Consensus meta-analysis of genome-wide association studies for Alzheimer's disease and related dementias.
Level 3 - non-randomized controlled study
Meta-analysis of observational genetic association cohorts and case-control studies.
PubMed 42237039 · doi:10.1038/s41588-026-02583-1
What was done
A meta-analysis of European-ancestry genome-wide association studies was conducted in 128,681 cases or proxy cases of Alzheimer's disease and related dementias (ADRD) and 849,833 controls or proxy controls to identify risk loci and assess the neuropathological impact of a non-APOE polygenic risk score.
What was found
The meta-analysis identified 91 ADRD risk loci (16 novel) and 18 additional loci (15 novel) requiring external validation; 56 of the 91 loci were specifically detected in clinically diagnosed AD cases. A non-APOE polygenic risk score was primarily associated with AD rather than non-AD pathology, with individuals in the tenth decile having a twofold increased risk of exhibiting Braak neurofibrillary tangle stage >4 and moderate-to-severe neuritic amyloid plaque pathology at autopsy compared to median-score individuals.
Why it matters
This study expands the known common-variant genetic architecture of ADRD and links non-APOE polygenic burden directly to post-mortem amyloid and tau neuropathology.
Limits
The study was restricted to European-ancestry populations, limiting generalizability to other demographic groups. A major fraction of the sample relied on proxy-reported diagnoses rather than gold-standard clinical assessments, and 18 identified loci still require external validation.
Cited by
- context Genome-wide association studies (GWAS) have identified well over 100 genetic risk loci associated with Alzheimer's disease.