Food for Thought 2020

Can nutrition support healthy cognitive ageing BMJ: first published as 10.1136/bmj.m2269 on 26 June 2020. Downloaded from and reduce risk? Amy Jennings and colleagues describe the evidence and potential for food and food bioactive components to reduce the population prevalence of dementia

round 50 million people world- toms temporarily (donepezil, rivastigmine, improved cardiometabolic health and wide have dementia, the main galantamine, and memantine). Therefore, perfusion, and direct effects within form of which is Alzheimer’s behaviour which prevents or delays pro- the brain on neuronal function, energy disease. Dementia is a major gression of neuropathology and brain , and β amyloid processing. cause of disability and depend- vascular dysfunction could help to reduce The randomised controlled trial evidence Aency in older adults and, owing to expand- the individual risk and population burden is more limited and less convincing,7 10 with ing and ageing populations, its prevalence of the disease. The 2014 report, “The tra- and brain volume (as assessed by is expected to almost triple by 2050. This jectory of dementia in the UK–making a MRI) as the main study endpoints, and few increase is being partly offset by decreas- difference,” estimated that a two or five primary prevention randomised controlled ing age standardised dementia rates in year delay in the onset of dementia would trials with incident dementia as an outcome some high income countries, attributed to reduce the number of people with the dis- measure. more years of education and improved car- ease in the UK by 19% and 33%. respec- diovascular health.1 In England and Wales, tively, by 2050.3 In a US based analysis, Nutrition and cognition dementia is the first and second leading Brookmeyer and colleagues predicted that Some evidence suggests that individual cause of death in women and men, respec- interventions associated with a five year food bioactive components protect cogni- tively, responsible for 16.3% and 8.7% of delay would almost halve cases of dementia tive health (for review see Scarmeas et al8), total mortality in 2017 (www.ons.gov.uk). over 50 years.4 including , antioxidant vitamins, Almost two thirds of cases of dementia It is estimated that about one third of selenium, vitamin D, medium chain triglyc- are in women. The cause of this difference cases of Alzheimer’s disease worldwide erides, and long chain omega-3 fatty acids between the sexes is poorly understood.2 are attributable to modifiable risk (see supplementary table on bmj.com). This http://www.bmj.com/ factors,5 many of which are nutrition and evidence is not conclusive, however. Any Interventions to improve cognition and reduce lifestyle dependent (, mid-life effects of intervention with such individual dementia risk obesity, mid-life hypertension, and type components are most likely to appear after No licensed drugs are available that pre- 2 diabetes). Cardiometabolic health is a long term exposure, and in those with a vent or reverse dementia. For Alzheimer’s major determinant of age related cognition low baseline habitual intake. Evidence that disease four drugs are used to treat symp- function and risk of dementia. Research nutrition has a beneficial effect on brain

into the role of nutrition in age related function is stronger for healthy dietary on 24 September 2021 by guest. Protected copyright. cognitive decline is in its relative infancy patterns, probably because the synergis- Key Messages compared with other chronic conditions, tic effect of several bioactive components • Global prevalence of dementia is pre- such as cardiovascular diseases, type affects many physiological processes and dicted to almost triple by 2050 and 2 diabetes mellitus, osteoporosis, and signalling pathways underlying cognitive no current treatments are effective gastrointestinal disorders. function and decline. Intuitively, one would Improved eating behaviour could Although the results are not fully predict that the effect of nutrition would be • 6 reduce the risk and population preva- consistent, a growing body of prospective more evident in people who are still cogni- lence of dementia cohort evidence shows that bioactive tively healthy or prodromal, rather than in components of food are associated with a those with diagnosed dementia, where sig- • Owing to dementia’s multifactorial 7 8 aetiology, multiple dietary compo- reduced risk of dementia. Much of the nificant neuronal loss has already occurred, nents that target several physiological research has considered dementia as a but this has not been rigorously tested. pathways and risk factors simultane- composite, despite the recognition that Here we focus on fish/the omega-3 ously are needed owing to differences in pathology, dementia docosahexaenoic acids (DHAs), subtypes (eg, Alzheimer’s disease, vascular ketogenic interventions, and a plant based Changes to dietary patterns and foods • dementia, dementia with Lewy bodies) are dietary pattern (eg, Mediterranean diet) (rather than single dietary compo - probably influenced by differing dietary as approaches to nutrition with a strong nents) therefore hold most promise to factors. Furthermore, a large retrospective potential to mitigate age related cognitive meaningfully improve cognition cohort study9 has shown that behaviour, decline. The state of advancement of • Randomised controlled trials with including a healthy diet, partly mitigates knowledge and inconsistencies in these robust validated cognitive outcomes the penetrance of a high dementia genetic areas provide insight into the research are needed to support the prospective risk score. Model systems have provided approaches used and the challenges cohort evidence, establish efficacy and insight into the potential underlying encountered in confirming nutrition- effect size, and inform public health molecular and physiological mechanisms cognition causal relations, especially policy for the associations observed, including during ageing. the bmj | BMJ 2020;369:m2269 | doi: 10.1136/bmj.m2269 1 Food for Thought 2020

Omega-3 fatty acids and improved brain Cognitive benefits are reported for healthy gradually becoming energy (glucose) BMJ: first published as 10.1136/bmj.m2269 on 26 June 2020. Downloaded from function younger adults20 and in mild cognitive starved, but perhaps their function could Oily fish, which includes salmon, mackerel, impairment,21 in contrast to those with be revived or maintained by ketones, an herring, fresh tuna, and sardines, are the more advanced disease.22 Early indications emerging therapeutic concept called “brain almost exclusive dietary source of the long are that APOE4 carriers (25% of white energy rescue”.32 chain n-3 fatty acids, eicosapentaenoic populations), and particularly older Under normal circumstances, glucose acid and (DHA). women with the APOE4 variant, may supplies about 95% of the brain’s fuel. It Algal oil capsules provide a vegan source have lower brain DHA uptake and status, is, however, effectively replaced by ketones of DHA. The brain is highly enriched in and would benefit from higher dose DHA (β-hydroxybutyrate and acetoacetate) DHA, which constitutes 15% of brain lipids supplementation.2 23 24 For DHA and other when dietary carbohydrate or total dietary compared with less than 5% in most other dietary components, several variables energy is limited. Furthermore, when tissues.11 The role of DHA in the developing need to be considered, including delivery a ketogenic supplement is included in fetal and infant brain is widely accepted. to the brain and time taken to reach a the diet, the brain of someone with mild In prospective cohort studies, high fish steady state, and whether the cognitive cognitive impairment or Alzheimer’s and DHA intake has been consistently benefits are direct effects on brain disease uses ketones in direct proportion associated with improved cognitive health structure, perfusion, or metabolism, or an to the increased ketones provided by the in older age, with a 10-30% reduced risk indirect effect attributable to, for example, circulation, thereby sparing brain glucose of Alzheimer’s disease and death, brain cardiometabolic health. Brain DHA half use.33 34 atrophy, and cognitive decline, and effect life is estimated to be 2.5 years,25 and thus Recent experimental clinical studies sizes equivalent to two to four years of age- supplementation periods of at least a year have shown that brain energy rescue ing12-16; there is some indication of greater are probably needed to detect the cognitive with ketones is associated with improved effects in women.15 In a meta-analysis of benefits associated with DHA enrichment cognitive outcomes in both mild cognitive 21 cohort studies, a 100 mg increment of of neuronal cells, and effects on β-amyloid impairment and Alzheimer’s disease. dietary DHA was associated with lower and tau protein metabolism and synaptic These studies used either a very low risks of dementia (relative risk 0.86, 95% plasticity.2 26 carbohydrate (ketogenic) diet35-37 or confidence interval 0.76 to 0.96) and Alz- 20-30 g/day of ketogenic medium chain heimer’s disease (0.63, 0.51 to 0.76).14 Brain glucose use, ketones, and cognitive triglyceride supplement.34 38 39 With ketone Fish is also a source of multiple health positron emission tomography imaging,

needed by the brain, including , One of the challenges facing the ageing two of these studies showed that not only

selenium, and vitamin D, which may con- brain is a chronic deficit in brain glucose did ketones access the brain of someone http://www.bmj.com/ tribute to the observed cognitive benefits. uptake. Cognitively healthy older adults with mild cognitive impairment37 but Thus, where possible, fish itself rather than have about 7-8% lower brain glucose that improvement on several cognitive fish oil supplements is recommended as a uptake than younger adults, a decline tests was directly proportional to the rise source of DHA. accentuated in mild cognitive impairment in plasma ketones,34 implying a direct For a dietary component such as (the prodromal phase of Alzheimer’s dis- mechanistic link between restoration of DHA/fish, which could be considered a ease) and even more so in Alzheimer’s dis- brain energy levels by ketones and the signature of an overall healthy diet (such ease itself.27 Although low brain glucose improved cognitive performance. Ketogenic as a Mediterranean-style diet discussed could be a consequence of the disease pro- interventions may also be disease on 24 September 2021 by guest. Protected copyright. below) and healthy behaviour, the cess, two facets of the declining glucose modifying because preclinical and clinical possibility of residual confounding should uptake, brain cell loss, cognitive decline reports show that the neuropathological be considered, as some of the cognitive continuum suggest that this interpreta- process involving accumulation of the benefits associated with DHA seen in tion should be reconsidered. Firstly, brain dementia associated proteins, amyloid β prospective cohorts could be due to a yet glucose uptake is already lower in those at and phosphorylated tau, can be partially unknown factor associated with intake,17 risk of Alzheimer’s disease (that is, older blocked by ketogenic supplements.37 40 41 and the benefits associated with eating fish age but still cognitively normal, carriers These results are encouraging but comp­ and DHA could be biased.18 of the presenilin mutation or APOE4, or liance is low with ketogenic diets, and A number of randomised controlled type 2 diabetes) but before their cognition ketogenic medium chain triglycerides can trials have reported mixed findings with declines.28 cause gastrointestinal discomfort. Thus DHA supplementation over periods of up Secondly, studies with positron emission more work is needed to optimise ketogenic to three years (see supplementary data). tomography imaging and a ketone tracer interventions (dose, duration, formulation) DHA is one of the bioactive ingredients in (11C-acetoacetate) show that, unlike and test them in larger randomised Souvenaid (Fortasyn Connect) medicinal glucose, brain ketone uptake is normal controlled trials in order to convincingly food, designed to support cognitive ageing. during ageing, mild cognitive impairment, assess their efficacy in improving In the LipiDiDiet trial, Souvenaid had no and Alzheimer’s disease.29-31 Ketones are cognitive outcomes in people with mild effect on the primary outcome measure, the brain’s second most important fuel cognitive impairment or Alzheimer’s but was associated with an improved and, as for glucose, brain ketone uptake disease. Ketogenic interventions may clinical dementia rating score and reduced is an active, transporter mediated process. indirectly affect cognitive outcomes, in hippocampal (a main brain region affected Hence, many of the brain cells in which part, by improving insulin sensitivity or in Alzheimer’s disease) atrophy.19 glucose metabolism is deteriorating stimulating weight loss; they would also Response to DHA interventions is owing to age or Alzheimer’s disease are be predicted to be more efficient in slowing heterogeneous and may partly depend not apoptotic (or dead) because they can down Alzheimer’s disease if combined with on DHA and cognitive status at baseline. still metabolise ketones. Rather, they are exercise.42 Given the emerging evidence

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for the cardiometabolic safety of the the PREDIMED study reported a lower speciation and metabolism could influence BMJ: first published as 10.1136/bmj.m2269 on 26 June 2020. Downloaded from ketogenic diet and the growing interest prevalence of mild cognitive impairment the cognitive response to dietary change in its use to treat type 2 diabetes,43 a long after a Mediterranean diet,52 longitudinal and may emerge as a tractable target for term controlled intervention assessing its randomised controlled trials, with interventions. effect on cognitive outcomes and risk of incident mild cognitive impairment/ In addition to the nutrients needed for Alzheimer’s disease is warranted. Alzheimer’s disease as the primary end brain function, the reduced content of point, are still lacking. refined sugars in Mediterranean-type diets Dietary patterns and cognitive health The totality of evidence supports the may also help to improve glucose tolerance. Recent research has moved away from the protective effect of adherence to diets rich This would help the ageing brain meet its reductionist approach to nutrition, health, in whole foods for dementia and cognitive energy needs (both glucose and ketones) by and chronic disease,17 and focused on the function, but there are inconsistencies reducing creeping insulin resistance during effect of dietary patterns, such as the Medi- within and between diets.45 Contradictory ageing, thereby improving the chance of terranean diet, DASH (Dietary Approaches findings may be due to the geographical maintaining optimal cognition. to Stop Hypertension) diet, and the hybrid region, with a recent systematic review MIND (Mediterranean-DASH Intervention reporting that 80% of cohort studies Conclusions for Neurodegenerative Delay) diet. Addi- conducted in Mediterranean regions Prospective cohort evidence suggests that tionally, the World Health Organization showed significant associations with a change in eating behaviour may delay and Public Health England have advo- cognitive health, compared with only 50% the onset of dementia, possibly by several cated whole diet approaches to delay or in non-Mediterranean regions.53 Possible years. The trial evidence to date is reliant prevent cognitive decline.7 44 A Mediter- reasons for this geographical disparity are on cognitive or other surrogate markers ranean diet is high in fruits, vegetables, firstly, diet adherence scores may reflect of dementia risk with often, uncertain olive oil, whole grains, unsaturated fatty different food patterns in Mediterranean prognostic value, and lacking sensitiv- acids, and fish, with restrictions of red versus non-Mediterranean countries—for ity and specificity to dementia subtypes. meat, and moderate but regular drinking example, olive oil, fish, and legumes are Longitudinal randomised controlled tri- of alcohol. A meta-analysis of 34 168 par- more commonly eaten in Mediterranean als with robust cognitive outcomes are ticipants showed that higher adherence to regions; secondly, adherence scores do still needed, ideally, with incident disease a Mediterranean diet was associated with not consider foods reflective of Western- (either dementia or mild cognitive impair- a 21% reduced risk of developing cogni- style diets in non-Mediterranean regions; ment) as the primary outcome. Metabolic tive disorders and a 40% reduced risk of or, thirdly, in Mediterranean regions the and preclinical studies will help to provide 45

Alzheimer’s disease. In a recent analysis Mediterranean diet score is “capturing” insights into mechanisms so as to collec- http://www.bmj.com/ of the EPIC (European Prospective Investi- a lifestyle with characteristics protective tively provide the evidence needed to make gation into Cancer and Nutrition)-Norfolk of cognitive decline, including increased causal inferences, fully establish efficacy, cohort, the global cognitive benefit of high social interactions when eating, and and inform policy.17 Randomised controlled versus low adherence to a Mediterranean physical activity.54 55 trials are often expensive and long term. diet was equivalent to 1.7 fewer years of Heterogeneity in dietary response could They should be supported by validated cognitive ageing.46 also be due to individual differences imaging and biochemical biomarkers of Numerous foods in modern Western- in metabolism. Beneficial disease, both to select at risk and respon- style diets are not traditionally included changes in the gut microbiome, together sive subgroups, and to screen potentially on 24 September 2021 by guest. Protected copyright. in a Mediterranean diet, such as high with taxonomic shifts in microbiota effective interventions. fat dairy products, processed meats, composition, have been seen in those Are we yet in a position to provide carbonated drinks, sweets, and pastries. following plant based diets.56 A higher dietary guidelines specifically to promote The PREDIMED, MIND, and DASH diets intake of plant based foods is associated cognitive health and reduce the risk of are Mediterranean-style diets and all with lower trimethylamine oxide levels dementia in later life? Global and national three improved cognitive outcomes,47 48 and increased faecal short chain fatty dietary macronutrient (particularly fat with respectively a 53%, 54%, and 39% acids, fibre degrading microbiota, and and carbohydrate) and food guidelines lower incidence of Alzheimer’s disease gut microbial diversity.57 58 These gut (eg, eating fruit and vegetables and after 4.5 years.49 A multidomain lifestyle microbial changes are linked to the gut- reducing salt) are, in large part, based intervention trial (FINGER), which brain axis. Thus short chain fatty acids— on the management of cardiometabolic included modified eating behaviour as one in particular, butyrate, enhance brain risk (obesity, cardiovascular diseases, of four concurrent interventions, improved derived neurotrophic factor expression, and type 2 diabetes mellitus). Given the cognitive outcomes. After two years, a and trimethylamine oxide is linked to established importance of cardiometabolic 25% improvement in global cognition reduced expression of health on cognitive function (especially in (as assessed by the neuropsychological related proteins, including N-methyl- mid-life), greater adherence to existing test battery), and higher executive D-aspartate-receptors, both important dietary recommendations is likely to function (150%) and processing speed factors for and .59 60 If reduce the incidence of dementia. To (89%) was evident in the intervention the microbiome can affect the gut-brain develop dietary guidelines specifically versus control group.50 51 These findings axis then diet induced changes in the focused on prevention of dementia or indicate that whole diet approaches gut microbiota, through plant based or improving mild cognitive decline, further that encourage Mediterranean-style Mediterranean diets associated with research is needed to gain insight into elements and discourage energy dense higher consumption of fibre, polyphenols, which dietary strategies most effectively foods typical of a Western-style diet are and probiotics could affect development of improve neuronal function and reduce beneficial for cognitive health. Although cognitive impairment. Equally, microbiome neuropathology. the bmj | BMJ 2020;369:m2269 | doi: 10.1136/bmj.m2269 3 Food for Thought 2020

Neurol 2018;17:1006-15. doi:10.1016/S1474- BMJ: first published as 10.1136/bmj.m2269 on 26 June 2020. Downloaded from Box 1: Controversies and research gaps 4422(18)30338-7 • Strong associations between dietary patterns and food bioactive components in prospective 9 Lourida I, Hannon E, Littlejohns TJ, et al. Association of lifestyle and genetic risk with incidence of cohort studies and experimental preclinical studies are often not replicated in human dementia. JAMA 2019;322:430-7. doi:10.1001/ randomised controlled trials jama.2019.9879 • Randomised controlled trial design should assess whether the intervention indirectly affects 10 Solfrizzi V, Agosti P, Lozupone M, et al. Nutritional intervention as a preventive approach for systemic processes, such as cardiometabolic function or inflammation, or whether it directly cognitive-related outcomes in cognitively healthy affects neuronal function, brain energy metabolism, or the “hallmarks” of dementia, such older adults: a systematic review. J Alzheimers as amyloid β and tau protein metabolism. The time and dose needed to produce meaningful Dis 2018;64(s1):S229-54. doi:10.3233/JAD-179940 increases in brain function must be considered in the trial design to preclude the risk of a 11 Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of n-3 fatty acids type 2 error (false positive findings) in humans. Am J Clin Nutr 2006;83(Suppl):1467S- • Longitudinal follow-up randomised controlled trials are needed, ideally with incident disease 76S. doi:10.1093/ajcn/83.6.1467S as the primary outcome measure 12 Pottala JV, Yaffe K, Robinson JG, Espeland MA, Wallace R, Harris WS. Higher RBC EPA + DHA corresponds • It is unclear when to intervene in the cognitive course from health to diagnosed dementia, with larger total brain and hippocampal volumes: and which interventions are best suited to dementia subtype and disease progression WHIMS-MRI study. Neurology 2014;82:435-42. • Little is known about the overall effect of neuropathology on the brain uptake and doi:10.1212/WNL.0000000000000080 metabolism of dietary components 13 Samieri C, Morris MC, Bennett DA, et al. Fish intake, genetic predisposition to Alzheimer disease, and • Identification is needed of targeted approaches to nutrition for at risk subgroups, such as decline in global cognition and memory in 5 cohorts women with the APOE4 gene or insulin resistant individuals of older persons. Am J Epidemiol 2018;187:933-40. doi:10.1093/aje/kwx330 14 Zhang Y, Chen J, Qiu J, Li Y, Wang J, Jiao J. Intakes of fish and polyunsaturated fatty acids and mild- Contributors and sources: The authors have a permits others to distribute, remix, adapt, build to-severe cognitive impairment risks: a dose- wide range of expertise: nutritional epidemiology upon this work non-commercially, and license response meta-analysis of 21 cohort studies. (AJ), randomised controlled trials (AMM, SCC, and their derivative works on different terms, provided Am J Clin Nutr 2016;103:330-40. doi:10.3945/ AJ), the impact of dietary patterns (AJ and AMM) the original work is properly cited and the use is ajcn.115.124081 and select bioactive components (SCC and AMM) non-commercial. See: http://creativecommons.org/ 15 Zhang Y, Zhuang P, He W, et al. Association of fish on neurophysiology and cognition, nutrigenetics licenses/by-nc/4.0/. and long-chain omega-3 fatty acids intakes with total (AMM), and brain macronutrient metabolism (SCC). All and cause-specific mortality: prospective analysis of authors contributed to drafting this manuscript, with 421 309 individuals. J Intern Med 2018;284:399- AMM taking a lead role; she is also the guarantor of 417. doi:10.1111/joim.12786 the manuscript. All authors gave intellectual input to 16 Wu S, Ding Y, Wu F, Li R, Hou J, Mao P. Omega-3 improve the manuscript and have read and approved fatty acids intake and risks of dementia and the final version. 1 Matthews FE, Arthur A, Barnes LE, et al, Medical Alzheimer’s disease: a meta-analysis. Neurosci http://www.bmj.com/ Research Council Cognitive Function and Ageing Biobehav Rev 2015;48:1-9. doi:10.1016/j. Competing interests: We have read and understood Collaboration. A two-decade comparison of neubiorev.2014.11.008 BMJ policy on declaration of interests and declare prevalence of dementia in individuals aged 65 years 17 Mozaffarian D, Forouhi NG. Dietary guidelines the following interests: SCC was supported by the and older from three geographical areas of England: and health—is nutrition science up to the Alzheimer Association (USA), Canadian Institutes of results of the Cognitive Function and Ageing Study task?BMJ 2018;360:k822. doi:10.1136/bmj.k822 Health Research, Fonds de la recherche en santé du I and II. Lancet 2013;382:1405-12. doi:10.1016/ 18 Ioannidis JPA. The challenge of reforming nutritional Québec, Natural Sciences and Engineering Research S0140-6736(13)61570-6 epidemiologic research. JAMA 2018;320:969-70. Council of Canada, and Nestlé Health Sciences. SCC 2 Pontifex M, Vauzour D, Minihane A-M. The effect doi:10.1001/jama.2018.11025 has done consulting for, and received honorariums, of APOE genotype on Alzheimer’s disease risk is 19 Soininen H, Solomon A, Visser PJ, et al, LipiDiDiet

test products, or research funding from Abitec, Nestlé on 24 September 2021 by guest. Protected copyright. influenced by sex and docosahexaenoic acid status. clinical study group. 24-month intervention Health Sciences, Cerecin, and Bulletproof, and is the Neurobiol Aging 2018;69:209-20. doi:10.1016/j. with a specific multinutrient in people with founder of Senotec. neurobiolaging.2018.05.017 prodromal Alzheimer’s disease (LipiDiDiet): a Provenance and peer review: Commissioned; 3 Lewis F, Schaffer SK, Sussex J, et al. The trajectory randomised, double-blind, controlled trial. Lancet externally peer reviewed. of dementia in the UK–making a difference, Office Neurol 2017;16:965-75. doi:10.1016/S1474- of health Economics, 2014. https://www.ohe.org/ 4422(17)30332-0 This article is part of a series commissioned by The system/files/private/publications/401%20-%20 20 Stonehouse W, Conlon CA, Podd J, et al. DHA BMJ. Open access fees were paid by Swiss Re, which Trajectory_dementia_UK_2014.pdf supplementation improved both memory and had no input into the commissioning or peer review 4 Brookmeyer R, Gray S, Kawas C. Projections of reaction time in healthy young adults: a randomized of the articles. The BMJ thanks the series advisers, Alzheimer’s disease in the United States and the controlled trial. Am J Clin Nutr 2013;97:1134-43. Nita Forouhi, Dariush Mozaffarian, and Anna Lartey public health impact of delaying disease onset. Am doi:10.3945/ajcn.112.053371 for valuable advice and guiding selection of topics in J Public Health 1998;88:1337-42. doi:10.2105/ 21 Zhang YP, Lou Y, Hu J, Miao R, Ma F. DHA the series. AJPH.88.9.1337 supplementation improves cognitive function via Amy Jennings, senior postdoctoral fellow1 5 Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne enhancing Aβ-mediated autophagy in Chinese Stephen C Cunnane, professor2 C. Potential for primary prevention of Alzheimer’s elderly with mild cognitive impairment: a randomised 1 disease: an analysis of population-based data. placebo-controlled trial. J Neurol Neurosurg Anne Marie Minihane, professor Lancet Neurol 2014;13:788-94. doi:10.1016/ Psychiatry 2018;89:382-8. doi:10.1136/jnnp- 1Nutrition and Preventive Medicine Group, Norwich S1474-4422(14)70136-X 2017-316176 Medical School, University of East Anglia, Norwich 6 Akbaraly TN, Singh-Manoux A, Dugravot A, 22 Quinn JF, Raman R, Thomas RG, et al. NR4 7UK, UK, Brunner EJ, Kivimäki M, Sabia S. Association of Docosahexaenoic acid supplementation and 2Research Center on Aging and Department of midlife diet with subsequent risk for dementia. cognitive decline in Alzheimer disease: a randomized Medicine, Université de Sherbrooke, Sherbrooke, QC, JAMA 2019;321:957-68. doi:10.1001/ trial. JAMA 2010;304:1903-11. doi:10.1001/ Canada jama.2019.1432 jama.2010.1510 7 Scientific Advisory Commission on Nutrition. 23 Martinsen A, Tejera N, Vauzour D, et al. Altered Correspondence to: A M Minihane Statement on diet, cognitive impairment and SPMs and age-associated decrease in brain DHA in [email protected] . Public Health England, UK, 2018. https:// APOE4 female mice. FASEB J 2019;33:10315-26. assets.publishing.service.gov.uk/government/ doi:10.1096/fj.201900423R uploads/system/uploads/attachment_data/ 24 Yassine HN, Braskie MN, Mack WJ, et al. Association file/685153/SACN_Statement_on_Diet__Cognitive_ of docosahexaenoic acid supplementation with This is an Open Access article distributed in Impairment_and_Dementias.pdf Alzheimer disease stage in apolipoprotein e ε4 accordance with the Creative Commons Attribution 8 Scarmeas N, Anastasiou CA, Yannakoulia M. Nutrition carriers: a review. JAMA Neurol 2017;74:339-47. Non Commercial (CC BY-NC 4.0) license, which and prevention of cognitive impairment. Lancet doi:10.1001/jamaneurol.2016.4899

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