Functional Heritability Partitioning, Multi-Tissue Transcriptomic Colocalization, and Pharmacogenomic Target Deconvolution Across 127 Alzheimer's Disease Susceptibility Loci

Non-APOE Alzheimer’s disease risk heritability is concentrated in MICROGLIAL_IMMUNE (39.22% share; h2_SNP = 6.28%) and PROTEOPATHY_AUTOPHAGY (36.34%; h2_SNP = 5.81%), with 12.88-fold enrichment across 48 effector genes.

• Why it matters: Translating 127 AD susceptibility loci into pathway-stratified trials requires knowing which cellular programs carry non-APOE genetic signal and which effector mechanisms map to relevant tissues.
• What they did: Using NHGRI-EBI GWAS Catalog summary statistics (GCST90695466; 8,159,496 autosomal variants) and stratified excess chi-square partitioning across +/-50 kb windows for 50 fine-mapped effector genes in five Axis 2 programs.
• The result: The non-APOE functional heritability (normalized to 16.0% liability) is dominated by microglial immune surveillance and proteopathic clearance networks, supporting genotype-stratified pathway targeting in sporadic AD.

AI summary of the abstract · may contain errors · not medical advice · read the paper.