Introduction
3. Livingston G, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet. 2024 Aug 10;404(10452):572–628. doi: https://doi.org/10.1016/S0140-6736(24)01296-0 Epub 2024 Jul 31.
4. Nguyen D, et al. Payments by Drug and Medical Device Manufacturers to US Peer Reviewers of Major Medical Journals. JAMA. 2024;332(17):1480–1482. doi: https://doi.org/10.1001/jama.2024.17681
Part 1 – WHAT DOES & DOESN’T CAUSE ALZHEIMER’S
Chapter 1. Amyloid ≠ Alzheimer’s and the Tauist’s delusion
8. Herrup K. The case for rejecting the amyloid cascade hypothesis. Nat Neurosci. 2015 Jun;18(6):794–799. doi: https://doi.org/10.1038/nn.4017 (Also see references and full discussion in Chapter 8 of How Not to Study a Disease, K. Herrup, MIT Press. Lopez OL, et al. Association Between β-Amyloid Accumulation and Incident Dementia in Individuals 80 Years or Older Without Dementia. Neurology. 2024 Jan 23;102(2):e207920.)
9. Salloway S, et al. Dominantly Inherited Alzheimer Network–Trials Unit. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021 Jul;27(7):1187–1196. doi: https://doi.org/10.1038/s41591-021-01369-8 Epub 2021 Jun 21.
10. Volloch V, et al. Results of Beta Secretase-Inhibitor Clinical Trials Support Amyloid Precursor Protein-Independent Generation of Beta Amyloid in Sporadic Alzheimer’s Disease. Med Sci (Basel). 2018 Jun 2;6(2):45. doi: https://doi.org/10.3390/medsci6020045
11. van Dyck CH, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2023 Jan 5;388(1):9–21. doi: https://doi.org/10.1056/NEJMoa2212948 Epub 2022 Nov 29.
12. Walsh S, et al. Lecanemab for Alzheimer’s disease. BMJ. 2022;379:o3010. doi: https://doi.org/10.1136/bmj.o3010
15. Ackley SF, et al. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021 Feb 25;372:n156. doi: https://doi.org/10.1136/bmj.n156 Erratum in: BMJ. 2022 Aug 30;378:o2094.
16. Smith AD. Anti-amyloid trials raise scientific and ethical questions. BMJ. 2021;372:n805. doi: https://doi.org/10.1136/bmj.n805
17. Smith AD. Why are drug trials in Alzheimer’s disease failing? Lancet. 2010;376:1466. doi: https://doi.org/10.1016/S0140-6736(10)61994-0
18. Sims JR, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023 Aug 8;330(6):512–527. doi: https://doi.org/10.1001/jama.2023.13239
20. Cummings J, et al. Alzheimer’s disease drug development pipeline: 2024. Alzheimers Dement (N Y). 2024 Apr 24;10(2):e12465. Dutch. doi: https://doi.org/10.1002/trc2.12465
24. Smith AD, Refsum H. Homocysteine, B Vitamins, and Cognitive Impairment. Annu Rev Nutr. 2016 Jul 17;36:211–239. doi: https://doi.org/10.1146/annurev-nutr-071715-050947; see also Li JG, Chu J, Barrero C, Merali S, Pratico D. Homocysteine exacerbates β-amyloid, tau pathology, and cognitive deficit in a mouse model of Alzheimer’s disease with plaques and tangles. Ann Neurol. 2014;75:851–63; doi: https://doi.org/10.1002/ana.24166; see also Shirafuji N, et al. Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization. Int J Mol Sci.2018 Mar 17;19(3):891. doi: https://doi.org/10.3390/ijms19030891; see also Bossenmeyer-Pourié C, et al. N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer’s disease and vascular dementia. J Pathol. 2019 Jul;248(3):291–303. doi: https://doi.org/10.1002/path.5254 Epub 2019 Mar 19.
25. Wischik CM, et al. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11213–8. doi: https://doi.org/10.1073/pnas.93.20.1121
26. Al-Hilaly YK, et al. Cysteine-Independent Inhibition of Alzheimer’s Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT). J Mol Biol. 2018 Oct 19;430(21):4119–4131. Epub 2018 Aug 16. Doi: https://doi.org/10.1016/j.jmb.2018.08.010
27. Arvanitakis Z, et al. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol.2004 May;61(5):661–666. doi: https://doi.org/10.1001/archneur.61.5.661; see also Yaffe K, et al. Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology. 2004 Aug 24;63(4):658–663. doi: https://doi.org/10.1212/01.WNL.0000134665.93885.71; see also Tiehuis AM, et al. Diabetes Increases Atrophy and Vascular Lesions on Brain MRI in Patients With Symptomatic Arterial Disease. Stroke. 2008 May;39(5):1600–1603. doi: https://doi.org/10.1161/STROKEAHA.107.502963; see also Samaras K, et al. The impact of glucose disorders on cognition and brain volumes in the elderly: the Sydney Memory and Ageing Study. AGE. 2014;36(2):977–993. doi: https://doi.org/10.1007/s11357-013-9585-3; see also Mortby ME, et al. High ‘normal’ blood glucose is associated with decreased brain volume and cognitive performance in the 60s: the PATH through life study. PLoS One. 2013 Sep 4;8(9):e73697.
doi: https://doi.org/10.1371/journal.pone.0073697; see also Crane PK, et al. Glucose levels and risk of dementia. N Engl J Med. 2013 Aug 8;369(6):540–548. doi: https://doi.org/10.1056/NEJMoa1215740; see also Luchsinger JA, et al. Hyperinsulinemia and risk of Alzheimer disease. Neurology. 2004 Oct 12;63(7):1187–1192. doi: https://doi.org/10.1212/01.wnl.0000140292.04932.87; see also Abbatecola AM, et al. Insulin resistance and executive dysfunction in older persons. J Am Geriatr Soc. 2004 Oct;52(10):1713–1718. doi: https://doi.org/10.1111/j.1532-5415.2004.52466.x; see also Ye X, et al. Habitual sugar intake and cognitive function among middle-aged and older Puerto Ricans without diabetes. Br J Nutr. 2011 Nov;106(9):1423–1432. doi: https://doi.org/10.1017/S0007114511001760; see also Power SE, et al. Dietary glycaemic load associated with cognitive performance in elderly subjects. Eur J Nutr.2015 Jun;54(4):557–568. doi: https://doi.org/10.1007/s00394-014-0737-5; see also Seetharaman S, et al. Blood glucose, diet-based glycemic load and cognitive aging among dementia-free older adults. J Gerontol A Biol Sci Med Sci. 2015 Apr;70(4):471–479. doi: https://doi.org/10.1093/gerona/glu135; see also Taylor MK, et al. A high-glycemic diet is associated with cerebral amyloid burden in cognitively normal older adults. Am J Clin Nutr. 2017 Dec;106(6):1463–1470. doi: https://doi.org/10.3945/ajcn.117.162263; see also Gentreau M, et al. High Glycemic Load Is Associated with Cognitive Decline in Apolipoprotein E ε4 Allele Carriers. Nutrients. 2020 Nov 25;12(12):3619. doi: https://doi.org/10.3390/nu12123619
28. Xie W, et al. Association between disease-modifying antirheumatic drugs for rheumatoid arthritis and risk of incident dementia: a systematic review and meta-analysis. RMD Open. 2024 Feb 27;10(1):e004016. doi: https://doi.org/10.1136/rmdopen-2023-004016
29. Beydoun MA, et al. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014 Jun 24;14:643. doi: https://doi.org/10.1186/1471-2458-14-643
30. Teng Z, et al. Cerebral small vessel disease mediates the association between homocysteine and cognitive function. Front Aging Neurosci. 2022;14:868777. doi: https://doi.org/10.3389/fnagi.2022.868777
31. Chen C, et al. B vitamin intakes modify the association between particulate air pollutants and incidence of all-cause dementia: Findings from the Women’s Health Initiative Memory Study. Alzheimers Dement. 2022 Nov;18(11):2188–2198. doi: https://doi.org/10.1002/alz.12515 Epub 2022 Feb 1.
Chapter 2: Less than 1% is ‘in the Genes’ and the ApoE4 Exaggeration
32. McKay NS, Benzinger TLS. The Dominantly Inherited Alzheimer Network: A neuroimaging resource. Nat Neurosci.2023 Aug;26(8):1326–1327. doi: https://doi.org/10.1038/s41593-023-01360-1
33. Bekris LM, et al. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol. 2010 Dec;23(4):213–27. doi: https://doi.org/10.1177/0891988710383571
34. https://www.npr.org/2025/02/12/nx-s1-5293253/his-genes-forecast-alzheimers-his-brain-had-other-plans?utm_source=firefox-newtab-en-gb Llibre-Guerra JJ, et al. Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia. Nat Med. (2025). https://doi.org/10.1038/s41591-025-03494-0
35. Bellenguez C, et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet.2022;54:412–436. https://doi.org/10.1038/s41588-022-01024-z
36. Escott-Price V, et al. Polygenic risk score analysis of pathologically confirmed Alzheimer disease. Ann Neurol. 2017 Aug;82(2):311–314. doi: https://doi.org/10.1002/ana.24999
37. Heininger K. A unifying hypothesis of Alzheimer’s disease. III. Risk factors. Hum Psychopharmacol Clin Exp.2000;15:1–70. https://doi.org/10.1002/(SICI)1099-1077(200001)15:1<1::AID-HUP153>3.0.CO;2-1; see also Ridge PG, et al. Alzheimer’s Disease: Analyzing the Missing Heritability. PLoS ONE. 2013;8(11):e79771.
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38. Dunk MM, Driscoll I; Alzheimer’s Disease Neuroimaging Initiative. Total Cholesterol and APOE-Related Risk for Alzheimer’s Disease. J Alzheimers Dis. 2022;85(4):1519–1528. doi: https://doi.org/10.3233/JAD-215091
39. Walsh S, et al. Lecanemab for Alzheimer’s disease. BMJ. 2022;379:o3010. doi: https://doi.org/10.1136/bmj.o3010; see also van Dyck CH, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2023;388(1):9–21
40. Norwitz NG, et al. Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers. Nutrients. 2021;13:1362. https://doi.org/10.3390/nu13041362
41. Jia J, et al. Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study. BMJ. 2023;380:e072691. http://dx.doi.org/10.1136/bmj-2022-072691
42. Solomon A, et al. Effect of the Apolipoprotein E Genotype on Cognitive Change During a Multidomain Lifestyle Intervention: A Subgroup Analysis of a Randomized Clinical Trial. JAMA Neurol. 2018 Apr 1;75(4):462–470. doi: https://doi.org/10.1001/jamaneurol.2017.4365
43. Morris AA, et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2017;40:49–74 doi: https://doi.org/10.1007/s10545-016-9979-0; see also Bouguerra K, et al. The methylenetetrahydrofolate reductase C677T and A1298C genetic polymorphisms and plasma homocysteine in Alzheimer’s disease in an Algerian population. Int J Neurosci.2022 Dec 29:1–6. doi: https://doi.org/10.1080/00207454.2022.2158825; see also Zuin M, et al. Methylenetetrahydrofolate reductase C667T polymorphism and susceptibility to late-onset Alzheimer’s disease in the Italian population. Minerva Med. 2021 Jun;112(3):365–371
doi: https://doi.org/10.23736/S0026-4806.20.06801-9 (Epub 2020 Jul 22)
44. Teng Z, et al. Cerebral small vessel disease mediates the association between homocysteine and cognitive function. Front Aging Neurosci. 2022;14:868777. doi: https://doi.org/10.3389/fnagi.2022.868777
45. Niu YY, et al. Association of dietary choline intake with incidence of dementia, Alzheimer disease, and mild cognitive impairment: a large population-based prospective cohort study. Am J Clin Nutr. 2024 Nov 7:S0002-9165(24)00869-4. doi: https://doi.org/10.1016/j.ajcnut.2024.11.001
46. Smith AD, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010 Sep 8;5(9):e12244. doi: https://doi.org/10.1371/journal.pone.0012244; see also Smith AD, Refsum H. Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr. 2016;36:211–239.
47. Douaud G, et al. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. 2013;110:9523–9528. doi: https://doi.org/10.1073/pnas.130181611
Chapter 3. Alzheimer’s is Caused by a Systems Breakdown
48. Chen C, et al. B vitamin intakes modify the association between particulate air pollutants and incidence of all-cause dementia: Findings from the Women’s Health Initiative Memory Study. Alzheimers Dement. 2022 Nov;18(11):2188–2198. doi: https://doi.org/10.1002/alz.12515 Epub 2022 Feb 1.
49. Bloomberg M, et al. Associations of accelerometer-measured physical activity, sedentary behaviour, and sleep with next-day cognitive performance in older adults: a micro-longitudinal study. Int J Behav Nutr Phys Act. 2024;21:133. https://doi.org/10.1186/s12966-024-01683-7
50. Pending publication – details to follow.
51. Cummings JL, et al. The costs of developing treatments for Alzheimer’s disease: A retrospective exploration. Alzheimers Dement. 2022 Mar;18(3):469-477. doi: https://doi.org/10.1002/alz.12450
52. van Dyck CH, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2023 Jan;388(1):9-21. doi: https://doi.org/10.1056/NEJMoa2212948
53. Oulhaj A, et al. Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. J Alzheimers Dis. 2016;50(2):547-57. doi: https://doi.org/10.3233/JAD-150777
54. Ackley SF, et al. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021 Feb;372:n156. doi: https://doi.org/10.1136/bmj.n156
55. Nguyen D, et al. Payments by Drug and Medical Device Manufacturers to US Peer Reviewers of Major Medical Journals. JAMA. 2024;332(17):1480-1482. doi: https://doi.org/10.1001/jama.2024.17681
58. https://www.ncbi.nlm.nih.gov/search/research-news/17133/ here is the actual New York Times link, but behind a paywall https://www.nytimes.com/2022/09/15/health/fda-drug-industry-fees.html
59. https://edition.cnn.com/2024/05/18/health/alzheimers-blood-brain-improvement-wellness/index.html
PART 2 – THE 8 PREVENTION DOMAINS
Chapter 4. The Four Biological Horsemen of the Brain Apocalypse
60. GBD 2021 Diseases and Injuries Collaborators. Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet. 2024 May;403(10440):2133-2161. doi: https://doi.org/10.1016/S0140-6736(24)00757-8
62. Ren R, et al. The China Alzheimer Report 2022. General Psychiatry. 2022;0:e100751. doi: https://doi.org/10.1136/gpsych-2022-100751
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64. Crawford M, et al. The Shrinking Brain. Filament Publishing; 2023. https://www.amazon.co.uk/Shrinking-Brain-Michael-Crawford
65. von Bartheld CS, et al. The search for true numbers of neurons and glial cells in the human brain: A review of 150 years of cell counting. J Comp Neurol. 2016 Dec;524(18):3865-3895. doi: https://doi.org/10.1002/cne.24040
66. Wood T, et al. A systems-based unified model of age-related cognitive decline and its prevention.
Chapter 5. Brain Fats – Omega-3, Phospholipids and Vitamin D
68. Methylation is required in the synthesis of choline, the actual process of attaching the phospholipid to mega-3 or arachidonic acid is called acetylation.
69. Livingston G, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet. 2024 Aug;404(10452):572-628. doi: https://doi.org/10.1016/S0140-6736(24)01296-0
70. Thomas A, et al. Blood polyunsaturated omega-3 fatty acids, brain atrophy, cognitive decline, and dementia risk. Alzheimers Dement. 2020;17(3):407-16. doi: https://doi.org/10.3390/brainsci13091278
71. Thomas A, et al. “Blood polyunsaturated omega-3 fatty acids, brain atrophy, cognitive decline, and dementia risk.” Alzheimer’s & Dementia. 2021;17:407-416. doi: https://doi.org/10.1002/alz.12195; Schaefer EJ, et al. “Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study.” Archives of Neurology. 2006;63:1545-1550. doi: https://doi.org/10.1001/archneur.63.11.1545; Selley ML. “A metabolic link between S-adenosylhomocysteine and polyunsaturated fatty acid metabolism in Alzheimer’s disease.” Neurobiology of Aging. 2007 Dec;28(12):1834-9. doi: https://doi.org/10.1016/j.neurobiolaging.2006.08.006; Whiley L, et al. “Evidence of altered phosphatidylcholine metabolism in Alzheimer’s disease.” Neurobiology of Aging. 2014 Feb;35(2):271-8. doi: https://doi.org/10.1016/j.neurobiolaging.2013.08.001; Yuki D, et al. “DHA-PC and PSD-95 decrease after loss of synaptophysin and before neuronal loss in patients with Alzheimer’s disease.” Scientific Reports. 2014 Nov;4:7130. doi: https://doi.org/10.1038/srep07130.
72. Sala-Vila A, et al. Plasma Omega-3 Fatty Acids and Risk for Incident Dementia in the UK Biobank Study: A Closer Look. Nutrients. 2023 Nov;15(23):4896. doi: https://doi.org/10.3390/nu15234896
73. Avallone R, et al. Omega-3 Fatty Acids and Neurodegenerative Diseases: New Evidence in Clinical Trials. Int J Mol Sci. 2019;20:4256. https://doi.org/10.3390/ijms20174256
74. Sala-Vila A, et al. Plasma Omega-3 Fatty Acids and Risk for Incident Dementia in the UK Biobank Study: A Closer Look. Nutrients. 2023 Nov;15(23):4896. doi: https://doi.org/10.3390/nu15234896
75. Wei BZ, et al. The Relationship of Omega-3 Fatty Acids with Dementia and Cognitive Decline: Evidence from Prospective Cohort Studies of Supplementation, Dietary Intake, and Blood Markers. Am J Clin Nutr. 2023;117(6):1096-1109. doi: https://doi.org/10.1016/j.ajcnut.2023.04.001
76. Loong S, et al. Omega-3 Fatty Acids, Cognition, and Brain Volume in Older Adults. Brain Sci. 2023;13:1278. doi: https://doi.org/10.3390/brainsci13091278
77. Shinto LH, et al. ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults: A Randomized Clinical Trial. JAMA Netw Open. 2024;7(8):e2426872. doi: https://doi.org/10.1001/jamanetworkopen.2024.26872 78. https://www.newsweek.com/fish-oil-prevent-dementia-1933059
79. Witte AV, et al. Long-chain omega-3 fatty acids improve brain function and structure in older adults. Cereb Cortex.2014 Nov;24(11):3059-68. doi: https://doi.org/10.1093/cercor/bht163
80. Schaefer EJ, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006 Nov;63(11):1545-50. doi: https://doi.org/10.1001/archneur.63.11.1545
81. Niu Y, et al. Association of dietary choline intake with incidence of dementia, Alzheimer disease, and mild cognitive impairment: a large population-based prospective cohort study. Am J Clin Nutr. 2025;121(1):5-13. doi: https://doi.org/10.1016/j.ajcnut.2024.11.001
82. Pan Y, et al. Association of Egg Intake With Alzheimer’s Dementia Risk in Older Adults: The Rush Memory and Aging Project. J Nutr. 2024 Jul;154(7):2236-2243. doi: https://doi.org/10.1016/j.tjnut.2024.05.012
83. Jayedi A, et al. Vitamin D status and risk of dementia and Alzheimer’s disease: A meta-analysis of dose-response. Nutr Neurosci. 2019 Nov;22(11):750-759. doi: https://doi.org/10.1080/1028415X.2018.1436639
84. Chai B, et al. Vitamin D deficiency as a risk factor for dementia and Alzheimer’s disease: an updated meta-analysis. BMC Neurol. 2019 Nov;19(1):284. doi: https://doi.org/10.1186/s12883-019-1500-6
85. Feart C, et al. Associations of lower vitamin D concentrations with cognitive decline and long-term risk of dementia and Alzheimer’s disease in older adults. Alzheimers Dement. 2017 Nov;13(11):1207-1216. doi: https://doi.org/10.1016/j.jalz.2017.03.003
86. Jia J, et al. Effects of vitamin D supplementation on cognitive function and blood Aβ-related biomarkers in older adults with Alzheimer’s disease: a randomised, double-blind, placebo-controlled trial. J Neurol Neurosurg Psychiatry.2019 Dec;90(12):1347-1352. doi: https://doi.org/10.1136/jnnp-2018-320199
87. Ghahremani M, et al. Vitamin D supplementation and incident dementia: Effects of sex, APOE, and baseline cognitive status. Alzheimers Dement (Amst). 2023 Mar;15(1):e12404. doi: https://doi.org/10.1002/dad2.12404
88. You W. The Protective Role of Ambient Ultraviolet Radiation Against Dementia: An Ecological Analysis of Global Data. Health Sci Rep. 2025;8:e70302. doi: https://doi.org/10.1002/hsr2.70302
89. Patrick RP, et al. Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. FASEB J. 2015 Jun;29(6):2207-22. doi: https://doi.org/10.1096/fj.14-268342
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91. Zhong G, et al. Smoking is associated with an increased risk of dementia: a meta-analysis of prospective cohort studies with investigation of potential effect modifiers. PLoS One. 2015 Mar;10(3):e0118333. doi: https://doi.org/10.1371/journal.pone.0118333
92. Abolhasani E, et al. Air pollution and incidence of dementia: a systematic review and meta-analysis. Neurology.2023;100:e242-54. Doi: https://doi.org/10.1212/WNL.000000000020141
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103. Loong S, et al. Omega-3 fatty acids, cognition, and brain volume in older adults. Brain Sci. 2023;13(9):1278. doi: https://doi.org/10.3390/brainsci13091278
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106. Pan Y, et al. Association of egg intake with Alzheimer’s dementia risk in older adults: the Rush memory and aging project. J Nutr. 2024 Jul;154(7):2236-2243. doi: https://doi.org/10.1016/j.tjnut.2024.05.012
Chapter 6. Methylation, Homocysteine and the Causal Role of B vitamins
107. Response from ARUK (30/4/24): “The figures on research spend at that level of detail are not available on our website, but I have provided them here. £8.5 million funding on 66 non-drug prevention studies, the first study of this type was funded in 2002. Since 2002 we’ve funded a total of £194.3M. As a percentage of the whole that’s 4.36%.”
108. Smith AD, et al. Homocysteine and dementia: an international consensus statement. J Alzheimers Dis. 2018;62:561-70. doi: https://doi.org/10.3233/JAD-171042
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Chapter 7. Omega-3 and B vitamins – the Dynamic Duo
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Chapter 8. How our Sugared Brains are ‘Fructed’ and How Ketones Aid Recovery
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159. Li H, et al. Association of ultraprocessed food consumption with risk of dementia: a prospective cohort study. Neurology. 2022;99(10):e1056-e1066. doi: https://doi.org/10.1212/WNL.0000000000200871
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165. Crane PK, et al. Glucose levels and risk of dementia. N Engl J Med. 2013;369(6):540–548. doi: https://doi.org/10.1056/NEJMoa1215740
166. Ye X, et al. Habitual sugar intake and cognitive function among middle-aged and older Puerto Ricans without diabetes. Br J Nutr. 2011;106(9):1423–1432. doi: https://doi.org/10.1017/S0007114511001760
167. Seetharaman S, et al. Blood glucose, diet-based glycemic load and cognitive aging amongst dementia-free older adults. J Gerontol A Biol Sci Med Sci. 2015;70(4):471–479. doi: https://doi.org/10.1093/gerona/glu135
168. Power SE, et al. Dietary glycaemic load associated with cognitive performance in elderly subjects. Eur J Nutr.2015;54(4):557–568. doi: 10.1007/s00394-014-0737-5
169. Taylor MK, et al. A high-glycemic diet is associated with cerebral amyloid burden in cognitively normal older adults. Am J Clin Nutr. 2017;106(6):1463–1470. doi: https://doi.org/10.3945/ajcn.117.162263
170. Taylor MK, et al. A high-glycemic diet is associated with cerebral amyloid burden in cognitively normal older adults. Am J Clin Nutr. 2017;106(6):1463-1470. doi: https://doi.org/10.3945/ajcn.117.162263
171. Gentreau M, et al. High glycemic load is associated with cognitive decline in apolipoprotein E ε4 allele carriers. Nutrients. 2020;12(12):3619. doi: https://doi.org/10.3390/nu12123619
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173. Deng YT, et al. Association of life course adiposity with risk of incident dementia: a prospective cohort study of 322,336 participants. Mol Psychiatry. 2022;27(8):3385-3395. doi: https://doi.org/10.1038/s41380-022-01604-9; see also Bouret SG, et al. Hypothalamic neural projections are permanently disrupted in diet-induced obese rats. Cell Metab. 2008;7(2):179-85. doi: https://doi.org/10.1016/j.cmet.2007.12.001
174. Oron-Herman M, et al. Hyperhomocysteinemia as a component of syndrome X. Metabolism. 2003;52(11):1491-5. doi: 10.1016/s0026-0495(03)00262-2
175. Chen L, et al. Synergistically effects of n-3 PUFA and B vitamins prevent diabetic cognitive dysfunction through promoting TET2-mediated active DNA demethylation. Clin Nutr. 2025;45:111-123. doi: https://doi.org/10.1016/j.clnu.2025.01.002
176. Johnson RJ, 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. doi: https://doi.org/10.1016/j.ajcnut.2023.01.002
177. Hwang JJ, et al. The human brain produces fructose from glucose. JCI Insight. 2017;2(4):e90508. doi: https://doi.org/10.1172/jci.insight.90508
178. Xu J, 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. doi: https://doi.org/10.1038/srep27524
179. Johnson RJ, 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. doi: https://doi.org/10.1016/j.ajcnut.2023.01.002
180. Li Y, et al. Ketohexokinase-dependent metabolism of cerebral endogenous fructose in microglia drives diabetes-associated cognitive dysfunction. Exp Mol Med. 2023. doi: https://doi.org/10.1038/s12276-023-01112-y; see also, Sanli BA, et al. Unbiased metabolome screen links serum urate to risk of Alzheimer’s disease. Neurobiol Aging.2022;120:167–176. doi: https://doi.org/10.1016/j.neurobiolaging.2022.09.004
181. Johnson RJ, et al. A historical and scientific perspective of sugar and its relation with obesity and diabetes. Adv Nutr.2017;8(3):412-422. doi: https://doi.org/10.3945/an.116.014654
182. Underwood PC, et al. HbA1c time in range and dementia. JAMA Netw Open. 2024;7(8):e2425354. doi: https://doi.org/10.1001/jamanetworkopen.2024.25354
183. Yau PL, et al. Obesity and metabolic syndrome and functional and structural brain impairments in adolescence. Pediatrics. 2012;130(4):e856-64. doi: https://doi.org/10.1542/peds.2012-0324
184. Jia J, et al. A 19-year-old adolescent with probable Alzheimer’s disease. J Alzheimers Dis. 2023;91(3):915-922. doi: https://doi.org/10.3233/JAD-221065
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186. Vandenberghe C, et al. Tricaprylin alone increases plasma ketone response more than coconut oil or other medium-chain triglycerides: an acute crossover study in healthy adults. Curr Dev Nutr. 2017;1(4):e000257.https://pmc.ncbi.nlm.nih.gov/articles/PMC5998344/
187. Croteau E, et al. Ketogenic medium chain triglycerides increase brain energy metabolism in Alzheimer’s disease. J Alzheimers Dis. 2018;64(2):551-561. doi: https://doi.org/10.3233/JAD-180202
188. Fortier M, et al. A ketogenic drink improves cognition in mild cognitive impairment: results of a 6-month RCT. Alzheimers Dement. 2021;17(3):543-552. doi: https://doi.org/10.1002/alz.12206
189. Phillips MCL, et al. Randomized crossover trial of a modified ketogenic diet in Alzheimer’s disease. Alzheimers Res Ther. 2021;13(1):51. doi: https://doi.org/10.1186/s13195-021-00783-x
190. Sabia S, et al. Alcohol consumption and risk of dementia: 23 year follow-up of Whitehall II cohort study. BMJ.2018;362:k2927. doi: https://doi.org/10.1136/bmj.k2927
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Chapter 9. Anti-age your Brain with Antioxidants, Glutathione and NAC
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196. Carr AC, et al. Factors affecting the vitamin C dose-concentration relationship: implications for global vitamin C dietary recommendations. Nutrients. 2023;15(7):1657. doi: https://doi.org/10.3390/nu15071657
197. Mons U, et al. Effect of smoking reduction and cessation on the plasma levels of the oxidative stress biomarker glutathione – post-hoc analysis of data from a smoking cessation trial. Free Radic Biol Med. 2016;91:172-7. doi: https://doi.org/10.1016/j.freeradbiomed.2015.12.018
198. Peng M, et al. Dietary total antioxidant capacity and cognitive function in older adults. J Nutr Health Aging. 2023. Doi: https://doi.org/10.1007/s12603-023-1934-9
199. See Professor Jeremy Spencer’s presentation at the Alzheimer’s is preventable masterclass (2022) – foodforthebrain.org/aipmasterclass; also see Spencer JP. The impact of fruit flavonoids on memory and cognition. Br J Nutr. 2010 Oct;104 Suppl 3:S40-7. doi: 10.1017/S0007114510003934
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205. Foyer CH, Kunert K. The ascorbate-glutathione cycle coming of age. J Exp Bot. 2024;75(9):2682-2699. doi: https://doi.org/10.1093/jxb/erae023
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223. Feng L, et al. Tea for Alzheimer’s prevention. J Prev Alzheimers Dis. 2015;2(2):136-141. doi: https://doi.org/10.14283/jpad.2015.57
224. Cornelis MC, et al. Caffeinated coffee and tea consumption, genetic variation and cognitive function in the UK biobank. J Nutr. 2020;150(8):2164-2174. doi: https://doi.org/10.1093/jn/nxaa147
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Chapter 10. Use it or Lose it – Lifestyle Factors that Protect Your Brain
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234. Wei L, et al. Association of vitamin C with the risk of age-related cataract: a meta-analysis. Acta Ophthalmol.2016;94(3):e170-6. doi: https://doi.org/10.1111/aos.12688
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245. Wang W, et al. Total and regional fat-to-muscle mass ratio and risks of incident all-cause dementia, Alzheimer’s disease, and vascular dementia. J Cachexia Sarcopenia Muscle. 2022;13(5):2447-2455. doi: https://doi.org/10.1002/jcsm.13054
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Chapter 11. Brain Recovery and Repair – the Sleep, Stress and Hormone Connection
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258. Daviet R, et al. Associations between alcohol consumption and gray and white matter volumes in the UK Biobank. Nat Commun. 2022;13(1):1175. doi: https://doi.org/10.1038/s41467-022-28735-5
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261. Franks KH, et al. Association of stress with risk of dementia and mild cognitive impairment: a systematic review and meta-analysis. J Alzheimers Dis. 2021;82(4):1573-1590. doi: https://doi.org/10.3233/JAD-210094
262. Debono M, et al. Modified-release hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol Metab.2009;94(5):1548-54. doi: https://doi.org/10.1210/jc.2008-2380
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265. Siddiqui AN, et al. Neuroprotective role of steroidal sex hormones: an overview. CNS Neurosci Ther.2016;22(5):342-50. doi: https://doi.org/10.1111/cns.12538
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267. Bendis PC, et al. The impact of estradiol on serotonin, glutamate, and dopamine systems. Front Neurosci.2024;18:131223. doi: https://doi.org/10.3389/fnins.2024.1348551
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269. Behrman S, Crockett C. Severe mental illness and the perimenopause. BJPsych Bull. 2023. doi: 10.1192/bjb.2023.89
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272. Del Río JP, et al. Steroid hormones and their action in women’s brains: the importance of hormonal balance. Front Public Health. 2018;6:141. doi: https://doi.org/10.3389/fpubh.2018.00141
273. Glynne S, et al. Effect of transdermal testosterone therapy on mood and cognitive symptoms in peri- and postmenopausal women: a pilot study. Arch Womens Ment Health. 2024. doi: 10.1007/s00737-024-01513-6
274. Kim YJ, et al. Association between menopausal hormone therapy and risk of neurodegenerative diseases: implications for precision hormone therapy. Alzheimers Dement (N Y). 2021;7(1):e12174. doi: https://doi.org/10.1002/trc2.12174
275. Yahn GB, et al. The role of dietary supplements that modulate one-carbon metabolism on stroke outcome. Curr Opin Clin Nutr Metab Care. 2021;24(4):303-307. doi: https://doi.org/10.1097/MCO.0000000000000743
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Chapter 12. Microbes and the Mind
286. Walker AW, Hoyles L. Human microbiome myths and misconceptions. Nat Microbiol. 2023;8(8):1392-1396. doi: https://doi.org/10.1038/s41564-023-01426-7
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288. Williams ZAP, et al. Do microbes play a role in Alzheimer’s disease? Microb Biotechnol. 2024;17(4):e14462. doi: https://doi.org/10.1111/1751-7915.14462
289. Beydoun MA, et al. Clinical and bacterial markers of periodontitis and their association with incident all-cause and Alzheimer’s disease dementia in a large national survey. J Alzheimers Dis. 2020;75(1):157-172. doi: https://doi.org/10.3233/JAD-200064
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293. L’Heureux JE, et al. Oral microbiome and nitric oxide biomarkers in older people with mild cognitive impairment and APOE4 genotype. PNAS Nexus. 2025;4(1):pgae543. doi: https://doi.org/10.1093/pnasnexus/pgae543
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300. Readhead BP, et al. Alzheimer’s disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain. Alzheimers Dement. 2024. doi: https://doi.org/10.1002/alz.14401
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306. Devaraj RD, et al. Health-promoting effects of konjac glucomannan and its practical applications: a critical review. Int J Biol Macromol. 2019;126:273-281. doi: https://doi.org/10.1016/j.ijbiomac.2018.12.203
PART 3 – PREVENTION IN ACTION
Chapter 13. Assessing and Reversing Your Risk with the Cognitive Function Test
Chapter 14. Your Alzheimer’s Prevention Plan – Diet, Supplements & Lifestyle
307. Eskelinen MH, et al. Midlife healthy-diet index and late-life dementia and Alzheimer’s disease. Dement Geriatr Cogn Dis Extra. 2011;1(1):103-12. doi: https://doi.org/10.1159/000327518
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309. Singh B, et al. Association of Mediterranean diet with mild cognitive impairment and Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014;39(2):271-82. doi: https://doi.org/10.3233/JAD-130830
310. Croll PH, et al. Better diet quality relates to larger brain tissue volumes: the Rotterdam study. Neurology.2018;90(24):e2166-e2173. doi: https://doi.org/10.1212/WNL.0000000000005691
311. Li Y, et al. Long-term intake of red meat in relation to dementia risk and cognitive function in US adults. Neurology.2025;104(3):e210286. doi: https://doi.org/10.1212/WNL.0000000000210286
312. Li H, et al. Association of ultraprocessed food consumption with risk of dementia: a prospective cohort. Neurology.2022;99(10):e1056-e1066. doi: https://doi.org/10.1212/WNL.0000000000200871
313. Devore E, et al. Dietary intakes of berries and flavonoids in relation to cognitive decline. Ann Neurol. 2012;72:135-43. doi: https://doi.org/10.1002/ana.23594: see also Agarwal P, et al. Association of strawberries and anthocyanidin intake with Alzheimer’s dementia risk. Nutrients.2019;11(12):3060. doi: https://doi.org/10.3390/nu11123060
314. Godos J, et al. Fish consumption, cognitive impairment and dementia: an updated dose-response meta-analysis of observational studies. Aging Clin Exp Res. 2024;61:3731–3739. doi: https://doi.org/10.1007/s40520-024-02823-6
315. Beydoun MA, et al. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014;14:643. doi: https://doi.org/10.1186/1471-2458-14-643
316. Pan Y, et al. Association of egg intake with Alzheimer’s dementia risk in older adults: the Rush memory and aging project. J Nutr. 2024;154(7):2236-2243. doi: https://doi.org/10.1016/j.tjnut.2024.05.012
317. Román GC, et al. Extra-virgin olive oil for potential prevention of Alzheimer disease. Rev Neurol (Paris).2019;175(10):705-723. doi: https://doi.org/10.1016/j.neurol.2019.07.017
318. Wang X, et al. Coffee drinking timing and mortality in US adults. Eur Heart J. 2025;ehae871. doi: https://doi.org/10.1093/eurheartj/ehae871
319. Nurk E, et al. Intake of flavonoid-rich wine, tea, and chocolate by elderly men and women is associated with better cognitive test performance. J Nutr. 2009;139(1):120-7. doi: https://doi.org/10.3945/jn.108.095182
320. Feng L, et al. Tea for Alzheimer prevention. J Prev Alzheimers Dis. 2015;2(2):136-141. doi: https://doi.org/10.14283/jpad.2015.57
321. Cornelis MC, et al. Caffeinated coffee and tea consumption, genetic variation and cognitive function in the UK biobank. J Nutr. 2020;150(8):2164-2174. doi: https://doi.org/10.1093/jn/nxaa147
322. Lamport DJ, et al. The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: a placebo controlled, crossover, acute trial. Psychopharmacology (Berl). 2015;232(17):3227-34. doi: https://doi.org/10.1007/s00213-015-3972-4
323. Sabia S, et al. Alcohol consumption and risk of dementia: 23 year follow-up of Whitehall II cohort study. BMJ.2018;362:k2927. doi: https://doi.org/10.1136/bmj.k2927
324. Li Y, et al. Long-term intake of red meat in relation to dementia risk and cognitive function in US adults. Neurology.2025;104(3):e210286. doi: https://doi.org/10.1212/WNL.0000000000210286
325. Clayton P, Rowbotham J, et al. An unsuitable and degraded diet? Part one: public health lessons from the mid-Victorian working class diet. J R Soc Med. 2008;101:282–289. doi: https://doi.org/10.1258/jrsm.2008.080112; see also Clayton P, Rowbotham J, et al. An unsuitable and degraded diet? Part two: realities of the mid-Victorian diet. J R Soc Med. 2008;101:350–357. doi: https://doi.org/10.1258/jrsm.2008.080113
326. Hemilä H, Chalker E. Vitamin C for the common cold and pneumonia. Pol Arch Intern Med. 2025;135:16926. doi: https://doi.org/10.20452/pamw.16926; see also Holford P, et al. Vitamin C—an adjunctive therapy for respiratory infection, sepsis and COVID-19. Nutrients.2020;12(12):3760. doi: https://doi.org/10.3390/nu12123760
Chapter 15. The Global Citizen Science Alzheimer’s Prevention Revolution
329. Zhang L, et al. Altered gut microbiota in a mouse model of Alzheimer’s disease. J Alzheimers Dis. 2017;56(4):1241-1257. doi: https://doi.org/10.3233/JAD-170020
330. Zhang Y, et al. Identifying modifiable factors and their joint effect on dementia risk in the UK Biobank. Nat Hum Behav. 2023;7:1185–1195. doi: https://doi.org/10.1038/s41562-023-01585-x
332. Tsiachristas A, Smith AD, et al. B-vitamins are potentially a cost-effective population health strategy to tackle dementia: too good to be true? Alzheimers Dement (N Y). 2016;2(3):156-161. doi: https://doi.org/10.1016/j.trci.2016.07.002
