Neuropathology-based APOE genetic risk score better quantifies Alzheimer's risk

INTRODUCTIONAPOE {varepsilon}4-carrier status or{varepsilon} 4 allele count are included in analyses to account for the APOE genetic effect on Alzheimers disease (AD); however, this does not account for protective effects of APOE {varepsilon}2 or heterogeneous effect of{varepsilon} 2, {varepsilon}3, {varepsilon}4 haplotypes. METHODSWe leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimers Prevention, Wisconsin Alzheimers Disease Research Center, and Alzheimers Disease Neuroimaging Initiative (ADNI). RESULTSThe APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE {varepsilon}4-carrier status and{varepsilon} 4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired participants. DISCUSSIONThe APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses.