A new review published in Nature Reviews Neurology by Lara De Deyn and Kristel Sleegers sheds light on the role of rare genetic variants in Alzheimer’s disease.
While common risk factors and autosomal dominant mutations have been widely studied, the genetic basis of polygenic AD remains incompletely understood. This review highlights how rare variants contribute to the missing heritability of AD and their potential implications for disease mechanisms and treatment strategies.
Rare variant research gained momentum with the discovery of TREM2, along with loss-of-function mutations in ABCA7 and SORL1. Advances in whole-exome and genome sequencing, improved genetic imputation, and studies in diverse populations have led to an increasing number of rare variant discoveries. These findings not only enhance our understanding of AD pathogenesis but also pave the way for drug development and precision medicine approaches.
The review discusses at least 13 genes implicated in AD risk through rare variants and emphasizes the need for guidelines on risk prediction, genetic testing, and clinical interpretation. With early-stage clinical trials emerging from these discoveries, rare variants are proving to be valuable entry points for targeted therapies.