Nat. Genet. 54, 412–436 (2022)
The risk of Alzheimer’s disease and related dementias (ADD) differs among individuals, and a large proportion of this risk (estimated at up to 80%) is driven by genetics. This strong heritability component provides an opportunity to determine the pathophysiological processes in ADD and to identify new biological features, prognostic or diagnostic markers, and therapeutic targets, through translational genomics. However, much of the underlying heritability remains unexplained. In a recent study in Nature Genetics, Bellenguez and colleagues performed a genome-wide association study incorporating 111,326 clinically diagnosed or questionnaire-based ‘proxy’ ADD cases and 677,663 controls. The authors identified a total of 75 risk loci, amongst which 42 were novel. Pathway enrichment analysis revealed the contribution of the identified risk loci in the pathophysiology of ADD — namely, amyloid and tau, and innate immune response (for example microglia) pathways. The authors conducted a follow-up to identify the genes that are most likely to be responsible for the association signal with ADD at each new locus. This gene prioritization analysis identified 31 genes that indicated new genetically associated processes, including the tumor necrosis factor-α pathway through the linear ubiquitin chain assembly complex. Subsequently, on the basis of genome-wide significant variants, the authors calculated a genetic risk score to estimate the associated risk of future ADD or progression from mild cognitive impairment to ADD. The authors report a 1.6- to 1.9-fold increase in the Alzheimer’s disease risk from the lowest to the highest decile, in addition to the effects of age and APOE status. Together, the results of this study expand our current knowledge of the pathophysiology of ADD and identify novel genetic risk loci as potential therapeutic targets for ADD treatment.
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