An international genetic association study published in Nature has identified 127 human DNA regions linked to Alzheimer's disease risk, 48 of which are newly mapped. Analyzing genetic data from roughly 2.8 million individuals across 30 cohorts, researchers led by Ole Andreassen and Danielle Posthuma demonstrated that common variants account for 16 percent of risk variance. The findings highlight key biological processes involving microglia immune cells and specific neuronal cell types, offering new avenues for therapeutic research.
Identification of genetic risk loci
- ▪Prior genome-wide association studies had identified approximately 80 risk loci for Alzheimer's disease, highlighting roles for immune function, amyloid catabolism, and lipid function.
- ▪An international genome-wide association study published in Nature identified 127 human DNA regions associated with Alzheimer's disease risk (118 from multi-ancestry analysis and 9 from ancestry-specific analyses), including 48 not previously mapped to the disease.
Sample size and ancestral diversity
- ▪The multi-ancestry study analyzed genetic data from approximately 2.8 million individuals across 30 research cohorts, including 109,479 clinical cases, 74,141 proxy cases, 2,131,799 controls, and 499,708 proxy controls.
- ▪The total effective sample size of 416,493 comprised 91% European, 5% African, 3% East Asian, under 1% admixed American, and under 1% South Asian ancestry individuals.
Biological processes and microglia function
- ▪The genetic study linked Alzheimer's disease risk variants to microglia activation, immune cell recruitment, cellular material clearance, amyloid-β processing, astrocyte activation, and nerve fiber insulation maintenance.
- ▪Microglia are immune cells in the brain responsible for clearing away harmful substances and damaged cellular material.
Neuronal cell types linked to risk
- ▪The identification of specific neuronal cell types enriched for genetic signal provides new directions for investigating how Alzheimer's disease develops and identifying targets for therapeutic intervention.
- ▪The international study identified for the first time several specific neuronal cell types that are enriched for genetic signals associated with Alzheimer's disease risk.
Heritability estimates of Alzheimer's risk
- ▪The 16 percent population-level heritability figure does not mean a single individual's Alzheimer's risk is 16 percent genetic or that a genetic test can definitively determine if someone will develop the disease.
- ▪Earlier estimates using linkage disequilibrium score regression calculated SNP-based heritability for Alzheimer's disease risk at approximately 5 percent because they did not fully account for the APOE gene's effect.
- ▪Using the SBayesRC statistical method, researchers estimated that common single-nucleotide polymorphisms explain 16 percent of the differences in Alzheimer's disease risk between individuals on the liability scale.
Polygenic risk score performance
- ▪The researchers evaluated polygenic risk scores across five validation cohorts, including DemGene, Gothenburg H70, TwinGene, UK Biobank, and BioBank Japan.
- ▪The study's polygenic score models provided improved predictive performance for Alzheimer's disease risk over previous models, though the authors note clinical implementation requires further investigation.
Study organization and data sharing
- ▪The study was conducted under the Psychiatric Genomics Consortium and co-led by Ole Andreassen at the University of Oslo and Danielle Posthuma at Vrije Universiteit Amsterdam, with contribution from the University of Exeter's PROTECT study.
- ▪The researchers made summary statistics from the main and stratified analyses publicly available to allow other scientific teams to test new hypotheses.
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