Confronting the Alzheimer’s disease tsunami

Fifty million people worldwide live with dementia in 2020, the majority Alzheimer’s disease (AD), and this number will triple by 2050. Given the inexorable progression once the disease is established, efforts focused on AD prevention have recently gained increasing attention. About 40% of AD risk is potentially modifiable.¹ Here, we will explore three intervention domains (nutrition, physical exercise and cognitive stimulation), examine how they intersect in several landmark multidomain randomized controlled trials (RCTs), and explore the emerging approach of precision medicine in optimizing AD prevention at the individual level.

Alzheimer’s disease prevention in our plates

Observational studies examining the role of nutrition in AD showed mixed results – individual nutrients or food elements such as B-vitamins, antioxidants or fish and seafood have either protective, neutral or even detrimental on cognition. Dietary patterns such as the Mediterranean diet or the DASH (Dietary Approaches to Stop Hypertension) diet yielded more encouraging results, but outcomes remain mixed.² These findings also reflect inherent challenges of nutrition studies aimed at AD prevention including difficulty accurately assessing nutritional status, sample selection introducing various confounds (e.g., participants recruited are more health conscious and educated), and how nutrition enmeshes with other component processes within complex mechanisms regulating cognition.

Despite disappointing results, interesting patterns emerge and argue for a personalized approach targeting specific subpopulations with tailor-made dietary modifications rather than a one-size-fit-all approach. Folate improves information processing speed in those with baseline high homocysteine and low B12; combination of folate, B6 and B12 supplements preserve semantic memory or temporal orientation in individuals with previous coronary artery disease or ischemic stroke (i.e. heavier burden of vascular disease); protective effect of fish consumption is stronger for APOE4 (apolipoprotein E4) carriers.²

Despite disappointing results, interesting patterns emerge and argue for a personalized approach targeting specific subpopulations with tailor-made dietary modifications rather than a one-size-fit-all approach.

– Dr. Chenjie Xia

Physical exercise for cognitive health

Studies examining how physical exercise (e.g. aerobic training, resistance training or tai chi) impacts cognitive performance also show tepid outcomes. Despite positive findings in cohort studies, results are mixed in controlled studies.³ We understand poorly how physical exercise mediates cognitive health. Are they direct effects or indirect effects via mitigating vascular risk factors, reducing mood symptoms such as depression? Do muscles release factors beneficial for brain, could we synthetically reproduce and pharmacologically administer these factors?

Future studies should examine Intervention characteristics that influence efficacy (age when physical activity begins, intervention duration, baseline activity level), measure compliance and how exercise habits change over time. They should also last longer than a year or two as the impact of exercise on cognition likely takes effect over decades. We will need creativity and resourcefulness to avoid such studies being logistically and financially prohibitive.

Similarly to nutrition, cognitive improvements in exercise trials are highly variable – understanding the sources of variability will lead to strategies with specific exercise regimens taking into account individual factors in a precision medicine approach for AD prevention.

Storing up a buffer – the power of cognitive reserve

Cognitive reserve is “a condition in which an individual has observed cognitive performance better than expected given their brain’s

High cognitive reserve ensures normal cognition despite structural atrophy on brain imaging. Proxy measures of cognitive reserve include premorbid intelligence, education attainment, linguistic ability (e.g. bilingualism). One additional year of education confers 13-18% reduction in likelihood of receiving an AD diagnosis within 1 year of death; high cognitive activity level confers 50% reduction in dementia risk in next five

Again, inconclusive studies abound, attributable to difficulties in accounting for a large variety of cognitive activities (e.g. reading, board game/card games, playing musical instruments), rating the intensity of these activities, and teasing out confounding effect of social stimulation or physical exertion inherent to these activities. As a dementia care specialist, patients often ask me about cognitive training “games”; I usually advise focusing on personal hobbies or leisure activities. My advice is borne out by studies showing that gains in targeted function (e.g. memory, processing speed) from cognitive training tasks do not transfer to untrained task or daily life activities, therefore lack ecological

Putting it all to the test in randomized controlled trials

Three large landmark RCTs were completed recently. FINGER was a 2-year study in Finland examining the effect of a combined brain-healthy diet, exercise, cognitive training, stimulating social activity, vascular risk monitoring in 2,654 individuals pre-selected for vascular risk factors.⁶ PreDIVA was a 6-year study in the Netherlands assessing the effect of a multidomain cardiovascular intervention program including individually tailored lifestyle advice and medication treatment for vascular risk factors in 2,635 individuals.⁷ MAPT was a 3-year study in France and Monaco examining the effect of a multidomain program including exercise, cognitive activities, nutrition and omega-3 polyunsaturated fatty acids (PUFA) supplementation in 1,680 individuals.⁸

Only FINGER showed positive results for the primary outcome – multidomain intervention improved or maintained cognition. The other two studies showed negative primary outcomes, but subgroup analyses revealed benefit of aggressive vascular risk control in individuals who had not yet been treated in PreDIVA, and protective effect of multidomain intervention and omega-3 PUFA supplementation in individuals with high vascular risk and positive amyloid PET scan (i.e. higher risk for developing AD) in MAPT. These findings suggest more promise in multidomain approaches and carefully matching intervention with specific patient characteristics.

Precision medicine – the next frontier

Precision medicine prevents and treats diseases considering individual variability in genes, environment and lifestyle. The Alzheimer’s Prevention Clinic at Cornell University is applying such principles to AD prevention, conducting a comprehensive initial risk assessment and longitudinal follow-up with personalized care plan targeting individual risk factors.⁹ The cornerstone of their approach is collecting extensive data (“deep phenotyping”) of the ABC’s of AD – Anthropometrics (e.g. lean muscle mass), Blood biomarkers (e.g. genetic testing, lipid profile), and Cognition (neuropsychological testing), then “triangulating” between the ABCs. For example, if a patient has borderline high cholesterol, how aggressively it should be lowered depends on the patient’s anthropomorphic measures (e.g. high body fat may warrant earlier treatment) and cognition (e.g. poorer executive function may warrant more aggressive treatment). Crucially, patients assessed at this clinic walk away with a personalized plan adapted to each individual’s particular pattern of results. A recent data analysis of 174 patients followed over 18 months show that those with high treatment compliance performed better on the m-APCC (the modified Alzheimer’s Prevention Initiative Cognitive Composite) score, a validated composite cognitive tests score used in AD studies.¹⁰

Conclusion

Emerging evidence points to a multidomain, individualized precision medicine approach being most effective for AD prevention. We need to validate this approach in future trials, and then deploy resources to educate and encourage clinicians to implement it into both primary and specialized care settings.