Table of Contents
Some cognitive decline is normal with age. However, more significant cognitive decline is primarily due to disease-induced dementias (such as Alzheimer’s Disease). It also results from neurodegenerative disorders and chronic, prolonged degeneration of our neuronal pathways and functions.
Drug discovery for dementias have been largely unsuccessful, leaving no good treatments for this collection of diseases. This had led to research examining areas that may aid in preventing (or more accurately, slowing) cognitive decline.
In this episode the Sigma team look at the published data on a variety of nutrients, foods and dietary patterns, including: vitamin D, omega-3 fatty acids, B vitamins, caffeine, flavanoids, coffee and green leafy vegetables.
People in this Episode
Public Feed Time-stamps:
- [00:02:01] Definitions
- [00:08:40] What causes cognitive decline? Dementia? Mechanisms of ND pathogenesis.
- [00:11:33] Why might nutrition play a role?
- [00:18:18] Dietary patterns
- [00:26:30] Diet interaction with APOE genotype
- [00:31:18] Alcohol
- [00:36:36] Polyphenols – mechanisms
- [00:43:05] Coffee & Caffeine
- [00:45:03] Flavanoids
- [00:51:04] Vitamin D
- [01:04:22] Omega 3 fatty acids
- [01:21:42] B vitamins & green leafy veg
- [01:30:35] Vitamin E
- [01:38:24] How to assess cognitive health in ageing intervention studies
- [01:45:28] Concluding thoughts
Premium Feed Time-stamps:
- [00:01:01] Definitions
- [00:07:40] What causes cognitive decline? Dementia? Mechanisms of ND pathogenesis.
- [00:10:33] Why might nutrition play a role?
- [00:17:18] Dietary patterns
- [00:25:30] Diet interaction with APOE genotype
- [00:30:18] Alcohol
- [00:35:36] Polyphenols – mechanisms
- [00:42:05] Coffee & Caffeine
- [00:44:03] Flavanoids
- [00:50:04] Vitamin D
- [01:03:22] Omega 3 fatty acids
- [01:20:42] B vitamins & green leafy veg
- [01:29:35] Vitamin E
- [01:37:24] How to assess cognitive health in ageing intervention studies
- [01:44:28] Concluding thoughts
- [01:50:47] Key Ideas segment
- Episode 406: Polyphenols & Cognitive Health
- Episode 358: Coffee & Health
- Episode 276: Nick Gant, PhD – Neurometabolism: Brain Function, Fatigue & Nutritient Interventions
You can listen to the Key Ideas segment at 1:50:44 of the episode in your Premium feed.
First, a quick re-cap of the mechanisms mentioned in the episode:
- Cerebrovascular Blood Flow
- Blood Brain Barrier
- Oxidative Stress
- Secondary Vascular Protection/ Enhancement of Endothelial Functions
This episode explored the evidence on the status and intake of the following nutrients:
- Caffeine & Coffee
- Vitamin D
- B Vitamins (and green leafy vegetables)
- Omega 3
- Vitamin E
For details of both these mechanisms and the evidence relating to these nutrients, see the detailed study notes below.
Beyond the specifics of this episode, one key idea to remember is the problems with viewing neurodegenerative diseases through an entirely diet-centric perspective.
So we absolutely cannot say that a specific diet will guarantee you don’t develop a neurodegenerative disease, nor can we say that a diagnosis of such a disease is a result of someone’s food choice. We can’t think of diet as “preventing” a ND, but rather potentially modifying risk.
Not only is that type of commentary inaccurate (i.e. it stretches conclusions far beyond what current evidence would indicate) but it’s also damaging and stigmatizing. It’s laying blame at people’s feet, based on foods they did or didn’t eat, for a disease or set of symptoms that are largely driven by genetics and a series of other factors.
Now of course, this is to not say diet or nutrients don’t play a role. As we discussed in the episode, there is really interesting work that’s been done, with a lot of promise for certain dietary patterns or nutrients. And this should continue to be looked at. Diet matters for a range of health parameters.
But when it becomes the sole focus (for example, in quackish books like Grain Brain, which names carbohydrate and gluten as primary drivers of Alzheimer’s disease and other brain-related issues), then misleading and incorrect conclusions will likely occur.
Diet has a role to play, but even when better evidence comes along, that effect will likely still pale in significance to genetic, and even societal, factors.
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Detailed Study Notes
What is cognitive function? What is cognitive decline?
The term cognitive function refers to a variety of brain functions. It’s a wide range of mental abilities, e.g.:
- problem solving
- decision making
The American Psychological Association (APA) defines cognitive function as:
Cognitive function is “the performance of the mental processes of perception, learning, memory, understanding, awareness, reasoning, judgment, intuition, and language.”
While the APA defines cognitive decline as:
Cognitive decline is a ‘reduction in one or more cognitive abilities, across the adult lifespan.’ It’s a part of normal healthy ageing, but severe decline is not, and could be as a result of disease.
What causes cognitive decline?
Some cognitive decline is normal with age. The rate of decline is dependent on many factors, including genetics, environment and lifestyle.
However, more significant cognitive decline is primarily due to disease-induced dementias (such as Alzheimer’s Disease). It also results from neurodegenerative disorders and chronic, prolonged degeneration of our neuronal pathways and functions.
- These include conditions such as dementia, Parkinson’s disease and motor neuron disease.
- Due to the degenerative nature of the diseases, sufferers lose their ability to perform routine tasks, experience poor quality of life and a loss of autonomy.
In 2017, Public Health England reported dementia to be the leading cause of death in older adults in England; overtaking CVD, stroke and lung cancer for the first time. [The same was reported again in 2018 & 2019.]
Dementia risk is associated with:
- advancing age
- family history
- genetic factors (e.g. carriers of apolipoprotein E ɛ4 (APOE ɛ4) genotype).
Though several modifiable lifestyle risk factors have been identified that may preserve cognitive health including cardiovascular disease, diabetes, smoking and obesity.
Alzheimer’s Disease Pathogenesis
- There is a large body of evidence indicating that a cascade of events related to the faulty production, degradation and clearance of amyloid-β protein (Aβ).
- The imbalance between production and clearance results in excessive amounts of Aβ.
- This build-up of amyloid-β is believed to trigger a sequence of downstream, pathological changes such as:
- loss of synapses and neurons
- impaired glucose utilisation
- oxidative damage
- brain metabolic reduction
- associated neurofibrillary tangle formation
- amyloid-β deposition in plaques
- eventually neurotransmitter changes and widespread neurodegeneration.
- This sequence will continue throughout the course of the disease, which eventually results in cerebral damage, in turn causing the typical clinical feature of disease.
Current Treatments for Cognitive Decline & Neurodegenerative Diseases
Drug discovery for dementias such as Alzheimer’s disease have been fairly unsuccessful. No new drugs have been approved (FDA) since 2003 (some re-formulations have).
Despite massive financial investment (billions of dollars), there are over 100 failed studies.
- There are many reasons for these failures; e.g. low signal-to-noise and recruitment/retention.
Serge Gauthier et al. 2016 – Failed Drug Discovery for Alzheimer’s Disease and dementias
There are currently about 100 drugs targeting Alzheimer’s Disease in the pipeline in the USA with an additional 100 in development in the European Union. This includes targeting a range of progressions of disease – from mild to severe.
In the absence of pharmaceutical treatments, the focus on reducing the risk of developing dementia and delaying the onset is now a key priority for all public health authorities and governments. Thus it is proposed that interventions focused on lifestyle factors such as a healthy diet could provide a cost-effective and practical approach to reducing or slowing age-related cognitive decline.
Why is Nutrition Considered? Mechanisms
Several aspects of cognitive decline and neurodegenerative disease have led to hypotheses as to how certain nutrients could help. Some examples include:
Cerebrovascular Blood Flow
- Appears to underpin the acute (and potentially chronic) effects of polyphenols.
- Flavonoids activate the endothelial nitric oxide synthase [eNOS] enzyme which regulates angiogenesis and vasodilation
- Enhanced CBF may also increase BDNF levels, which may explain chronic effects
Blood Brain Barrier
- BBB impairment is prevalent in about 25% of autopsy confirmed Alzheimer’s Disease cases and is associated with more rapid decline over time.
- One of the structural changes in the brain that precedes cognitive decline is the accumulation of deep white matter hyperintensities (WMH).
- These may indicate a breakdown of the blood-brain barrier (BBB) via ischemic changes and demyelination of axons and are a risk factor for cognitive decline.
- Bowman et al. 2012: Specific nutrient concentrations (ascorbic acid, vit C) in the cerebrospinal fluid appear to be influenced by BBB integrity
- Another study has demonstrated that BBB function is modifiable through vitamin therapies – Vitamin B12-B6-folate with hyperhomocysteinaemia and mild cognitive impairment.
- BBB also important for mechanisms of action of polyphenols – parent compounds may be too large to cross, secondary metabolites more likely to cross BBB and accumulate, acting through signalling pathways which regulate neuronal morphology, viability, inflammation and vascular effects
- The brain is a highly metabolically active tissue that relies on oxidative phosphorylation as a way for maintaining energy.
- The level of oxidative stress plays a pivotal role in brain functioning and growing evidence suggests a delicate balance between free radicals production and brain protection or damage.
- Accumulation of oxidative damages is a key mechanism of the ageing process and a common feature of ageing brain (Wang et al., 2014).
- Insulin resistance (IR) and T2DM is one of the main causes of oxidative stress.
- Several dietary components, acting as antioxidant, anti-inflammatory and/or insulin action potentiating factors, could positively participate in a preventive nutritional strategy for healthy ageing of brain.
Secondary Vascular Protection/ Enhancement of Endothelial Functions
- Vascular dementia is the second most commonly occurring type of dementia after AD.
- Vascular dementia is characterised by cognitive dysfunction secondary to ischemic or haemorrhagic brain lesions due to cerebrovascular disease or CVD.
- This type of brain damage may result from an influx of excitatory amino acids, inflammatory responses and changes in cell function, which result in excessive calcium entry.
- In a longitudinal study, Yaffe and colleagues examined the association between Metabolic Syndrome (MetS) and cognitive change in elderly Latinos.
- Participants with MetS with high inflammation (median serum CRP level ≥3.2 mg/L) had significantly reduced cognitive function, measured by using the Modified Mini-Mental State Examination (3MS)
- Yaffe et al. (2004): Metabolic syndrome (MetS) and T2DM have comparable impacts on dementia risk and have been reported in overweight and obese individuals, respectively.
- For example, a 20% increase in relative risk of cognitive impairment was evident in MetS subjects (RR of 1.20 [1.02–1.41; 95% CI]), as compared to healthy controls.
So potentially some nutrients may help improve vascular-related brain disease by mediating harmful effects of inflammation, calcium dysregulation and increased oxidative stress.
Several groups have published evidence that adherence to a Mediterranean diet is associated with less cognitive decline, dementia, or AD. For example:
Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) Diet
The MIND diet is associated with greater protective effects vs. Mediterranean or DASH dietary patterns:
- Chicago MAP study:
- high adherence to the MIND diet recommendations was associated with delayed cognitive ageing equivalent to 7.5yrs.
- Only the highest tertile of adherence to either the Mediterranean diet or DASH diet lower risk, while the mid-tertile of MIND diet adherence still conferred a moderate reduction in risk for cognitive decline.
Nutrients & Foods
This episode explored the evidence on the status and intake of the following nutrients:
- Caffeine & Coffee
- Vitamin D
- B Vitamins (and green leafy vegetables)
- Omega 3
- Vitamin E
Caffeine & Coffee
Coffee/caffeine consumption in later-life cognitive decline and dementia.
From episode 358: “Yeah, I think one of the challenges with this area is coffee, for how ubiquitously consumed it is, is not necessarily a common exposure of interest in a lot of studies. And although you do get many studies that look at coffee specifically, you get less that look at kind of hard endpoint neurodegenerative disease, whether that’s mild cognitive impairment, dementia, Alzheimer’s or Parkinson’s, certainly relative to other conditions like cardiovascular disease. So there’s a smaller overall pool of studies that have looked specifically at coffee intake with one of these kind of neurodegenerative disease outcomes, but the direction of effect, particularly in some of the kind of larger cohort studies, which gives us a bit more confidence – so in studies of over 3000 people in any of the cohorts of over 3000 people, there’s quite a consistent reduction in risk for dementia and Alzheimer’s.”
FINE Study – van Gelder et al., 2007:
- People from Finland, Italy and the Netherlands participated in a 10-year prospective cohort study
- Used the MMSC cognitive score
- Looked at how much coffee consumers were protected against cognitive decline, relative to non-consumers
- The difference was quite significant over the decade:
- J-shaped curve of risk, with approx 3 cups a days being lowest risk
Systematic review by Panza et al., 2015:
- Included 28 studies, which reported a potential correlation of moderate consumption of coffee or caffeine-rich beverages with a reduction in cognitive decline.
Systematic review and meta-analysis by Santos et al. 2010:
- Included nine cohort and two case control studies
- Didn’t find an a risk reduction of cognitive decline based on coffee/caffeine intake
- Reported a non-significant relative risk (RR) of 0.98 [95% Confidence Interval (CI): 0.87–1.11]
- Despite the lack of a linear dose-response relationship, most of reviewed population-based studies pointed to a neuroprotective effect of coffee or caffeine consumption against cognitive impairment and neurodegenerative disorders
- This assocation seemed to be stronger in women than men.
Coffee/Caffeine & Parkinson’s Disease
Of all of these conditions, Parkinson’s appears to be the strongest and most consistent association with coffee intake and health.
Mechanistic plausibility: psycho stimulation effect of caffeine, increasing sympathetic activity and dopaminergic activity.
The benefit associated with coffee/caffine for Parkinson’s is even higher than that seen in dementias or mild cognitive decline. Studies reporting 30 to 40% relative risk reduction (with a minimum benefit of 20% risk reduction).
Nehlig et al., 2016 – Effects of coffee/caffeine on brain health and disease: What should I tell my patients?
For more on caffeine & coffee’s impact, see episode 358: Coffee & Health
There have been some suggestions that some alcohol consumption is associated with lower risk of cognitive decline, compared to zero intake or to high intakes.
- Review of 143 papers
- Two types of papers were found:
- 74 papers that provided ratios of risk between drinkers and nondrinkers
- 69 papers that rated cognition in drinkers as “better,” “no different,” or “worse” than cognition in nondrinkers
- Cognitive risk (dementia or cognitive impairment/decline) based on level of drinking:
- Light = 25% reduction in risk (RR = 0.75)
- Moderate = 31% reduction in risk (RR = 0.69)
- Heavy = 13% increase in risk (RR = 1.13)
- Infrequent “binge” drinkers with APOE ɛ4 had a large and significant increase in the risk of dementia (RR = 2.30), i.e. 130% increase in risk!
- The benefit of moderate drinking applied to all forms of dementia (dementia unspecified, Alzheimer’s disease, and vascular dementia) and to cognitive impairment (low test scores), but no significant benefit against cognitive decline (rate of decline in test scores).
- Light-moderate drinking & Alzheimer’s disease risk: 28% risk reduction (pooled risk ratio [RR] 0.72; 95% confidence interval [CI] 0.61-0.86)
- Light-moderate drinking & dementia risk: 26% risk reduction (RR 0.74; 95%CI 0.61-0.91)
- No systematic review categorised former drinkers separately from lifetime abstainers in their analysis. Definitions of alcohol consumption, light to moderate drinking and heavy-excessive drinking varied and drinking patterns were not considered.
What’s going on?
While there is some mechanistic rationale as to how alcohol itself could play a protective role (e.g. by its “preconditioning” effect on neurons and glia), it seems more likely that any “benefit” of light-moderate drinking is due to other factors (e.g. social behaviours associated with alcohol consumption).
It is not recommended that abstainers should initiate alcohol consumption to protect against dementia.
Related Podcast Episode – #373: Alcohol & Health: Is Zero Better Than Some?
Nutrients and bioactives in green leafy vegetables
Morris et al. 2018 – Relationship between cognitive decline and the primary nutrients and bio-actives in GLV (3 types – spinach, kale, lettuce; vit K, lutein, B-carotene, nitrate, folate, kaempferol and a-tocopherol)
- Study population:
- Rush Memory and Ageing Project
- participants are from retirement communities, senior public housing, churches in the Chicago area
- Average age 81, mostly female (74%) with high educational attainment.
- Completed FFQ (at baseline) and had 2 or more cognitive assessments. They agreed to annual clinical investigations and organ donation after death. 95% sample were white.
- Health profile:74% had high blood pressure, 10% had a stroke, about 20% had MCI.
- Other data – adjusted for age, sex, education, participating in cognitive activities, physical activities, smoking and seafood and alcohol consumption, total energy, APOE genotyping, BMI, medication use in pervious 2 weeks, depressive symptoms (CES-D), diabetes.
- Cognitive assessment:
- Battery of cognitive tests administered by a trained professional.
- Composite scores of 19 of the tests were used to characterise cognition in 5 domains – episodic memory, working memory, semantic memory, visuospatial ability and perceptual speed.
- Consumption of green leafy vegetables ranged from 0.09-1.3 servings per day
- Compared to the estimated effect of age on cognitive decline, decline rate for those in highest quintile of intake (median: 1.3 servings per day) was slower “or equivalent for 11 years younger” in age-adjusted models.
- Age-adjusted models are used to control for general decline in global cognitive score
- The individual nutrients or biomarkers were also independently associated with slower cognitive decline, except B-carotene.
- Didn’t take objective blood measures, particularly B12 and folate
- Didn’t compare overall diet quality
- Did not look at supplement use.
Hughes et al., 2017 – 4-year follow-up study – University of Ulster
- Investigated both dietary intake of B-vits and measured vit B status in cognitively healthy community dwelling older adults.
- Participants: n, 155; aged 60-88, Mainly female, well-educated, and regularly consumed foods fortified with B-vits.
- Assessments: 4-day food recall and FFQ validated for vitB foods.
- 12% had MCI at follow up.
- Lower vit B6 status was associated with a 5.6 times higher risk of accelerated cognitive decline, after adjustment for age and baseline MMSE score.
- No other biomarker/dietary intake of B-vits was observed.
- Mean cognitive scores decreased from 29.1 to 27.5.
- 27% of participants showed greater than expected rate of decline (i.e., decrease in MMSE >0.56 points per year).
- Objective and subjective measures of overall B status.
- Original cohort had 255 participants, 100 lost to follow up but apart from being slightly older in age, no other sig differences between the included and lost participant population.
- Single MMSE test; limited in use for research, however, it did indicate decline as anticipated in this population over time, so could most likely underestimates effect.
VITACOG Study – Smith et al., 2010
- Combined B-vitamin supplements (high doses beyond RDI) for 2 years, beneficial effects on cognitive performance in participants with MCI and elevated homocysteine levels.
- Participants: age ≥70 years; study partner available as informant, and diagnosis of amnestic or non-amnestic MCI according to Petersen’s criteria. The diagnosis included a subjective concern about memory that did not interfere with activities of daily living, assessed with 4 questions on subjective memory complaints from the Cambridge Mental Disorders of the Elderly Examination (CAMDEX)
- The treatment group received oral tablets containing 0.8 mg folic acid, 0.5 mg vitamin B12 (cyanocobalamin) and 20 mg vitamin B6 (pyridoxine HCl).
- Treatment with B vitamins significantly slowed the rate of brain atrophy.
- After adjustment for age, the rate of brain atrophy per year was 29.6% less in the active treatment group (0.76% [95% CI, 0.63–0.90]) compared to the placebo group (1.08% [0.94–1.22], P = 0.001).
- Neither baseline folate nor the vitamin B12 markers showed such a relation. The effect of treatment was dependent on baseline homocysteine.
- Gold standard assessment for brain atrophy- highly sensitive and accurate MRI.
- In a follow up study they demonstrated that the a reduction in rate of brain atrophy by 30% (MRI) particularly in grey matter area of the brain, which is particularly vulnerable to AD.
- Secondary analysis of VITACOG:
- effects of B-vitamin intervention relative to biomarker measures of marine omega-3 fatty acid levels indicated that B-vitamin supplementation had no effect in participants with low baseline omega-3 levels.
- Conversely, the effects of B-vitamin supplementation on protecting against brain atrophy were enhanced with the highest levels of omega-3 fatty acid levels, a relationship which was stronger overall for DHA compared to EPA.
- More on omega-3 later!
Vitamin D Status
Aspell et al., 2018 – review:
- Longitudinal Aging Study Amsterdam (LASA):
- Cross-sectional study demonstrated that older adults with low 25(OH)D status (<30 nmol/l) performed significantly worse cognitively than those with levels >75 nmol/l
- The largest cross-sectional study conducted to date (comprising 4831 participants from NHANES) found no association between 25(OH)D status and cognitive function (Tolppanen et al., 2011).
- The result may be attributed to the single memory outcome measure used to assess cognitive function.
- Three large population cohorts have since demonstrated a significant relationship between low 25(OH)D status (typically <30 nmol/l) and poorer cognitive performance, using comprehensive global and domain-specific outcomes, compared with adequate 25(OH)D levels.
- Other studies have demonstrated a relationship also, however, methodological issues were noted, with small sample sizes, limited analysis of confounding factors and single measures of cognitive performance.
- Cross-sectional studies are considered to provide weak evidence, due to the known issue of reverse causality, in that poorer cognitive performance and the onset of dementia may influence vitamin D concentrations through behavioural and dietary changes.
- Longitudinal studies suggest that vitamin D deficiency is associated with an increased risk of cognitive impairment and incidence of dementia and Alzheimer’s disease
- Most studies demonstrate a link between serum 25(OH)D deficiency and poorer cognitive performance or incidence of dementia using a measure of global or domain-specific cognitive function (Balion, Griffith and Strifler, 2012)
- It is not clear if vitamin D deficiency is a risk factor for cognitive impairments or a result of poorer overall status and ill health.
Vitamin D Supplementation
- Petterson et al., 2017 RCT:
- 50 µg/d (2000 IU) vitamin D3
- Reported no significant improvement in tasks of visual memory among eighty-two community-dwelling adults
- Note: significant heterogeneity between participants; only 30 % of this small sample were aged over 60 years.
- Annweiler et al., 2012:
- Small retrospective study (n 44)
- Cognition was measured using a global measure and a behavioural assessment among patients attending an outpatient clinic, without cognitive impairment at baseline.
- Reported positive findings: Patients with AD who took memantine (an Alzeihmer’s drug) plus vitamin D for 6 months had a “statistically and clinically relevant gain in cognition, underlining possible synergistic and potentiating benefits of the combination”.
- Incomplete 25(OH)D data were available for all participants, so determining optimal levels for cognitive performance are unobtainable from this investigation.
Omega-3 Fatty Acids
A number of trials have looked at the omega-3 fatty acids:
- French Personnes Agées QUID study
- a cohort of >68yo participants located in the southwest of France
- consumption of fish a minimum of once weekly was associated with a 34% [HR 0.66, 95% CI 0.47-0.93] reduction in dementia risk 7yrs later.
- Not significant after adjusting for education status.
- Dutch Doetinchem Cohort Study
- fatty fish associated with a 23% [OR 0.77, 95% CI 0.60-0.97] reduction in risk for cognitive impairment
- while EPA and DHA were together associated with a 19% [OR 0.81, 95% CI 0.66-1.00] lower risk.
- Chicago Health and Ageing Project study
- one fish meal per week associated with a 60% [RR 0.4, 95% CI 0.2-0.9] reduction in risk for AD
- DHA specifically was associated with significant reductions in AD risk, but not ALA or EPA.
- Framingham Offspring Study
- participants with the lowest RBC DHA levels displayed significantly lower total cerebral brain volume and performed worse on cognitive testing, compared to the highest DHA levels.
- Women’s Health Initiative Brain MRI Study [WHIMS-MRI]
- women had MRI scans conducted 8yrs after baseline RBC omega-3 samples were collected – high baseline Omega-3 Index correlated with a 2.1cm larger brain volume determined by MR.
South African RCT Alan mentioned: Kühn et al., J Nutr Health Aging. 2022;26(2):119-126.
Why are results of DHA interventions inconsistent?
There are few possible explanatory reasons:
- There is ~2.5yr half-life of brain DHA, so shorter-term interventions may not show effect.
- Stage of cognitive decline examined:
- Probably won’t protect from further decline in dementia/AD, but some evidence of protection from mild cognitive impairment or otherwise healthy.
- Dose: Studies using <900mg/d may be too low.
- Yurko-Mauro et al., 2010: May need ~900mg/d to show effect.
A number of trials have looked at vitmain E intakes and supplementation:
- Chicago Health and Ageing Project study:
- Each 5mg/d increase in total dietary vitamin E was associated with a 26% [RR 0.74, 95% CI 0.62-0.88] reduction in risk for AD after 6yrs follow-up (highest mean level of vitamin E 26.5mg/d from dietary intake).
- Rotterdam Study:
- Highest dietary vitamin E intake of >15.5mg was associated with a 43% [RR 0.57, 95% CI 0.35-0.91] reduction in AD risk, compared to the lowest <10mg/d.
- Kungsholm Project:
- Total plasma tocopherols and tocotrienols were associated with reduced AD risk (none of the individual tocopherols in isolation were associated with reduced risk, which is relevant to ‘null’ findings in intervention studies using isolated a-tocopherol)
- Rush Memory and Aging Project:
- Brain autopsy study showed no significant association between brain α-tocopherol levels and amyloid plaque load or neurofibrillary tangles, however, there was a significant and linear association between γ-tocopherol levels and lower amyloid plaque load and less severe neurofibrillary tangles.
Intervention trials on vitamin E are largely null (and differ from epidemiological studies). Why?
Essentially they tested the wrong hypotheses…
In epidemiology there are associations for:
- Dietary intake
- Total vitamin E (combined tocopherols/tocotrienols)
- In the brain specifically, γ-tocopherol > α-tocopherol
- Appropriate comparison: Effect sizes observed when compared higher intakes compared to <10mg/d
- Subgroup analysis of the Women’s Health Initiative RCT which found no effect in the overall study group of 430mg/d vitamin E on cognition, found benefit in participants with baseline vitamin E of <6mg/d.
Meanwhile the intervention trials test a synthetic α-tocopherol, i.e., isolated single isoform of vitamin E, in participants already replete with vitamin E.
As Alan stated in this episode: “The observational findings found apples and the interventions went and tested oranges.”
- Nurses’ Health Study cohort
- cognitive function examined at 2yr intervals, dietary intake was assessed every 4yrs, in 16,010 participants aged >70yo. Consumption of blueberries >1/week and strawberries >2/week – and high total flavonoid intake – associated with a delay in cognitive ageing equivalent to 2.5yrs on cognitive scoring [i.e., 75yo average scores were equivalent to a 73yo].
- Chicago Health and Ageing Project
- >1 serving/week strawberry intake was associated with a 34% [HR 0.66, 95% CI 0.46-0.95] lower risk of AD compared to those consuming none or <1/month consumption. Effect attributable to anthocyanin compounds in strawberries.
Interventions are mostly acute studies, or short-term:
- Older adults with MCI
- anthocyanin-rich concord grape juice consumed daily over 12-weeks significantly increased verbal recall, while non-significant increases in spatial memory and list learning were observed.
- Healthy older adults – blueberry
- significant increases in word recall and word list learning after 12-weeks supplementation with pure blueberry juice.
- 7-10 yo children – powder
- 253mg anthocyanins taken in powdered form, before cognitive testing over 6hrs, demonstrated improvements in cognitive function in response to cognitively demanding tasks.
- Healthy young adults – smoothie
- mixed berry smoothie containing 569.7mg total flavonoids (mainly anthocyanidins and proanthocyanidins) found significant preservation in cognitive testing scores over 6hrs.
For more on flavonoids, episode 406 is specifically on Polyphenols & Cognitive Health.
How to assess cognitive health in ageing intervention studies
One of the greatest methodological barriers across nutrition and cognition studies is the wide variety of cognitive assessments used, which will ultimately influence the outcome and the interpretation of the findings.
- Cognitive function can be seen as a hierarchy, going from overall (global) to domain-specific cognitive function.
- The most commonly used cognitive outcome measure in nutrition and cognitive studies are global tests, namely the Mini-Mental State Examination (MMSE).
- Widely used, it has limited use in research for detecting subtle changes in cognitive function in response to short-term interventions, such as vitamin D supplementation trials.
- Domain-specific functions include memory, executive functioning, attention, perceptual functions, psychomotor abilities and language skills.
- Domain-specific measures are useful but reliance on a single domain assessment may lead to cognitive changes going undetected due to intra-individual variability.
- Inter-individual performance in different domains vary and each individual has a unique profile of strengths and weaknesses in different domains, so it is not explicit to define people on global function or domain-specific function alone.
- Performing well on one domain is often dependent on traits of another cognitive process or domains, for example, retaining new information in a memory test is highly dependent on attention
Other Factors Impacting Cognitive Assessments
- Mood, sleep, anxiety and depression are highly correlated with cognitive performance and can significantly alter the outcome.
- Emerging mobile technologies which obtain real-time information regarding abilities to perform activities of daily living, which are highly correlated with neuropsychological tests, may change the way cognitive research is conducted, in way of preventative strategies for dementia
From a pragmatic perspective, considering what an overall healthy dietary pattern may look like for lowering cognitive risk is of most value. In addition to general healthy diet, the pattern may be particularly beneficial if including the following components:
- Oily fish
- Foods containing vitamin E, like avocado, almonds, vegetable oils
- Green leafy vegetables
- Flavonoid- or polyphenol-rich foods: Coffee, mixed berries, dark pigmentation plants, high cacao chocolate, extra virgin olive oil
Importantly, it is important not to over-emphasise diet as something that will prevent cognitive decline or neurodegenerative diseases. For more on this see the Key Ideas section.
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