Alzheimer’s Genetic Study of 2.8 Million People Finds 48 New Risk Regions, 127 in All

The largest Alzheimer’s genetic study to date has mapped 127 regions of human DNA tied to the disease, 48 of them new, using data from about 2.8 million people. The Psychiatric Genomics Consortium work, led from Amsterdam and published in Nature, also finds genes explain about 16% of differences in Alzheimer’s risk.

The paper appeared online on Oct. 28, and Amsterdam UMC highlighted the findings on Monday, Nov. 2. The study was led by Danielle Posthuma and carried out by Douglas Wightman and Emil Uffelmann of Vrije Universiteit Amsterdam, with data pooled from 30 research groups, biobanks and companies, the university said.

What the Alzheimer’s genetic study found

The researchers analyzed 183,620 people with Alzheimer’s disease. According to the Nature paper, that total includes 109,479 diagnosed cases and 74,141 proxy cases, typically people who report a parent with the disease, compared against 2,131,799 controls and 499,708 proxy controls. About 91% of the sample has European ancestry, and the authors call for more data from underrepresented groups.

“This is the largest genetic association study on Alzheimer’s to date, bringing together data from individuals with diverse genetic backgrounds,” first author Douglas Wightman said in the university’s release. Of the 127 risk loci, 118 came from the multi-ancestry analysis and nine appeared only in the European-ancestry analysis.

The results reinforce the role of microglia, the brain’s resident immune cells, which clear away damaged material. “We discovered new genetic evidence for processes related to the activation of these cells, the recruitment of immune cells, and the clearance of material within the brain,” Posthuma said. For the first time, the team also linked the genetic signal to specific neuron types, including Sncg, Sst and L6 IT Car3 cells, which the authors say opens new lines of research.

By the numbers: how this study compares

Genetic studies of Alzheimer’s have grown quickly. A 2019 study by Jansen and colleagues reported 29 risk loci from about 455,000 people, and Wightman’s own 2021 study found 38 loci in 1,126,563 people. The 2022 study led by Céline Bellenguez reported 75 loci.

By The Boston Report’s calculation, the new count of 127 loci is 52 more than the 2022 study, an increase of about 69%, and more than four times the 2019 tally. The roughly 2.8 million participants are about 2.5 times the 2021 sample. Because the studies used different methods and samples, the counts are not strictly comparable.

Two other figures stand out. Common genetic variants explain about 16% of the variation in Alzheimer’s risk, nearly three times earlier estimates of around 5%, the team said, mainly because a new statistical method better accounts for APOE, the gene with the largest known effect. And the APOE-ε4 variant carried a larger risk for women, with an odds ratio of 2.85 compared with 2.52 for men, about 13% larger by TBR’s math. People in the top 10% of the study’s polygenic risk score had about seven times the case prevalence of those in the bottom 10%.

What it means for treatment

The authors identified 17 newly implicated genes whose products interact with already approved drugs, including SYK, AXL, KEAP1 and RRM2B, the kind of overlap researchers use to look for drug-repurposing candidates. They also flagged QPCT, which encodes the enzyme that produces the modified form of amyloid targeted by the antibody drug donanemab.

The researchers caution that the associations are “a starting point rather than proof,” as the university release puts it. Uffelmann stressed that the 16% figure applies to populations, not individuals: it “does not mean that 16 percent of any one person’s Alzheimer’s is caused by their genes, and it does not mean a genetic test can determine whether someone will develop the disease.”

Why it matters in Massachusetts

About 7.4 million Americans age 65 and older live with Alzheimer’s, according to the Alzheimer’s Association 2026 Facts and Figures report. In Massachusetts, the group estimates 135,200 residents 65 and older have the disease, about 11.3% of that age group. Worldwide, the university’s release cites projections of more than 150 million dementia cases by 2050.

Boston-area researchers are pursuing the same targets. Mass General Brigham recently won up to $41.2 million in federal funding to test Alzheimer’s prevention drugs in a platform trial, and Cambridge-based Biogen reported its latest Leqembi sales in its third-quarter results. Studies like this one can point such programs toward the genes and cell types most likely to matter.

Sources

• Nature: Wightman, Uffelmann et al., genome-wide association study of Alzheimer’s disease (Oct. 28, 2026)
• Vrije Universiteit Amsterdam: Largest genetic study on Alzheimer’s identifies 48 new risk loci
• Amsterdam UMC: Largest genetic study on Alzheimer’s identifies 48 new risk loci (Nov. 2, 2026)
• Nature Genetics: Jansen et al., 2019; Wightman et al., 2021; Bellenguez et al., 2022
• Alzheimer’s Association: Massachusetts Alzheimer’s facts and figures