Shared Genetic Architecture Between COVID-19 Severity and Alzheimer's Disease Across European and African Ancestries

The global outbreak of COVID-19, caused by the SARS-CoV-2 virus, has been linked to long-term neurological complications, including an increased risk of Alzheimer's disease (AD) among older adults. However, the precise genetic impact of COVID-19 on long-term AD development remains unclear. This study leveraged genome-wide association study (GWAS) data and genotype data to explore the genetic association between AD and various COVID-19 phenotypes across European ancestry (EA) and African ancestry (AA) cohorts, and the possibility of a causal effect of COVID-19 on AD. We first calculated polygenic risk scores (PRSs) of three COVID-19 phenotypes in AD cases and controls from both EA and AA populations, then determined the genetic associations between COVID-19 PRSs and AD by logistic regression analyses with or without adjusting for age, sex, and APOE genotypes. Significant positive associations were found between AD diagnosis and COVID-19 PRSs in both populations, with the strongest associations identified in the AA population. However, Mendelian randomization (MR) analyses revealed no evidence of a causal effect of COVID-19 phenotypes on AD liability. We explored this finding further through the analysis of shared genomic regions between the COVID-19 phenotypes and AD and found a region of overlap on chromosome 17 that was highly pleiotropic for traits implicating immune function, psychiatric disorders, and lung function phenotypes. These findings suggest that while COVID-19 and AD share overlapping polygenic contributions involving peripheral genes across multiple traits, they lack a direct connection involving core genes that drive the development of their respective pathologies.