Genetic Study Expands Understanding of Alzheimer’s Disease Risk

The team pooled data across 30 cohorts totaling more than 2.8 million participants, including 109,479 diagnosed Alzheimer’s cases, 74,141 proxy cases, 2,131,799 controls, and 499,708 proxy controls. The dataset was 91% European, 5% African, 3% East Asian, and under 1% each of admixed American and South Asian ancestry. Across the cohorts, the team analyzed more than 8.1 million common DNA variants, adjusting for age, sex, genetic ancestry, and study-specific factors while excluding cases diagnosed before age 40 where possible to avoid rare single-gene forms of the disease. Researchers then combined the genetic map with machine-learning tools, single-cell brain RNA atlases, and regulatory drug databases to identify likely causal genes, relevant cell types, and drug interactions (source ID: 1). [1]

The findings revealed that genetic risk concentrated in genes expressed at higher levels in microglia and lower levels in neurons in people with Alzheimer’s compared with unaffected donors. Three neuronal subtypes initially stood out, including two types of inhibitory neurons that produce somatostatin or small signaling peptides and are known to be vulnerable early in Alzheimer’s. After adjusting for average expression changes across all brain cell types, however, the microglial link held firm while the individual subtype signals weakened, indicating broader neuronal dampening. Pathway analyses reinforced roles for immune activation, fat binding, cell adhesion, and amyloid clearance, alongside five processes new to Alzheimer’s genetic scans, including oxidative-stress regulation via glutathione metabolism and membrane recycling at nerve junctions (source ID: 1). [1]

A large-scale genetic study involving over 2.8 million individuals has identified 127 regions of human DNA associated with Alzheimer’s disease, including 48 regions linked to the condition for the first time. The study pooled data across 30 cohorts totaling more than 2.8 million participants, including 109,479 diagnosed Alzheimer’s cases and 2,131,799 controls. Using statistical models and polygenic scores, the team estimated that common variants account for 16% of population differences in underlying susceptibility to Alzheimer’s among people of European ancestry. This work was published in Nature and involved researchers from multiple institutions, including the Complex Trait Genetics lab at Vrije Universiteit Amsterdam (source ID: 1). [1]

The findings revealed that genetic risk concentrated in genes expressed at higher levels in microglia and lower levels in neurons in people with Alzheimer’s compared with unaffected donors. This pattern was observed through comparisons with single-cell RNA data from donated brain tissue, suggesting that inherited risk variants may push microglial immune genes toward overactivity while lowering gene expression in vulnerable neurons. Pathway analyses reinforced roles for immune activation, fat binding, cell adhesion, and amyloid clearance, alongside five processes new to Alzheimer’s genetic scans, including oxidative-stress regulation via glutathione metabolism and membrane recycling at nerve junctions (source ID: 1). [1]

Combined into a polygenic score, a single number summarizing inherited risk across millions of DNA variants, the predictors explained nearly 13% of the variation in disease susceptibility on average across held-out European cohorts, outperforming APOE status alone. Among European-ancestry UK Biobank adults aged 65 and older, Alzheimer’s prevalence was seven times higher in the top 10% of polygenic scores than in the bottom 10%, and three times higher than the whole-sample average. The study also identified 17 genes in the new regions that interact with approved non-Alzheimer’s medications, some of which showed promise in earlier animal studies of Alzheimer’s (source ID: 1). [1]

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