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

• Published in: Neurobiology of aging Vol. 110; pp. 122 - 131
• Main Authors: Kulminski, Alexander M., Philipp, Ian, Shu, Leonardo, Culminskaya, Irina
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2022
• Subjects: Aged; Alleles; Alzheimer Disease - genetics; Alzheimer's disease; Apolipoprotein C-I - genetics; Apolipoprotein E polymorphism; Apolipoproteins E - genetics; Cohort Studies; Female; Genetic Association Studies; Genetic Predisposition to Disease - genetics; Haplotypes; Heterozygote; Homozygote; Humans; Linkage disequilibrium; Male; Mitochondrial Precursor Protein Import Complex Proteins - genetics; Polymorphism, Genetic - genetics; Risk; Haplotypes; Apolipoprotein E polymorphism; Alzheimer's disease; Linkage disequilibrium
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2021.09.009

1The ε2 and ε4 alleles are associated with different molecular signatures of AD2AD is associated with polygenic profiles rather than with individual APOE alleles3Complex architecture of these profiles is more affected by the ε4 than ε2 allele4The ε4-bearing haplotype, but not ε4 allele alone, confers the strongest AD 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 ε4 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 × 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.