👤 Alzheimer’s Disease Genetics Consortium (ADGC)

Epidemiological studies have consistently shown that chronic kidney disease is associated with increased Alzheimer disease risk. However, the underlying genetic architecture connecting these two conditions remains largely unexplored beyond genome-wide correlation analyses. Here, we conducted the first comprehensive, multi-ancestry, large-scale genetic investigation to identify shared genetic components between kidney function and Alzheimer disease. We leveraged large-scale genome-wide association study summary statistics for estimated glomerular filtration rate (N≈1.5 million European, N≈145,000 African ancestry) and late-onset Alzheimer disease (N=63,926 and N=398,058 in two European cohorts; N=9,168 in African ancestry) corrected for competing risk bias. We deployed a novel analytical framework integrating linkage disequilibrium score regression and polygenic risk score analysis, local analysis of [co]variant association, conjunctional false discovery rate analysis with Bayesian colocalization and fine-mapping, and bidirectional cis-Mendelian randomization to identify vertical pleiotropy. Despite the absence of genome-wide genetic correlation (r Show less

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers. Show less