Genetic risk for alzheimer disease is distinct from genetic risk for amyloid deposition

Objective Alzheimer disease (AD) is the most common form of dementia and is responsible for a huge and growing health care burden in the developed and developing world. The polygenic risk score (PRS) approach has shown 75 to 84% prediction accuracy of identifying individuals with AD risk. Methods In this study, we tested the prediction accuracy of AD, mild cognitive impairment (MCI), and amyloid deposition risks with PRS, including and excluding APOE genotypes in a large publicly available dataset with extensive phenotypic data, the Alzheimer's Disease Neuroimaging Initiative cohort. Among MCI individuals with amyloid‐positive status, we examined PRS prediction accuracy in those who converted to AD. In addition, we divided polygenic risk score by biological pathways and tested them independently for distinguishing between AD, MCI, and amyloid deposition. Results We found that AD and MCI are predicted by both APOE genotype and PRS (area under the curve [AUC] = 0.82% and 68%, respectively). Amyloid deposition is predicted by APOE only (AUC = 79%). Further progression to AD of individuals with MCI and amyloid‐positive status is predicted by PRS over and above APOE (AUC = 67%). In pathway‐specific PRS analyses, the protein–lipid complex has the strongest association with AD and amyloid deposition even when genes in the APOE region were removed ( p  = 0.0055 and p  = 0.0079, respectively). Interpretation The results showed different pattern of APOE contribution in PRS risk predictions of AD/MCI and amyloid deposition. Our study suggests that APOE mostly contributes to amyloid accumulation and the PRS affects risk of further conversion to AD. ANN NEUROL 2019;86:427–435