Alzheimer's disease causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Alzheimer’s disease may be caused by trisomy of chromosome 21, familial inheritance of mutations in either presenilin 1 gene, presenilin 2 gene or APOE4 gene. Presenilin mutations are associated with early onset Alzheimer’s disease, whereas APOE mutations are associated with late onset disease. Environmental factors, such as aging, low level of education and head trauma may also contribute to the development of Alzheimer’s disease.

The following are the causes of Alzheimer’s dementia (AD):^[1]^[2]^[3]^[4]^[5]

Cause	Specific characteristics	Percentage of cases
Chromosomal (Down syndrome)	Trisomy 21 Over expression of amyloid precursor protein (APP) on chromosome 21 Develop the neuropathologic hallmarks of AD after age 40 years	<1%
All familial		~25%
Late-onset familial (AD2)	APOE gene: Locus: AD2 Protein: Apolipoprotein E TREM2 gene: Variant: p.Arg47His allelic variant PLD3 gene UNC5C gene AKAP9 gene: In African-Americans only	15%-25% of familial cases
Early-onset familial AD (AD1, AD3, AD4)	PSEN1 gene: Locus: AD3 Proportion: 20-70 % of early onset AD cases Protein: Presenilin-1 PSEN2 gene: Locus: AD4 Proportion: Rare Protein: Presenilin-2 APP gene: Locus: AD1 Proportion: 10-15 % of early onset AD cases Protein: Amyloid precursor protein (APP)	<2% of familial cases
Unknown (includes genetic/environment interactions)	Multifactorial: (combination of) Aging Genetic predisposition Exposure to one or more environmental agents including head trauma, low education level, viruses, and/or toxins	~75%

↑ “Alzheimer Disease Overview – GeneReviews® – NCBI Bookshelf”.
↑ Brickell KL, Steinbart EJ, Rumbaugh M, Payami H, Schellenberg GD, Van Deerlin V, Yuan W, Bird TD (2006). “Early-onset Alzheimer disease in families with late-onset Alzheimer disease: a potential important subtype of familial Alzheimer disease”. Arch. Neurol. 63 (9): 1307–11. doi:10.1001/archneur.63.9.1307. PMID 16966510.
↑ Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T (1999). “Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum”. Am. J. Hum. Genet. 65 (3): 664–70. doi:10.1086/302553. PMC 1377972. PMID 10441572.
↑ Munoz DG, Feldman H (2000). “Causes of Alzheimer’s disease”. CMAJ. 162 (1): 65–72. PMC 1232234. PMID 11216203.
↑ Hölscher C (1998). “Possible causes of Alzheimer’s disease: amyloid fragments, free radicals, and calcium homeostasis”. Neurobiol. Dis. 5 (3): 129–41. doi:10.1006/nbdi.1998.0193. PMID 9848086.