Aetiology

Environmental factors which predispose to Alzheimer's disease include:

• a history of head injury
• low educational attainment
• there is evidence that increased plasma homocysteine levels is a risk factor for Alzheimer's disease (1,2)
• type 2 diabetes (T2D) has been associated with a modest increased risk in cognitive dysfunction across all cognitive domains (1,3)
  • effect appears to be consistent across all age groups and mimics an accelerated ageing of brain function - however there is also an increased risk of more severe impairment of cognition and developing dementia in older age groups that would appear to be a different phenomenon (3).

Three genes have been linked to the pathogenesis of Alzheimer's disease (4):

• beta-amyloid precursor protein:
  • chromosome 21
  • specific mutations result in familial Alzheimer's disease with onset in the sixth decade
  • proteolytic processing of the mutant protein favours the formation of the amyloidogenic A-beta fragment
• apolipoprotein E4:
  • chromosome 19
  • the E4 allele increases the risk of Alzheimer's disease and reduces the mean age of onset
  • the E2 allele protects against Alzheimer's disease
• presenilin 1:
  • transmembrane protein which is mutated in some forms of familial Alzheimer's disease
  • increases the proportion of amyloidogenic peptides derived from beta-amyloid precursor protein
  • may be involved in apoptosis
  • gene on chromosome 14
• presenilin 2:
  • homologous in structure and function to presenilin 1
  • gene on chromosome 1.

Reference:

• (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) 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.
• (3) Pal K, Mukadam N, Petersen I, Cooper C. Mild cognitive impairment and progression to dementia in people with diabetes, prediabetes and metabolic syndrome: a systematic review and meta-analysis. Soc Psychiatry Psychiatr Epidemiol. 2018 Nov;53(11):1149-1160.
• (4) Schellenberg GD, Montine TJ. The genetics and neuropathology of Alzheimer's disease. Acta Neuropathol. 2012 Sep;124(3):305-23. doi: 10.1007/s00401-012-0996-2.