New insights into the genetic etiology of Alzheimer’s disease and related dementias

TLDR

The genetic landscape of Alzheimer’s disease and related dementias offers insight into their underlying pathophysiology. A two‑stage genome‑wide association study of 111,326 AD cases and 677,663 controls was performed. The study uncovered 75 AD risk loci, 42 of which were novel, with enrichment in amyloid/tau and microglial pathways, prioritized 31 genes including TNF‑α signaling, and produced a genetic risk score that raised AD risk prediction 1.6‑ to 1.9‑fold across deciles beyond age and APOE ε4.

Abstract

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.