Alzheimer’s geneticists came together last year to produce an enormous GWAS meta-analysis of 111,326 cases and 677,663 controls that turned up 42 new AD risk loci and confirmed 33 known ones (Feb 2021 news). The findings, first posted to medRXiv as a preprint, are now published in the April 4 Nature Genetics. The number of scientists involved has grown since the preprint, with a total of 402 authors, including eight co-first and nine senior authors, led by Jean-Charles Lambert at the Institut Pasteur de Lille in France.

New in the published paper is an analysis of protein-protein networks that found the candidate genes interacted with known AD genes, suggesting biological relevance. In addition, the authors refined their process for prioritizing candidates, allowing them to home in on the likely causal factor for a few additional loci.

For example, they determined that the risk signal in the vicinity of the Parkinson’s gene IDUA probably arises not from that gene itself but from the kinase DGKQ, which regulates the signaling of bioactive lipids. The authors also selected the calcium sensor DOC2A as the likely causal factor out of seven candidate genes in its region, and picked the adaptor protein LIME1 in another region with multiple candidates. They have now identified candidate causal genes for 36 of the 42 regions.

Genes Hasten Progression. People who carried the most risk alleles (red) were likelier to progress from cognitively healthy to AD over 10 years (left), or from MCI to AD over five years (right), than those with the fewest risk alleles (blue). [Courtesy of Bellenguez et al., Nature Genetics.]

Finally, the authors added to the growing evidence that a genetic risk score (GRS) based on all 75 genes could aid prognosis. In two population-based cohorts, people who carried the most risk variants were nearly twice as likely to develop AD as those with the fewest, putting the cumulative effect of the variants on a par with that of a single APOE4 allele (see image above). In populations that already had mild cognitive impairment, a high burden of risk variants boosted their odds of developing dementia within three years from 22 to 38 percent. Adding the GRS to a model that included sex, age, and APOE genotype modestly improved its predictive power.—Madolyn Bowman Rogers


No Available Comments

Make a Comment

To make a comment you must login or register.


News Citations

  1. Massive GWAS Meta-Analysis Digs Up Trove of Alzheimer’s Genes

Further Reading

Primary Papers

  1. . New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022 Apr;54(4):412-436. Epub 2022 Apr 4 PubMed.