Basic Science and Pathogenesis.

APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), with a higher effect in females than in males. Identifying factors that may reduce the detrimental impact of APOE4 on AD is an important research objective. Accumulating evidence points to a key role of the innate and adaptive immune system in AD, including natural killer (NK) and cytotoxic CD8+ T cells infiltrating the Central Nervous System (CNS) in AD, contributing to neuroinflammation and neuronal death. Here, we investigated how polymorphism of the HLA-C (Human Leucocyte Antigen-C) gene, a major regulator of NK and CD8+ T cells, may influence AD risk in the presence of the APOE4 allele in males and females.We assessed the association of the HLA-C genetic variation in study participants of the UK Biobanks (UKB), who were double carriers of the APOE4 allele, with AD reported in their mothers and fathers who carried at least one APOE4 allele (1562 and 798 in the case and 7572 and 8336 in the control groups, respectively). The analysis used a logistic regression model in the REGENIE and was repeated using the PLINK2 software package. The PLINK2 clumping procedure was used to reduce the number of statistical tests.The SNPs rs2074488 and rs2074491 in the HLA-C region, genotyped in UKB participants, were significantly associated with lower chances of AD in mothers who carried at least one copy of the APOE4. Three SNPs in the HLA-C region (+/-2KB): rs13203722, rs13218306, and rs12207404 showed deleterious associations with AD in mothers. Both analyses (using PLINK2 and REGENIE) supported these results. The protective SNPs and the deleterious ones were not in linkage disequilibrium. A similar analysis did not produce significant associations of HLA-C genetic variants with AD in fathers.The detected significant associations of HLA-C genetic variants in offspring with AD odds in mothers carrying at least one APOE4 allele suggest that HLA-C may modulate (attenuate or aggravate) the impact of APOE4, the strongest genetic risk factor, on AD occurrence. This finding further supports the role of infections and other factors initiating immune response in AD.

Duke Scholars

Author Dequing Wu  

Author Konstantin Arbeev Social Science Research Institute

Author Svetlana Ukraintseva Social Science Research Institute