Definitive roles of TOMM40-APOE-APOC1 variants in the Alzheimer's risk

Despite advances, the roles of genetic variants from the APOE-harboring 19q13.32 region in Alzheimer's disease (AD) remain controversial. We leverage a comprehensive approach to gain insights into a more homogeneous genetic architecture of AD in this region. We use a sample of 2,673 AD-affected and 16,246 unaffected subjects from 4 studies and validate our main findings in the landmark Alzheimer's Disease Genetics Consortium cohort (3,662 AD-cases and 1,541 controls). We report the remarkably high excesses of the AD risk for carriers of the epsilon 4 allele who also carry minor alleles of rs2075650 (TOMM40) and rs12721046 (APOC1) polymorphisms compared to carriers of their major alleles. The exceptionally high 4.37-fold ( p = 1.34 x 10(-3)) excess was particularly identified for the minor allele homozygotes. The beneficial and adverse variants were significantly depleted and enriched, respectively, in the AD-affected families. This study provides compelling evidence for the definitive roles of the APOE-TOMM40-APOC1 variants in the AD risk. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

This study explores the roles of genetic variants in the APOE-TOMM40-APOC1 region in Alzheimer's disease risk, showing that carriers of certain alleles have significantly higher risk for AD.