New genetic risk factors found in Alzheimer’s disease.

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.

IANEC has participated in an international study led by the European Alzheimer & Dementia Biobank (EADB) that 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.

In conclusion, we have validated 33 previous loci, doubled the total number of genetic loci associated with the ADD risk, expanded our current knowledge of the pathophysiology of ADD, identified new opportunities for the development of GRSs and gene-specific treatments and opened up a pathway to translational genomics and personalized medicine.

Nature Genetics