimulus Accuracy	Immediate Memory	Yes	.07
Picture Recognition Original Stimulus Accuracy	Long-Term Memory	Yes	.08

Contextual Memory Accuracy	Long-Term Memory/ Attention	Yes	.08
Contextual Memory RT	Long-Term Memory/ Attention	Yes	.03
Delayed Recognition Memory Novel Stimuli RT	Long-Term Memory	Yes	.08
Serial 3 s	Immediate Memory	Yes	.08
Serial 7s	Immediate Memory	Yes	.03

2018101460 28 Sep 2018 [0112] The descriptive statistics for each cognitive factor were computed for the two treatment groups (Blackmore’s micronutrient combination versus placebo) independently for the tests conducted at baseline and after taking the treatment for three months. Similarly, difference scores for tests taken at these two times were calculated for each cognitive variable for both groups, with subsequent independent groups t-tests being run on each to determine if the means scores varied across groups. The main aim of these analyses was to obtain an indication of the general pattern of results displayed and hence provide insight into the potential effects of taking the Blackmore’s micronutrient combination, relative to those of a placebo, over a short period of time.

[0113] Table 1 presents the descriptive statistics for all cognitive variables of both treatment groups at baseline and 3 months into treatment duration. The mean score obtained on all cognitive measures was compared across treatment groups to obtain an indication of the general trends present within the data and whether or not they provided support for the use of the Blackmores micronutrient combination as a cognitive enhancement supplement.

Table 1

Descriptive statistics of all cognitive variables for both treatment groups at the baseline and 3 months test times

Measure	Variable	Treatment Group	M baseline	SD baseline	N baseline	M 3 months	SD 3 months	N 3 months
CDR	Immediate word recall # Correct	Blackmores	5.64	1.96	36	6.32	2.14	25
Placebo	5.89	1.55	35	5.45	1.37	22
Immediate Word recall accuracy	Blackmores	30.76	18.81	34	32.92	21.68	32
Placebo	33.50	16.96	41	25.81	18.44	31
Immediate word recall # errors	Blackmores	.67	1.04	36	.36	.70	25
Placebo	.34	.48	44	.59	.73	22
Simple Reaction time (ms)	Blackmores	300.13	42.29	46	298.12	46.51	35
Placebo	430.17	37.05	43	311.37	65.49	35
Digit	Blackmores	428.29	36.74	46	427.49	38.85	35

2018101460 28 Sep 2018

	Vigilance RT	Placebo	430.17	37.05	43	433.91	40.57	35
Digit Vigilance Accuracy	Blackmores	94.71	16.18	46	98.10	2.59	35
Placebo	91.66	23.41	43	98.22	3.04	36
Digit Vigilance False Alarms	Blackmores	2.29	5.55	46	1.34	1.57	35
Placebo	4.54	15.08	43	1.31	1.60	35
Choice RT	Blackmores	502.57	56.22	46	495.31	62.31	35
Placebo	512.42	25.22	43	506.37	64.35	35
Choice RT accuracy	Blackmores	97.14	9.16	46	97.89	2.27	35
Placebo	97.52	8.44	44	97.89	3.22	36
Spatial WM RT	Blackmores	1147.71	528.05	46	978.73	263.93	33
Placebo	1193.59	761.51	44	1192.77	474.95	36
Spatial WM Original Stimulus RT	Blackmores	1027.10	480.61	46	947.77	305.22	32
Placebo	1040.59	275.46	43	1254.98	495.51	36
Spatial WM Novel Stimulus RT	Blackmores	1147.20	444.70	46	999.47	231.95	33
Placebo	1223.52	768.43	42	1139.04	420.91	36
Spatial WM Original Stimulus Accuracy	Blackmores	87.09	19.29	46	85.45	29.06	34
Placebo	87.58	24.16	43	83.51	29.81	36
Spatial WM Novel Stimulus Accuracy	Blackmores	88.15	21.97	46	83.68	30.58	34
Placebo	87.07	25.42	44	83.75	26.28	36
Numeric WM RT	Blackmores	871.06	191.98	46	821.08	161.53	34
Placebo	912.50	12.08	44	913.28	181.56	36
Numeric WM Original Stimulus RT	Blackmores	815.48	163.00	46	775.23	154.49	34
Placebo	846.26	9.98	44	840.33	159.14	36
Numeric WM Novel Stimulus RT	Blackmores	925.90	226.30	46	866.94	176.35	34
Placebo	976.62	371.19	44	924.78	194.18	36

2018101460 28 Sep 2018

	Numeric WM Original Stimulus Accuracy	Blackmores	94.69	5.12	46	91.77	9.83	34
Placebo	93.49	231.15	44	94.09	6.67	36
Numeric WM Novel Stimulus Accuracy	Blackmores	96.91	5.67	46	94.51	8.11	34
Placebo	96.06	1.96	35	96.29	6.15	36
Delayed Word Recall # Correct	Blackmores	3.92	2.22	46	4.40	2.50	34
Placebo	4.09	14.16	37	3.68	1.57	19
Delayed Word Recall Accuracy	Blackmores	25.41	15.22	46	24.44	18.82	34
Placebo	25.77	.98	35	21.21	12.96	22
Delayed Word recall # Errors	Blackmores	.56	.81	46	.85	.81	34
Placebo	.60		44	1.05	1.08	19
Word Recognition RT	Blackmores	976.80	142.93	46	918.03	150.69	35
Placebo	1028.86	210.59	44	989.14	159.26	35
Word Recognition Original Stimulus RT	Blackmores	962.24	172.53	46	894.14	192.75	35
Placebo	978.81	210.47	44	978.16	228.80	35
Word Recognition Novel Stimulus RT	Blackmores	996.23	156.70	46	957.68	179.04	35
Placebo	1077.46	278.16	44	1002.86	163.85	35
Word Recognition Original Stimulus Accuracy	Blackmores	72.17	17.80	46	73.53	21.78	35
Placebo	87.58	12.58	44	73.14	14.32	35
Word Recognition Novel Stimulus Accuracy	Blackmores	88.26	11.52	46	89.90	15.28	35
Placebo	89.90	15.28	44	88.57	10.30	35
Picture	Blackmores	87.17	10.94	46	87.86	9.02	35

2018101460 28 Sep 2018

	Recognition Novel Stimulus Accuracy	Placebo	87.86	9.98	44	88.43	9.22	35
Picture Recognition Novel Stimulus RT	Blackmores	1153.87	385.66	46	1176.39	291.40	35
Placebo	1138.83	371.19	44	1237.30	288.22	35
Picture Recognition Original Stimulus Accuracy	Blackmores	92.39	8.22	46	90.71	9.17	35
Placebo	92.27	7.35	35	94.00	6.84	36
Picture Recognition Original Stimulus RT	Blackmores	1224.79	322.00	46	1121.14	234.50	35
Placebo	996.53	156.70	35	1106.55	233.00	36
Rapid Visual Information Processing RT	Blackmores	531.65	66.58	46	508.76	78.47	35
Placebo	549.79	64.24	35	543.90	78.26	36
Rapid Visual Information Processing Accuracy	Blackmores	48.32	21.02	46	45.64	23.86	35
Placebo	50.06	19.56	44	44.57	22.08	35
Rapid Visual Information Processing False Alarms	Blackmores	4.02	4.12	46	6.14	11.04	35
Placebo	7.05	8.44	44	10.31	18.18	35
Quality of Episodic Secondary Memory	Blackmores	192.41	50.95	38	188.22	53.77	35
Placebo	201.02	45.76	36	168.01	85.17	26
Quality of WM	Blackmores	1.64	.51	47	1.52	.70	35
Placebo	1.64	.52	44	1.55	.65	35
Power of Concentration	Blackmores	1204.81	208.50	47	1220.91	120.28	35
Placebo	1235.94	128.83	44	1216.04	256.42	35
Speed of Memory	Blackmores	4137.68	1050.36	47	3778.44	624.12	35
Placebo	4384.14	949.50	43	4140.83	970.81	35

2018101460 28 Sep 2018

	Continuity of Attention	Blackmores	80.15	35.18	47	91.74	3.05	35
Placebo	78.23	125.81	44	89.14	15.95	35
SUCCA B	Simple Recognition Memory Novel Stimulus Accuracy	Blackmores	62.37	17.76	59	62.27	20.49	47
Placebo	63.33	17.77	48	61.08	20.21	43
Simple Recognition Memory Novel Stimulus RT	Blackmores	1025.16	150.29	59	1033.61	141.41	47
Placebo	1052.57	113.98	48	1034.87	128.50	42
Simple Recognition Memory Original Stimulus Accuracy	Blackmores	59.55	22.62	59	62.41	19.13	47
Placebo	62.78	16.26	48	62.33	21.96	43
Simple Recognition Memory Original Stimulus RT	Blackmores	975.02	156.95	58	968.63	152.63	47
Placebo	954.95	113.98	48	971.22	129.73	42
Stroop Congruent Accuracy	Blackmores	96.57	5.59	59	97.02	5.65	47
Placebo	86.30	22.30	48	96.05	6.27	43
Stroop Congruent RT	Blackmores	779.82	115.71	59	771.86	112.55	47
Placebo	810.74	22.30	48	817.98	95.40	43
Stroop Incongruent Accuracy	Blackmores	90.08	19.68	60	92.34	15.26	47
Placebo	86.30	22.30	48	87.21	21.35	43
Stroop Incongruent RT	Blackmores	906.21	127.03	60	897.12	135.78	47
Placebo	962.01	15.15	48	979.98	128.71	43
Spatial WM Novel Stimuli Accuracy	Blackmores	71.19	18.87	60	76.90	18.21	47
Placebo	69.49	14.38	48	67.28	15.93	43

2018101460 28 Sep 2018

	Spatial WM Novel Stimuli RT	Blackmores	1022.52	123.12	59	1003.56	134.46	47
Placebo	1053.91	139.68	48	1058.65	120.55	43
Spatial WM Original Stimuli Accuracy	Blackmores	72.80	17.76	60	76.22	16.74	47
Placebo	69.12	20.60	48	69.19	18.00	43
Spatial WM Original Stimuli RT	Blackmores	943.27	153.93	60	928.44	149.87	47
Placebo	975.60	148.23	48	947.35	130.20	42
Contextual Memory Accuracy	Blackmores	68.58	18.53	60	71.70	17.76	47
Placebo	65.73	20.60	48	70.93	18.04	43
Contextual Memory RT	Blackmores	1053.22	122.22	60	1026.26	114.55	47
Placebo	1081.06	129.17	48	1070.26	146.57	43
Delayed Recognition Memory Novel Stimuli Accuracy	Blackmores	67.33	16.95	60	66.52	19.44	47
Placebo	73.52	13.65	48	66.20	19.32	43
Delayed Recognition Memory Novel Stimuli RT	Blackmores	1037.85	132.05	60	1057.07	135.53	47
Placebo	1081.06	129.17	48	1072.32	146.45	43
Delayed Recognition Memory Original Stimuli Accuracy	Blackmores	70.93	16.41	60	75.64	13.55	47
Placebo	73.52	13.65	48	76.62	17.06	43
Delayed Recognition Memory Original Stimuli RT	Blackmores	968.12	135.32	60	981.44	123.34	47
Placebo	991.38	105.73	47	976.64	121.16	42
Inspectio n Time		Blackmores	101.12	32.54	58	98.99	29.70	47
Placebo	97.29	30.56	48	101.86	43.06	43

2018101460 28 Sep 2018

Jenson 8	Choice Decision Time	Blackmores	422.15	61.50	54	419.56	49.02	47
Placebo	428.66	56.14	48	432.58	66.15	44
Choice Movement Time	Blackmores	773.91	93.25	54	779.26	88.89	47
	Placebo	771.61	94.50	48	797.55	126.22	44
Jenson 4	Choice Decision Time	Blackmores	387.33	47.10	54	386.27	45.29	47
Placebo	388.73	45.10	48	386.31	58.74	44
Choice Movement Time	Blackmores	702.00	85.80	54	706.57	95.69	47
Placebo	702.01	100.67	48	723.50	137.88	44
Jenson 2	Choice Decision Time	Blackmores	359.60	42.09	54	366.08	47.55	47
Placebo	374.47	51.51	48	369.91	59.03	44
Choice Movement Time	Blackmores	664.48	100.75	54	676.65	103.08	47
Placebo	673.78	103.14	46	697.35	142.30	44
Jenson 1	Choice Decision Time	Blackmores	333.52	46.63	53	342.33	50.79	45
Placebo	340.75	50.31	46	344.68	61.62	44
Choice Movement Time	Blackmores	620.01	99.31	53	637.67	114.72	45
Placebo	623.77	105.17	12	640.27	132.57	44
Serial 3	Subtraction, Average, RT	Blackmores	5473.39	3249.23	43	5083.24	2356.05	17
Placebo	5631.58	2877.48	46	5752.58	2230.53	19
Subtraction Accuracy	Blackmores	89.03	11.32	23	87.98	14.54	46
Placebo	86.65	18.16	12	87.36	14.32	44
Serial 7	Subtraction, Average, RT	Blackmores	7923.17	5224.63	23	6474.65	2604.56	17
Placebo	10502.42	8842.42	46	7654.37	3406.70	19
Subtraction Accuracy	Blackmores	84.24	14.16	57	74.37	24.11	46
Placebo	76.09	25.12	46	75.84	23.70	44

Note: RT = Reaction time (ms); WM = Working memory; Blackmores = Blackmores micronutrient supplement.

[0114] Participants receiving the Blackmores micronutrient supplement obtained scores indicative of better cognitive functioning, than the placebo group, after taking the supplement

2018101460 28 Sep 2018 for 3 months that wasn’t present at baseline on several measures, including: immediate word recall accuracy, spatial WM RT, Numerical WM original stimulus RT, delayed word recall, picture recognition novel stimuli accuracy, rapid visual information processing novel stimuli accuracy, congruent Stroop RT, spatial WM novel stimuli RT and spatial WM original stimuli RT. These results provide evidence for the use of the Blackmores supplement and as cognitive enhancer.

2018101460 28 Sep 2018

Claims

CLAIMS:

1. A method for maintaining/improving cognitive function and/or mood, and/or slowing age-related decline in cognitive function and/or mood of an adult subject comprising administering a composition consisting of:

(i) one or more B vitamins selected from the group consisting of vitamins Bi, B2, B3, B₅, Ββ, B₇, Bg, B12, or salt(s) thereof, and/or combinations thereof;

(ii) phosphatidylserine, or salt(s) thereof and/or phosphatidylserine-rich source(s);

(iii) lipoic acid, or salt(s) thereof; and (iv) one or more pharmaceutically acceptable carriers and excipients, and wherein the composition comprises:

a) about 50 pg to about 100 mg of each B vitamin or salt(s) thereof, and/or combinations thereof;

b) about 1 mg to about 200 mg of phosphatidylserine or salt(s) thereof; and

c) about 50 mg to about 500 mg of lipoic acid or salt(s) thereof.

2. Use of an effective amount of a composition consisting of:

(iii) lipoic acid, or salt(s) thereof; and (iv) one or more pharmaceutically acceptable carriers and excipients, in the manufacture of a medicament, dietary/nutritional supplement, or nutraceutical for maintaining/improving cognitive function and/or mood, and/or slowing age-related decline in cognitive function and/or mood of an adult subject;

wherein the medicament comprises:

b) about 1 mg to about 200 mg of phosphatidylserine or salt(s) thereof; and

c) about 50 mg to about 500 mg of lipoic acid or salt(s) thereof.

3. The method claim 1 or use of claim 2, wherein the composition is to be administered once or twice daily for 6 months, or for 12 months or for 24 months.

2018101460 28 Sep 2018

4. The method or the use of claim 3, wherein the adult subject is an elderly subject between the ages of about 50 to 65 years or about 60 to 75 years, or about 70 to 85 years, or about 80 to 95 years.

5. The method or the use of any one of the preceding claims, wherein the composition comprises vitamins Ββ, Bg and B12, the phosphatidylserine (Ptd-L-Ser or PS) selected from a purified form from bovine brain and/or soy bean or combinations thereof, an extract or foodstuff rich PS or conjugated phoshpatidylserine-omega-3 compound, and/or the lipoic acid (5-(1,2-dithiolan-3-yl)valeric acid), is selected from α-lipoic acid (ALA), thioctic acid and 6,8-Dithioctanoic acid.