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

0 2 years ago

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.


AD is the most common form of dementia. The heritability is high, estimated to be between 60% and 80%1. This strong genetic component provides an opportunity to determine the pathophysiological processes in AD and to identify new biological features, new prognostic/diagnostic markers and new therapeutic targets through translational genomics. Characterizing the genetic risk factors in AD is therefore a major objective; with the advent of high-throughput genomic techniques, a large number of putative AD-associated loci/genes have been reported2. However, much of the underlying heritability remains unexplained. Hence, increasing the sample size of genome-wide association studies (GWASs) is an obvious solution that has already been used to characterize new genetic risk factors in other common, complex diseases (e.g., diabetes).


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