Incidence and prevalence of AD/dementia
WHO – 27,000 dementia diagnosis a day – https://www.who.int/news-room/fact-sheets/detail/dementia
Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A, Cohen-Mansfield J, Cooper C, Costafreda SG, Dias A, Fox N, Gitlin LN, Howard R, Kales HC, Kivimäki M, Larson EB, Ogunniyi A, Orgeta V, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020 Aug 8;396(10248):413-446. doi: 10.1016/S0140-6736(20)30367-6. Epub 2020 Jul 30. PMID: 32738937; PMCID: PMC7392084.
Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N. Dementia prevention, intervention, and care. Lancet 390, 2673-2734, doi:10.1016/s0140-6736(17)31363-6 (2017).
Definition of AD, dementia, MCI
Smith AD. Imaging the progression of Alzheimer pathology through the brain. Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4135-7. doi: 10.1073/pnas.082107399. PMID: 11929987; PMCID: PMC123611.
Morris JC. Mild cognitive impairment and preclinical Alzheimer’s disease. Geriatrics. 2005 Jun;Suppl:9-14. PMID: 16025770.
Winblad B Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC. Mild cognitive impairment–beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004 Sep;256(3):240-6. doi: 10.1111/j.1365-2796.2004.01380.x. PMID: 15324367.
De Jager CA, Hogervorst E, Combrinck M, Budge MM. Sensitivity and specificity of neuropsychological tests for mild cognitive impairment, vascular cognitive impairment and Alzheimer’s disease. Psychol Med. 2003 Aug;33(6):1039-50. doi: 10.1017/s0033291703008031. PMID: 12946088.
Perry RJ, Hodges JR. Attention and executive deficits in Alzheimer’s disease. A critical review. Brain. 1999 Mar;122 ( Pt 3):383-404. doi: 10.1093/brain/122.3.383. PMID: 10094249.
Oulhaj A, Wilcock GK, Smith AD, de Jager CA. Predicting the time of conversion to MCI in the elderly: role of verbal expression and learning. Neurology. 2009 Nov 3;73(18):1436-42. doi: 10.1212/WNL.0b013e3181c0665f. Epub 2009 Sep 30. PMID: 19794124; PMCID: PMC2882176.
Glucose, insulin resistance and cognitive decline
Yau PL, Castro MG, Tagani A, Tsui WH, Convit A. Obesity and metabolic syndrome and functional and structural brain impairments in adolescence. Pediatrics. 2012 Oct;130(4):e856-64. doi: 10.1542/peds.2012-0324. Epub 2012 Sep 3. PMID: 22945407; PMCID: PMC3457620.
Zhang X, Tong T, Chang A, Ang TFA, Tao Q, Auerbach S, Devine S, Qiu WQ, Mez J, Massaro J, Lunetta KL, Au R, Farrer LA. Midlife lipid and glucose levels are associated with Alzheimer’s disease. Alzheimers Dement. 2023 Jan;19(1):181-193. doi: 10.1002/alz.12641. Epub 2022 Mar 23. PMID: 35319157.
Do genes cause AD?
Bekris LM, Yu CE, Bird TD, Tsuang DW. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol. 2010 Dec;23(4):213-27. doi: 10.1177/0891988710383571. PMID: 21045163; PMCID: PMC3044597.
Norwitz N.G.;Saif,N.; Ariza, I.E.; Isaacson, R.S. Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers. Nutrients 2021, 13, 1362. https://doi.org/10.3390/ nu13041362
Heininger K. (2000), A unifying hypothesis of Alzheimer’s disease. III. Risk factors. Hum. Psychopharmacol. Clin. Exp., 15: 1-70. https://doi.org/10.1002/(SICI)1099-1077(200001)15:1<1::AID-HUP153>3.0.CO;2-1;
Ridge PG, Mukherjee S, Crane PK, Kauwe JSK, (2013) Alzheimer’s Disease: Analyzing the Missing Heritability. PLoS ONE 8(11): e79771. doi: 10.1371/journal.pone.0079771
Bellenguez C., Küçükali, F., Jansen, I.E. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet 54, 412–436 (2022). https://doi.org/10.1038/s41588-022-01024-z
Escott-Price V Myers AJ, Huentelman M, Hardy J. Polygenic risk score analysis of pathologically confirmed Alzheimer disease. Ann Neurol. 2017 Aug;82(2):311-314. doi: 10.1002/ana.24999. Epub 2017 Aug 9. PMID: 28727176; PMCID: PMC5599118.
Apoe4 exaggeration and diet trials
Jia J, Zhao T, Liu Z 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
Ngandu T, Lehtisalo J, Solomon A, Levälahti E, Ahtiluoto S, Antikainen R, Bäckman L, Hänninen T, Jula A, Laatikainen T, Lindström J, Mangialasche F, Paajanen T, Pajala S, Peltonen M, Rauramaa R, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015 Jun 6;385(9984):2255-63. doi: 10.1016/S0140-6736(15)60461-5. Epub 2015 Mar 12. PMID: 25771249.
Solomon A, Turunen H, Ngandu T, Peltonen M, Levälahti E, Helisalmi S, Antikainen R, Bäckman L, Hänninen T, Jula A, Laatikainen T, Lehtisalo J, Lindström J, Paajanen T, Pajala S, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M. 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: 10.1001/jamaneurol.2017.4365. PMID: 29356827; PMCID: PMC5885273.
Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A 2013; 110: 9523-8.
Jernerén F, Elshorbagy AK, Oulhaj A, Smith SM, Refsum H, Smith AD. Brain atrophy in cognitively impaired elderly: the importance of long-chain omega-3 fatty acids and B vitamin status in a randomized controlled trial. Am J Clin Nutr 2015; 102: 215-21.
Oulhaj A, Jernerén F, Refsum H, Smith AD, de Jager CA. Omega-3 fatty acid status enhances the prevention of cognitive decline by B vitamins in Mild Cognitive Impairment J Alzheimer’s Dis 2016; 50: 547-57.
van Soest, A.P.M., van de Rest, O., Witkamp, R.F. et al. DHA status influences effects of B-vitamin supplementation on cognitive ageing: a post-hoc analysis of the B-proof trial. Eur J Nutr (2022). https://doi.org/10.1007/s00394-022-02924-w
Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, Pan A, Zhang C, Jia J, Feng L, Kua EH, Wang YJ, Wang HF, Tan MS, Li JQ, Hou XH, Wan Y, Tan L, Mok V, Tan L, Dong Q, Touchon J, Gauthier S, Aisen PS, Vellas B. Evidence-based prevention of Alzheimer’s disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-1209. doi: 10.1136/jnnp-2019-321913. Epub 2020 Jul 20. PMID: 32690803; PMCID: PMC7569385.
Studies Assessing Population Attributable Risk
[1] Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014 Jun 24;14:643. doi: 10.1186/1471-2458-14-643. PMID: 24962204; PMCID: PMC4099157.
Beydoun M et al, ‘Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis’ BMC Public Health 2014, 14:643
Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, Pan A, Zhang C, Jia J, Feng L, Kua EH, Wang YJ, Wang HF, Tan MS, Li JQ, Hou XH, Wan Y, Tan L, Mok V, Tan L, Dong Q, Touchon J, Gauthier S, Aisen PS, Vellas B. Evidence-based prevention of Alzheimer’s disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-1209. doi: 10.1136/jnnp-2019-321913. Epub 2020 Jul 20. PMID: 32690803; PMCID: PMC7569385.
Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A, Cohen-Mansfield J, Cooper C, Costafreda SG, Dias A, Fox N, Gitlin LN, Howard R, Kales HC, Kivimäki M, Larson EB, Ogunniyi A, Orgeta V, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020 Aug 8;396(10248):413-446. doi: 10.1016/S0140-6736(20)30367-6. Epub 2020 Jul 30. PMID: 32738937; PMCID: PMC7392084. ; see also Livingstone_LancetCommission2017.pdf
Elwood P, Galante J, Pickering J, Palmer S, Bayer A, et al. (2013) Healthy Lifestyles Reduce the Incidence of Chronic Diseases and Dementia: Evidence from the Caerphilly Cohort Study. PLoS ONE 8(12): e81877. doi:10.1371/journal.pone.0081877
Norton S et al, ‘Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data’, Lancet Neurol 2014;13(8):788-94
Ashby-Mitchell K et al. Alzheimer’s Research & Therapy (2017) 9:11 DOI 10.1186/s13195-017-0238-x
Mayer F et al.: An Estimate of Attributable Cases of AD and VaD due to Modifiable Risk Factors: The Impact of Primary Prevention in Europe and in Italy Dement Geriatr Cogn Disord Extra 2018;8:60–71
Homocysteine
Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, et al. (2010) Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLOS ONE 5(9): e12244. https://doi.org/10.1371/journal.pone.0012244
Lu Y, Sugawara Y, Zhang S, Tomata Y, Tsuji I. Smoking cessation and incident dementia in elderly Japanese: the Ohsaki Cohort 2006 Study. Eur J Epidemiol. 2020 Sep;35(9):851-860. doi: 10.1007/s10654-020-00612-9. Epub 2020 Feb 15. PMID: 32060675; PMCID: PMC7525275.
Pfeiffer CM, Osterloh JD, Kennedy-Stephenson J, Picciano MF, Yetley EA, Rader JI, Johnson CL. Trends in circulating concentrations of total homocysteine among US adolescents and adults: findings from the 1991-1994 and 1999-2004 National Health and Nutrition Examination Surveys. Clin Chem. 2008 May;54(5):801-13. doi: 10.1373/clinchem.2007.100214. Epub 2008 Mar 28. PMID: 18375482.
Teng Z, Feng J, Liu R, Ji Y, Xu J, Jiang X, Chen H, Dong Y, Meng N, Xiao Y, Xie X and Lv P (2022) Cerebral small vessel disease mediates the association between homocysteine and cognitive function. Front. Aging Neurosci. 14:868777. doi: 10.3389/fnagi.2022.868777
Omega 3 and B vitamin studies
Troen AM, Chao WH, Crivello NA, D’Anci KE, Shukitt-Hale B, Smith DE, Selhub J, Rosenberg IH. Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by dietary methionine without lowering plasma homocysteine. J Nutr. 2008 Dec;138(12):2502-9. doi: 10.3945/jn.108.093641. PMID: 19022979; PMCID: PMC2755637.
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. Arch Neurol. 2006 Nov;63(11):1545-50. doi: 10.1001/archneur.63.11.1545. PMID: 17101822.
Selley ML. A metabolic link between S-adenosylhomocysteine and polyunsaturated fatty acid metabolism in Alzheimer’s disease. Neurobiol Aging. 2007 Dec;28(12):1834-9. doi: 10.1016/j.neurobiolaging.2006.08.003. Epub 2006 Sep 25. PMID: 16996649.
Yuki D, Sugiura Y, Zaima N, Akatsu H, Takei S, Yao I, Maesako M, Kinoshita A, Yamamoto T, Kon R, Sugiyama K, Setou M. DHA-PC and PSD-95 decrease after loss of synaptophysin and before neuronal loss in patients with Alzheimer’s disease. Sci Rep. 2014 Nov 20;4:7130. doi: 10.1038/srep07130. PMID: 25410733; PMCID: PMC5382699.
van Soest, A.P.M., van de Rest, O., Witkamp, R.F. et al. DHA status influences effects of B-vitamin supplementation on cognitive ageing: a post-hoc analysis of the B-proof trial. Eur J Nutr (2022). https://doi.org/10.1007/s00394-022-02924-w
Jernerén F, Cederholm T, Refsum H, Smith AD, Turner C, Palmblad J, Eriksdotter M, Hjorth E, Faxen-Irving G, Wahlund LO, Schultzberg M, Basun H, Freund-Levi Y. Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer’s Disease: The OmegAD Study. J Alzheimers Dis. 2019;69(1):189-197. doi: 10.3233/JAD-181148. PMID: 30958356.
Walsh S, Merrick R, Richard E, Nurock S, Brayne C. Lecanemab for Alzheimer’s disease. BMJ. 2022 Dec 19;379:o3010. doi: 10.1136/bmj.o3010. PMID: 36535691.
Li M, Li W, Gao Y, Chen Y, Bai D, Weng J, Du Y, Ma F, Wang X, Liu H, Huang G. Effect of folic acid combined with docosahexaenoic acid intervention on mild cognitive impairment in elderly: a randomized double-blind, placebo-controlled trial. Eur J Nutr. 2021 Jun;60(4):1795-1808. doi: 10.1007/s00394-020-02373-3. Epub 2020 Aug 28. PMID: 32856190.
Maltais, M., de Souto Barreto, P., Bowman, G.L. et al. Omega-3 Supplementation for the Prevention of Cognitive Decline in Older Adults: Does It Depend on Homocysteine Levels?. J Nutr Health Aging 26, 615–620 (2022). https://doi.org/10.1007/s12603-022-1809-5
Fairbairn P, Dyall SC, Tsofliou F. The effects of multi-nutrient formulas containing a combination of n-3 PUFA and B vitamins on cognition in the older adult: a systematic review and meta-analysis. Br J Nutr. 2023 Feb 14;129(3):428-441. doi: 10.1017/S0007114522001283. Epub 2022 Apr 27. PMID: 35473808; PMCID: PMC9876812.
Huang Y, Deng Y, Zhang P, Lin J, Guo D, Yang L, Liu D, Xu B, Huang C, Zhang H. Associations of fish oil supplementation with incident dementia: Evidence from the UK Biobank cohort study. Front Neurosci. 2022 Sep 7;16:910977. doi: 10.3389/fnins.2022.910977. PMID: 36161159; PMCID: PMC9489907.
Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, et al. ω-3 Fatty Acid Treatment in 174 Patients With Mild to Moderate Alzheimer Disease: OmegAD Study: A Randomized Double-blind Trial. Arch Neurol. 2006;63(10):1402–1408. doi:10.1001/archneur.63.10.1402
Failure of anti-amyloid drugs and how homocysteine makes tau
Alves F, Kallinowski P, Ayton S. Accelerated Brain Volume Loss Caused by Anti-β-Amyloid Drugs: A Systematic Review and Meta-analysis. Neurology. 2023 Mar 27:10.1212/WNL.0000000000207156. doi: 10.1212/WNL.0000000000207156. Epub ahead of print. PMID: 36973044.
Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer’s disease: clinical trials and drug development. Lancet Neurol. 2010 Jul;9(7):702-16. doi: 10.1016/S1474-4422(10)70119-8. Erratum in: Lancet Neurol. 2011 Jun;10(6):501. PMID: 20610346.
Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014 Jul 3;6(4):37. doi: 10.1186/alzrt269. PMID: 25024750; PMCID: PMC4095696.
Ackley SF, Zimmerman SC, Brenowitz WD, Tchetgen Tchetgen EJ, Gold AL, Manly JJ, Mayeda ER, Filshtein TJ, Power MC, Elahi FM, Brickman AM, Glymour MM. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021 Feb 25;372:n156. doi: 10.1136/bmj.n156. Erratum in: BMJ. 2022 Aug 30;378:o2094. PMID: 33632704; PMCID: PMC7905687
Walsh S, Merrick R, Richard E, Nurock S, Brayne Lecanemab for Alzheimer’s disease
C BMJ 2022;379:o3010 – https://www.bmj.com/content/bmj/379/bmj.o3010.full.pdf
Smith AD, Refsum H. Homocysteine, B Vitamins, and Cognitive Impairment. Annu Rev Nutr. 2016 Jul 17;36:211-39. doi: 10.1146/annurev-nutr-071715-050947. PMID: 27431367.
Li JG, Chu J, Barrero C, Merali S, Praticò D. Homocysteine exacerbates β-amyloid pathology, tau pathology, and cognitive deficit in a mouse model of Alzheimer disease with plaques and tangles. Ann Neurol. 2014 Jun;75(6):851-63. doi: 10.1002/ana.24145. Epub 2014 May 28. PMID: 24644038; PMCID: PMC4362695.
Shirafuji N, Hamano T, Yen SH, Kanaan NM, Yoshida H, Hayashi K, Ikawa M, Yamamura O, Kuriyama M, Nakamoto Y. Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization. Int J Mol Sci. 2018 Mar 17;19(3):891. doi: 10.3390/ijms19030891. PMID: 29562600; PMCID: PMC5877752.
Bossenmeyer-Pourié C, Smith AD, Lehmann S, Deramecourt V, Sablonnière B, Camadro JM, Pourié G, Kerek R, Helle D, Umoret R, Guéant-Rodriguez RM, Rigau V, Gabelle A, Sequeira JM, Quadros EV, Daval JL, Guéant JL. 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: 10.1002/path.5254. Epub 2019 Mar 19. PMID: 307349
Xia, Y., Prokop, S. & Giasson, B.I. “Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies. Mol Neurodegeneration 16, 37 (2021). https://doi.org/10.1186/s13024-021-00460-5
Teng Z, Feng J, Liu R, Ji Y, Xu J, Jiang X, Chen H, Dong Y, Meng N, Xiao Y, Xie X, Lv P. Cerebral small vessel disease mediates the association between homocysteine and cognitive function. Front Aging Neurosci. 2022 Jul 15;14:868777. doi: 10.3389/fnagi.2022.868777. PMID: 35912072; PMCID: PMC9335204.
M. Bird, C. Cooper, F. Patel, C. Copeman, J.L. Stansfeld, G. Charlesworth, E. Aguirre
The psychological determinants of making lifestyle and dietary behaviours after using an online cognitive health tool and its associated recommendations for protective cognitive health behaviours Eur J Psychiatry. 2021;35:145-56
Notes re possible funding source:
The Investment and Impact Fund (IIF) is an incentive scheme focussed on supporting PCNs to deliver high quality care to their population, and the delivery of the priority objectives articulated in the NHS Long Term Plan and in Investment and Evolution; a five-year GP contract framework: https://www.england.nhs.uk/wp-content/uploads/2019/01/gp-contract-2019.pdf
The scheme contains indicators that focus on where PCNs can contribute significantly towards the ‘triple aim’:
We are currently exploring if there are Domains/Areas/Indicators that would allow GPs to make an application to fund COGNITION to their PCN from the IIF.
