Neuropathology-basedAPOEgenetic risk score better quantifies Alzheimer’s risk

AbstractINTRODUCTIONAPOE ε4-carrier status orε4allele count are included in analyses to account for theAPOEgenetic effect on Alzheimer’s disease (AD); however, this does not account for protective effects ofAPOE ε2or heterogeneous effect ofε2, ε3, ε4haplotypes.METHODSWe leveraged results from an autopsy-confirmed AD study to generate a weighted risk score forAPOE(APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers onAPOEvariables from the Wisconsin Registry for Alzheimer’s Prevention, Wisconsin Alzheimer’s Disease Research Center, and Alzheimer’s Disease Neuroimaging Initiative (ADNI).RESULTSTheAPOE-npscore explained more variance and provided a better model fit for all three CSF measures thanAPOE ε4-carrier status andε4allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired participants.DISCUSSIONTheAPOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account forAPOEin AD-related analyses.