Alzheimer's disease

For early-onset Alzheimer's, more than 150 mutations of the presenilin-1 PSEN1, presenilin-2 PSEN2, and amyloid precursor protein APP genes have been associated with autosomally dominant inheritance (of early-onset ALZ).

The most notable late-onset SNPs are

• APP rs63750847 rare 1% geno is protective
• APOE rs7412 and rs429358 rare 3% genotype increases risk
• PLD3 rs145999145 rare 4% genotype doubles risk
• TREM2 rs75932628
• TM2D3 rs139709573, at least in Icelanders

Most genes other than APOE and TREM2 have much smaller individual effects on the risk for developing Alzheimer's disease, however, numerous such reports have been published (see below).

APOE-ε4 homozygosity (gs216) is associated with increased risk of Alzheimer's PMID 15956169. However, according to some studies, APOE-ε4 differences only affect cognition significantly after age 60. The memory changes that occur from 20 to 60 may not be connected to APOE-ε4 at all. See People at genetic risk for Alzheimer's age mentally just like noncarriers. Other studies, however, show brain changes and decreases in cognitive function in epsilon-4 carriers starting at an early age.

Conversely: although SNPs in the MAPT gene do not influence the risk of having Alzheimer's, they appear to lead to increased MAPT mRNA production, which leads to increased levels of the tau protein in cerebrospinal fluid, which ultimately led to an earlier age of onset of Alzheimer symptoms (in those who eventually developed Alzheimer's). So if - and only if - a person is fated to develop Alzheimer's for other reasons, then these MAPT SNPs are correlated with exhibiting symptoms sooner. PMID 18541914

One hypothesis is that genes relevant to viral infection, and in particular herpes simplex virus (HSV-1) infection, may increase the risk for Alzheimer's, especially in individuals already predisposed to Alzheimer's, such as those carrying APOE-ε4 alleles. PMID 16406033 In connection to this hypothesis, rs2254958, a SNP in a gene influencing HSV-1 infection, has been found in higher frequency in certain AD patients. PMID 17420072

Two studies (Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-? Levels in Aged Alzheimer's Disease Mice and Caffeine Suppresses Amyloid-? Levels in Plasma and Brain of Alzheimer's Disease Transgenic Mice published in the July 2009 issue of the Journal of Alzheimer's Disease point to caffeine as reducing a protein (beta amyloid) that is a sign of Alzheimer's disease. More recent studies (such as "High Blood Caffeine Levels in MCI Linked to Lack of Progression to Dementia") have lent further support to this finding.

List of related genes

• SNPs defining a haplotype of the TRPC4AP gene on chromosome 20q11.22 appear to be associated with late-onset Alzheimer's disease in two large affected families. The relevance outside of these families is unclear. PMID 18449908
• Multiple genetic variants in SORL1 are associated with AD. SORL1 and APOE associations differ markedly [1][2]
• rs5984894, X-linked and formerly thought to be associated with increased risk in females; has not held up in further studies
• SNPs in the CLU, CR1 and PICALM genes, rs11136000, rs3818361, and rs3851179, which have been replicated in independent (European-descent) populations
• rs10519262, an intergenic SNP on ch 15
• rs908832 a SNP in ABCA2, associated with a 3.8x risk for early-onset AD
• rs1050283 in the OLR1 gene may increase risk for both early- and late-onset Alzheimer's PMID 18191876
• rs2227564 a SNP in PAU
• rs2333227 in the MPO gene, and rs669 in the A2M gene, and possible synergistic interaction between them
• rs2373115 is one of several SNPs in the GAB2 gene that are associated with a 3-4X higher risk of Alzheimer's PMID 17553421
• rs2986017 a SNP in the CALHM1 gene
• rs3025786 which can decrease risk slightly among APOE-ε4 carriers
• rs5963409 in the OTC gene promoter region
• PMID 17998437 A study of ~1100 Canadian and UK patients found significant risks (positive or negative) associated with SNPs rs10868366, rs7019241, rs9886784
• PMID 17293537 Alzheimer's disease risk for non APOE-ε4 carriers is affected by the heterozygous form of rs6265, as well as the diplotypes of rs6265, rs11030104, and rs2049045.
• PMID 17221831 The G51S purine nucleoside phosphorylase polymorphism is associated with cognitive decline in Alzheimer's disease patients.
• PMID 17517621 Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease
• A SNP in the PON1 gene PMID 16319130
• A SNP in intron 9 of the CHAT gene PMID 16223550
• 2 SNPs in the DAPK1 gene, rs4878104 and rs4877365 PMID 16847012, PMID 16847012
• SNPs in the DNMBP gene PMID 16740596, PMID 18359537
• Several SNPs in the MME gene, most notably, rs1836915 PMID 17928142
• A SNP in the TLR4 gene, rs4986790, with many disease associations PMID 18991680
• A SNP in the BACE1 gene, rs4938369 PMID 19441127
• "Supergene" gives long life, clear mind Lucidity in old age may be associated with the CETP VV genotype
• Gene tied to longevity also preserves ability to think clearly
• An estimated 25 percent of the population has a protective XmnI polymorphism of the fetal hemoglobin gene that may reduce risk of Alzheimer's
• Numerous SNPs in the ACE gene are associated with susceptibility to Alzheimer's disease. [3]
  • rs4293 (risk allele appears to be A)
  • rs1799752

• rs1868402 in the PPP3R1 gene is associated with progression of dementia, according to an article in PLoS Genetics

Links to external information

• Wikipedia provides a good introduction to the disease
• ApoE4.Info provides support and information useful to carriers of the ε4 variant of APOE
• OMIM has numerous articles on many genes implicated in at least some forms of Alzheimer's
• AlzForum is very current and written for a wider audience
• PMID 17192785 AlzGene database
• The National Institutes on Aging have this report
• Molecular janitors help explain Alzheimer's is a layman's explanation of the results of this research paper PMID 16902091
• Researchers have managed to reverse Alzheimer's in mice
• This research suggests it may be possible to stop further deterioration if symptoms are caught early: Insulin receptor stops progression of Alzheimer's disease

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