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

BELLENGUEZ C; KUCUKALI F; JANSEN IE; CASTAÑO EM

Nature Genetics

Nature Research

Año: 2022 vol. 54 p. 412 - 436

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