Consensus meta-analysis of genome-wide association studies for Alzheimer's disease and related dementia.

To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementia (ADRD), we performed a meta-analysis of European ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, including 16 which are novel, and 56 which are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 novel) requiring further external validation. A polygenic score combining the effect of the ADRD loci except APOE was primarily associated with AD rather than non-AD pathology. Individuals in the 10th decile of the score had a 2-fold increased risk to present with Braak neurofibrillary tangles stage above 5 and moderate/severe neuritic amyloid plaque pathology at death compared to individuals in the median score group.