Combating Genetic Heterogeneity for Polygenic Prediction of Susceptibility to Brain β-Amyloid Deposition

Abstract

Background and Objectives The APOE (apolipoprotein E) e4 allele is the strongest known genetic risk factor for sporadic Alzheimer disease (AD) and for brain amyloidosis, an early marker of disease pathophysiology. However, APOE e4 is present in only 25% of the general population and is by itself inadequate for explaining susceptibility to amyloid accumulation or AD diagnosis. Existing studies have been limited by potential confounding due to inclusion of individuals carrying APOE e4 or e2 (which has a modest protective association). We hypothesized that genome-wide association study (GWAS) and genetic risk score (GRS) analyses in APOE e3/e3 individuals would uniquely identify novel predictors of β-amyloid pathology in older adults. Methods We analyzed data from the Mayo Clinic Study of Aging (MCSA), Alzheimer’s Disease Neuroimaging Initiative (ADNI), and Rush Religious Orders Study and Memory and Aging Project. Frequency of APOE e3/e3 in those samples ranged from 48% to 61%. A GWAS was performed across 1,496 individuals with amyloid PET to identify candidate variants for GRS generation. Postmortem neuropathologic data (N = 710) were used to refine the variant list to capture high-likelihood true associations. An independent sample (N = 641) with plasma p-tau181 data was used for validation. Results The GWAS identified previously implicated (e.g., PICALM and RBFOX1) and novel potential associations with amyloid PET burden. A non-APOE GRS of top variants was strongly associated with amyloid PET levels in the MCSA (p = 4.34 × 10−9, β = 5.88) and ADNI (p = 1.87 × 10−8, β = 12.1) cohorts. In both cohorts, this non-APOE amyloid GRS outperformed a comparator GRS (based on variants associated with clinically diagnosed AD dementia risk) in explaining phenotypic variation. The non-APOE amyloid GRS was also associated with postmortem neuropathologic β-amyloid and neurofibrillary tangle burden and in an independent sample was associated with plasma p-tau181 concentrations (a robust indicator of cerebral amyloidosis).