Letter to the Editor of Lancet
The Report by Livingston et al. cited only one observational study linking higher blood levels of omega-3 fatty acids with risk for dementia (Thomas 2022), which concluded there was “compelling evidence for a relationship between long-chain omega-3 fatty acids levels and lower risks for dementia.”[1] Essentially the same conclusions were reached by several other similar studies between 2006 and 2024 (e.g., [2-4]) plus Sala-Vila 2023, Loong 2023, Schaefer 2006, Samieri 2008, Ammann 2017, Melo van Lent 2021 and He 2023 among others. A 2019 review of observational and randomized clinical trials concluded that omega-3 fatty acids were “safe and well tolerated”, representing “a valuable and biologically plausible tool in the management of neurodegenerative diseases in their early stages” [5]. The vast majority of adults in the Western world have suboptimal blood omega-3 fatty acid levels (Schuchardt, 2024). Correcting this deficit would not only reduce risk for dementia, but also cardiovascular and other inflammation-related diseases. Importantly, the discovery that the cognitive benefits of omega-3s and homocysteine lowering B vitamins are co-dependent by the VITACOG, B-Proof, OmegaAD, and MAPT trials highlights the fact that some neutral omega-3 studies may have been a consequence of this nutrient interplay (i.e., that the omega-3s work in individuals with low (healthy) but not high homocysteine levels). Increased consumption of marine omega-3 fatty acids is safe, simple, cheap and effective tool in the fight to forestall the development of Alzheimer’s dementia. Why were these nutrients and the studies supporting their efficacy ignored in the Lancet Commission report?
William S. Harris, PhD, FASN
Thomas Wood BM BCh, PhD
Simon Dyall, PhD
1. Thomas A, Baillet M, Proust-Lima C, Féart C, Foubert-Samier A, Helmer C, Catheline G, Samieri C: Blood polyunsaturated omega-3 fatty acids, brain atrophy, cognitive decline, and dementia risk. Alzheimer’s and Dementia 2021, 17:407-416.
2. Sala-Vila A, Tintle N, Westra J, Harris WS: Plasma Omega-3 Fatty Acids and Risk for Incident Dementia in the UK Biobank Study: A Closer Look. Nutrients 2023, 15.
3. Loong S, Barnes S, Gatto NM, Chowdhury S, Lee GJ: Omega-3 Fatty Acids, Cognition, and Brain Volume in Older Adults. Brain Sci 2023, 13.
4. Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, Tucker KL, Kyle DJ, Wilson PW, Wolf PA: Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. ArchNeurol 2006, 63:1545-1550.
5. Avallone R, Vitale G, Bertolotti M: Omega-3 Fatty Acids and Neurodegenerative Diseases: New Evidence in Clinical Trials. International Journal of Molecular Sciences 2019, 20:4256.
The Lancet ‘Omission’: Why are homocysteine and B vitamins missing from the Lancet Commission’s Report on Dementia Prevention, Intervention, and Care?
Joshua W. Miller1, Andrew McCaddon2, Jintai Yu3, Babak Hooshmond4, A. David Smith5
1Dept. of Nutritional Sciences,Rutgers University, New Brunswick, NJ, USA
2Faculty of Social and Life Sciences, Wrexham University, Wrexham, UK.
3Dept. of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
4Aging Research Center, Karolinska Institute, Stockholm, Sweden
5Dept. of Pharmacology, University of Oxford, Oxford, UK
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The Lancet Commission’s latest update on dementia is timely and important. We wish to point out a glaring omission from the report. Homocysteine is a sulphur amino acid product of methionine metabolism. It predominantly reflects the status of three B vitamins: folate, and vitamins B12 and B6. A consensus statement of international experts concluded that a raised blood level of homocysteine (hyperhomocysteinemia) is a modifiable risk factor for the development of cognitive decline and dementia, including Alzheimer’s disease, in older persons (1). The relative risk of dementia for moderately raised homocysteine ranges from 1.15 to 2.5, and between 4 and 31% of dementia might be caused by raised homocysteine (1). Homocysteine-lowering treatment with inexpensive and safe B vitamins markedly slows brain shrinkage and cognitive decline in elderly individuals with cognitive impairment (1,2). Notably, the effect of homocysteine on dementia risk is strongest when omega-3 status is inadequate, suggesting a synergistic effect (3).
Unfortunately, despite such robust scientific evidence, determination of homocysteine levels in individuals presenting with memory impairment is not routinely undertaken. Prevalence of hyperhomocysteinemia in older American adults is greater than 10% (4). Health economic analysis shows that homocysteine screening, followed by treatment with B vitamins, would be highly cost-effective in older adults presenting with cognitive impairment (5). It is therefore disappointing that the Lancet Commission fails to recognize hyperhomocysteinemia as an important, modifiable risk factor for age-related cognitive decline and dementia. We look forward to the Commission correcting this omission.
References
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To the Editor,
The authors present a comprehensive epidemiological-based review of risk factors for Alzheimer’s disease (AD). However, epidemiology can be misleading if the underlying pathophysiology is not considered. For example, the observation that obesity, gout, and diabetes are risk factors for AD at midlife but not at time of diagnosis is likely due to the marked weight loss that commonly presages diagnosis of dementia, similar to that seen in subjects with end-stage renal disease. Diet, which drives these conditions, follows these same confounding rules.
Recent studies argue that fructose generated and metabolized in the brain may account for the majority of cases of AD. Fructose is a risk factor that can explain development of AD from inception to end-stage 1. Endogenous production of fructose is largely driven by diet (sugar, refined carbohydrates, ultraprocessed foods, salt, red meats, and alcohol). Hyperglycemia also increases brain fructose production 2. Humans with AD show 5-fold higher intracerebral fructose levels as well as higher metabolites of the polyol pathway (which generates fructose) than age-matched controls 3. Fructose metabolism stimulates foraging as a survival response, but when chronically activated in animals causes CNS insulin resistance, mitochondrial dysfunction, ATP depletion, neuronal loss, and amyloid plaque and tau protein deposition, similar to AD1. The mechanism is mediated by fructokinase and resultant uric acid inhibition of mitochondria in microglia, a finding supported by animal data, metabolomics, and Mendelian studies.4,5
An essential strategy for preventing AD is to follow a healthy diet low in added sugars and refined carbohydrates.
Richard J Johnson1, Robert Lustig MD MSL2, David Perlmutter3
1Department of Medicine, University of Colorado, Aurora, CO, USA; 2Department of Pediatrics, University of California, San Francisco, CA, USA; 3 University of Miami Miller School of Medicine, Miami, FL, USA
Disclosures: RJJ has equity with Colorado Research Partners LLC, has part-time employment with RxSugar, and has consulted for Horizon. RL has no disclosures and DP has equity with RxSugar.
References
1. Johnson RJ, Tolan DR, Bredesen D, et al. Could Alzheimer’s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism? Am J Clin Nutr 2023; 117(3): 455-66.
2. Hwang JJ, Jiang L, Hamza M, et al. The human brain produces fructose from glucose. JCI Insight 2017; 2(4): e90508.
3. Xu J, Begley P, Church SJ, et al. Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer’s disease: metabolic basis for dementia. Sci Rep 2016; 6: 27524.
4. Li Y, Jiang T, Du M, et al. Ketohexokinase-dependent metabolism of cerebral endogenous fructose in microglia drives diabetes-associated cognitive dysfunction. Exp Mol Med 2023.
5. Sanli BA, Whittaker KJ, Motsi GK, Shen E, Julian TH, Cooper-Knock J. Unbiased metabolome screen links serum urate to risk of Alzheimer’s disease. Neurobiol Aging 2022; 120: 167-76.
