Increased homocysteine levels and risk of Alzheimer's disease and dementia

An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease (1):

• the results of a prospective , observational study indicate that there is strong, graded association between plasma total homocysteine levels and risk of dementia and Alzheimer’s disease.
  • increment in plasma homocysteine level of 5umol per liter increased the risk of Alzheimer’s disease by 40 percent
• elevated plasma homocysteine levels are associated with carotid atherosclerosis and an increased risk of stroke
  • atherosclerosis and stroke, in turn, increase the risk of clinical Alzheimer’s disease
• the multivariable-adjusted relative risk of dementia was 1.4 (95 percent confidence interval, 1.1 to 1.9) for each increase of 1 SD in the log-transformed homocysteine value either at base line or eight years earlier. The relative risk of Alzheimer's disease was 1.8 (95 percent confidence interval, 1.3 to 2.5) per increase of 1 SD at base line and 1.6 (95 percent confidence interval, 1.2 to 2.1) per increase of 1 SD eight years before base line. With a plasma homocysteine level greater than 14 micromol per liter, the risk of Alzheimer's disease nearly doubled.

High dose vitamin B supplementation:

• even in the absence of vitamin deficiency, homocysteine levels can be reduced by administration of high-dose supplements of folic acid and vitamins B(6) and B(12)(1,2)
• a study investigated using a regimen of high-dose B vitamin supplementation in patients with mild to moderate Alzheimer's disease
  • there was no slowing of cognitive decline in the group treated with high-dose vitamin B supplementation (2).

There is growing evidence that hypohomocysteinemia or low levels of homocysteine may also increase the risk of dementia and AD in older adults (3).

References:

1. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002 Feb 14;346(7):476-83. doi: 10.1056/NEJMoa011613.
2. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ; Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008 Oct 15;300(15):1774-83. doi: 10.1001/jama.300.15.1774.
3. Bae JB, Han JW, Song J, Lee K, Kim TH, Kwak KP, Kim BJ, Kim SG, Kim JL, Moon SW, Park JH, Ryu SH, Youn JC, Lee DY, Lee DW, Lee SB, Lee JJ, Jhoo JH, Kim KW. Hypohomocysteinemia may increases the risk of dementia and Alzheimer's disease: A nationwide population-based prospective cohort study. Clin Nutr. 2021 Jul;40(7):4579-4584. doi: 10.1016/j.clnu.2021.05.034.