The impact of rare genetic variants on Alzheimer disease

Abstract

Alzheimer disease (AD) is a progressive neurodegenerative disease with a strong genetic component. Although autosomal dominant mutations and common risk variants in AD risk have been extensively studied, the genetic underpinning of polygenic AD remains incompletely understood. Rare variants could elucidate part of the missing heritability in AD. Rare variant research gained momentum with the discovery of a rare variant in TREM2, along with loss-of-function variants in ABCA7 and SORL1, and has come into full bloom in recent years. Not only has the number of rare variant discoveries increased through large-scale whole-exome and genome sequencing studies, improved imputation in genome-wide association studies and increased focus on understudied populations, the number of studies mapping the functional effects of several of these rare variants has also significantly increased, leading to insights in the pathogenesis of AD and drug development. Here we provide a comprehensive overview of the known and novel rare variants implicated in AD risk, highlighting how they shine new light on AD pathophysiology and provide new inroads for drug development. We will review their impact on individual, familial and population levels, and discuss the potential and challenges of rare variants in genetic risk prediction. In this Review, the authors summarize the genetic and epidemiological characteristics of rare variants associated with Alzheimer disease so far, and explore the insights that these variants have provided into the pathogenic mechanisms of the disease.