Food for thought

According to WHO, around 50 million people worldwide have dementia, the main form of which is Alzheimer’s disease. Dementia is a major cause of disability and dependency in older adults and, owing to expanding and ageing populations, its prevalence is expected to almost triple by 2050. In England and Wales, dementia is the first and second leading cause of death in women and men, responsible for 16.3% and 8.7% of total mortality in 2017, according to the BMJ.

No licensed drugs are available to prevent or reverse dementia. For Alzheimer’s disease, four drugs are used to treat symptoms temporarily (donepezil, rivastigmine, galantamine and memantine). Therefore, measures that prevent or delay the progression of neuropathology and brain vascular dysfunction could help to reduce the individual risk and population burden of the disease. A 2014 report, ‘The Trajectory of Dementia in the UK – Making a Difference,’ estimated that a two or five-year delay in the onset of dementia would reduce the number of people with the disease in the UK by 19% and 33% by 2050.

Meanwhile, a 2016 paper in the Iranian Journal of Neurology estimated that about one-third of cases of Alzheimer’s disease worldwide are attributed to modifiable risk factors, many of which are nutrition and lifestyle dependent (depression, mid-life obesity, midlife hypertension and type 2 diabetes). Cardiometabolic health is a major determinant of age-related cognitive function and risk of dementia. Research into the role of nutrition in age-related cognitive decline is in its relative infancy compared with other chronic conditions, such as cardiovascular diseases, type 2 diabetes, osteoporosis and gastrointestinal disorders.

Nascent research area

Although the results are not fully consistent, a growing body of prospective cohort evidence shows that bioactive components of food are associated with a reduced risk of dementia. Much of the research has considered dementia as a composite, despite the recognition that owing to differences in pathology, dementia subtypes – such as Alzheimer’s disease, vascular dementia and dementia with Lewy bodies – are probably influenced by differing dietary factors.

Furthermore, a large retrospective cohort study has shown that behaviour – a healthy diet – partly mitigates the penetrance of a high dementia genetic risk score.

The randomised controlled trial evidence is more limited and less convincing, with cognition and brain volume (as assessed by MRI) as the main study endpoints, and few primary prevention randomised controlled trials with incident dementia as an outcome measure. Some evidence suggests that individual bioactive components in food – including B vitamins, antioxidant vitamins, selenium, vitamin D, medium chain triglycerides and long-chain omega-3 fatty acids – can protect cognitive health. This evidence is not conclusive, however.

Evidence that nutrition has a beneficial effect on brain function is stronger for healthy dietary patterns, most likely because the synergistic effect of several bioactive components affects many physiological processes and signalling pathways, which underlie cognitive function and decline. One would predict that the effect of nutrition would be more evident in people still cognitively healthy or prodromal, rather than in those with dementia already – but this has not been rigorously tested.

Oily fish – which includes salmon, mackerel, herring, fresh tuna and sardines – are almost the only dietary source of long chain n-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid (DHA). Algal oil capsules can provide a vegan source of DHA. The brain is highly enriched in DHA, which constitutes 15% of brain lipids – compared with less than 5% in most other tissues. In prospective cohort studies, high fish and DHA intake has been consistently associated with improved cognitive health in older age, with a 10–30% reduced risk of Alzheimer’s disease and death, brain atrophy and cognitive decline, and effect sizes equivalent to two to four years of ageing. In a metaanalysis of 21 cohort studies, a 100mg increment of dietary DHA was associated with lower risks of dementia (relative risk 0.86, 95% confidence interval 0.76–0.96) and Alzheimer’s disease (0.63, 0.51–0.76).

Fish is also a source of multiple nutrients needed by the brain, including vitamin B12, selenium and vitamin D, which may contribute to the observed cognitive benefits. Thus, where possible, fish itself, rather than fish oil supplements, is recommended as a source of DHA. For a dietary component such as DHA or fish, the possibility of residual confounding should be taken into account, as some of the cognitive benefits associated with DHA seen in prospective cohorts could be due to a yet unknown factor associated with intake, and the benefits associated with eating fish and DHA could be biased.

Fuel of the brain

One of the challenges facing the ageing brain is a chronic deficit in brain glucose uptake. Cognitively, healthy older adults have about 7–8% lower brain glucose uptake than younger adults, a decline accentuated in cases of mild cognitive impairment (the prodromal phase of Alzheimer’s) and even more so in Alzheimer’s itself.

Under normal circumstances, glucose supplies about 95% of the brain’s fuel. It is, however, effectively replaced by ketones (beta-hydroxybutyrate and acetoacetate) when dietary carbohydrate or total dietary energy is limited. And when a ketogenic supplement is included in the diet, the brain of someone with mild cognitive impairment or Alzheimer’s uses ketones in direct proportion to the increased ketones provided by the circulation, sparing brain use.

Ketogenic interventions may indirectly affect cognitive outcomes by improving insulin sensitivity or stimulating weight loss; they are also likely to be more efficient in slowing down Alzheimer’s disease if combined with exercise. Given the emerging evidence for the cardiometabolic safety of the ketogenic diet, and the growing interest in its use to treat type 2 diabetes, a long-term controlled assessment of its effect on cognition and risk of Alzheimer’s is warranted.

Recent research has moved away from the reductionist approach to nutrition, health and chronic disease, and focused on the effect of dietary patterns, dietary approaches to stop hypertension (the DASH) diet, and the hybrid Mediterranean-DASH intervention for neurodegenerative delay (MIND) diet. Additionally, WHO and Public Health England have advocated whole-diet approaches to delay or prevent cognitive decline. A Mediterranean diet is high in fruits, vegetables, olive oil, whole grains, unsaturated fatty acids and fish, with limited amounts of red meat and moderate but regular drinking of alcohol. In a 2019 analysis conducted by the Norfolk component of the European Prospective Investigation into Cancer and Nutrition, the global cognitive benefit of adherence to a Mediterranean diet was equivalent to a 1.7-year decrease in cognitive ageing.

The totality of evidence supports the protective effect of diets rich in whole foods for dementia and cognitive function, but there are inconsistencies within and between diets. Contradictory findings may be due to geographical region, for example. Nonetheless, prospective cohort evidence suggests that a change in eating behaviour may delay the onset of dementia, possibly even by several years. The trial evidence to date is reliant on cognitive or other surrogate markers of dementia risk, often with uncertain prognostic value, and lacking specificity to dementia subtypes.

Metabolic and preclinical studies will help to provide insights into mechanisms to collectively provide the evidence needed to make causal inferences, fully establish efficacy and inform policy. Randomised controlled trials are often expensive and long term, but they should be supported by validated imaging and biochemical biomarkers of disease, both to select at-risk and responsive subgroups, and to screen potentially effective interventions.

The original paper, ‘Can nutrition support healthy cognitive ageing and reduce dementia risk?’ in the BMJ, can be found online.