Genomic assessment of early‐onset AD identifies novel risk loci and an incomplete genetic overlap with late‐onset AD

Background Early Onset Alzheimer Disease (EOAD, age at onset [AAO] < = 65) is a severe form of AD, often occurring when patients are still caring for children or adults. Despite this, most genetic studies EOAD have focused on autosomal dominant forms, and there little understanding similarities differences between early late forms AD (LOAD, [AAO]>65). To address we present genome-wide association study non-Mendelian compare it to LOAD GWAS. Methods Primary single-variant analyses were performed using two additive logistic regression case-control models (full: SNPs, PCs, sex APOE-ɛ4 dosage as covariates; reduced: SNPs PCs); secondary included PCs+sex PCs+APOE. Models applied data derived from the Genetics Consortium (ADGC), composed by unrelated individuals. Samples varied 1293-1459 cases 8894-9366 controls EOAD, 8795-9508 9702-10273 LOAD, depending considered model. The SNP heritability (h2) correlation (rg) estimated LD score regression. Gene-based pathway analysis (gene sets Msigdb-v7.0) FUMA/MAGMA-v1.6. Results We identified novel loci associated with EOAD: Chromosome 4 (full model: chr4:102027610, P 2.98×10−08, near PPP3CA gene) 12 (PCs+sex rs117001070, 2.11×10−08, intergenic LINC02444 LINC02882). additionally confirmed BIN1 APOE in subset. Several known genes also showed significant LOAD. Heritability higher h2 values (h2 0.29, 0.29 0.27) than 0.19, 0.16, 0.15), full, reduced, PCs+APOE respectively. Genetic moderate but incomplete Other (p 3.89×10−12), gene-based tests nominal C8orf44-SGK3 9.95×10−06), SGK3 2.01×10−05) HIST1H2AC 3.04×10−05), plausible pathways such HDL remodeling 5.50×10−05) positive regulation cholesterol efflux 9.79×10−05). These nominally 0.04 p 4.05×10−03). Conclusions not previously reported studies. results suggest that etiology has an overlap