Besides older age and a family history of Alzheimer’s, carrying the ApoE-e4 gene is the greatest risk factor for late-onset Alzheimer’s.
The ApoE gene provides the blueprint for a protein that transports cholesterol in the bloodstream. Everyone inherits one of the three forms of the ApoE gene — e2, e3 or e4 — from each parent. The e3 form is the most common. The e4 form is the next most common, and the e2 form is the least common.
Having the e4 form increases one’s risk of developing Alzheimer’s compared with having the e3 form, while having the e2 form may decrease one’s risk compared with having the e3 form. Those who inherit one copy of the e4 form have three times the risk of developing Alzheimer’s compared with those with two copies of the e3 form, while those who inherit two copies of the e4 form have an eight- to 12-fold risk.
Those with the e4 form are more likely to develop Alzheimer’s at a younger age than those with the e2 or e3 forms of the ApoE gene.
A meta-analysis including 20 published articles describing the frequency of the e4 form among people in the US who had been diagnosed with Alzheimer’s found that 56 percent had one copy of the APOE-e4 gene, and 11 percent had two copies of the APOE-e4 gene. Another study conducted among 1,770 diagnosed individuals from 26 Alzheimer’s Disease Centers across US, 65 percent had at least one copy of the APOE-e4 gene.
Chromosome 21 and gene mutations
Certain genetic mutations and the extra copy of chromosome 21 that characterises Down syndrome are uncommon genetic changes that affect the risk of Alzheimer’s.
An estimated 1 percent or less of Alzheimer’s cases develop as a result of mutations involving the gene for the amyloid precursor protein (APP) and the genes for the presenilin 1 and presenilin 2 proteins.
Those inheriting an Alzheimer’s mutation to the APP or presenilin 1 genes are guaranteed to develop the disease. Those inheriting an Alzheimer’s mutation to the presenilin 2 gene have a 95 percent chance of developing the disease. Individuals with Alzheimer’s mutations in any of these three genes tend to develop symptoms before age 65, sometimes as young as age 30, according to 2018 Alzheimer’s Disease Facts and Figures by Alzheimer’s Association, Chicago. Recently, some more genes have been identified to affect Alzheimer’s risk, such as ABCA7, BIN1, CLU, CR1, CASS4, CD2AP, CELF1, EPHA1, FERMT2, HLA-DRB5, INPP5D, MEF2C, MS4A, NME8, PTK2B, PICALM, SORL1, SlC24A4 and ZCWPW1. These genes are believed to have a limited effect on the overall prevalence of Alzheimer’s because they are rare or increase risk only slightly.