Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

TLDR

Genetic discoveries of Alzheimer’s disease drive understanding and, combined with polygenic risk scores, can aid planning of efficient preventive and curative trials. The study performed a large genetic association meta‑analysis of 409,435 cases and 58,190 controls, adding six Alzheimer’s‑risk variants near APP, CHRNE, PRKD3/NDUFAF7, PLCG2, and two SHARPIN exonic variants. Polygenic risk scoring stratified by APOE revealed a 4–5.5‑year earlier median onset in ɛ4 carriers, and the identified variants offer a tool to select high‑risk individuals and refine the amyloid cascade.

Abstract

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.