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An international study using data from nearly 2.8 million people identified 127 genetic loci associated with Alzheimer’s disease, including 48 not previously reported. The researchers also examined why earlier methods may have captured only part of common-variant heritability; the findings point to immune and neuronal biology but do not establish new treatments.
An international team has identified 127 genetic loci associated with Alzheimer’s disease, including 48 not previously reported, in an analysis drawing on genetic data from nearly 2.8 million people. Published in Nature, the study also examined whether standard approaches have underestimated the contribution of common genetic variants to disease risk, while linking inherited risk to microglial immune activity and neuronal biology.
The researchers combined data from 30 cohorts, including people diagnosed with Alzheimer’s, people whose parent had Alzheimer’s or dementia, and control participants. The overall dataset included 109,479 people with Alzheimer’s, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls. Proxy cases reported a parent’s diagnosis and were not themselves counted as Alzheimer’s cases in that analysis. The study’s effective sample size was 416,493.
The multi-ancestry analysis found 118 significant loci; a further nine were identified in a European-ancestry-only analysis. The researchers reported 48 of the 127 loci as new. While the study included participants grouped by European, African, East Asian, admixed American and South Asian ancestry, about 91% of the effective sample was of European ancestry. The authors said results for ancestry groups with smaller samples were less precise.
The team used several gene-mapping and statistical approaches to connect associated locations in the genome with genes and biological processes. Analyses highlighted pathways involving immune activation, lipid binding, amyloid breakdown and cell adhesion. They also found enrichment of Alzheimer’s genetic associations among genes active in microglia, immune cells in the brain. Signals involving some neuronal populations were also observed, but their relationship to disease is less clear.
Why Genetic Estimates May Change
Twin studies have put the heritability of Alzheimer’s susceptibility at 60% to 80%, while earlier studies of common genetic variants estimated that they accounted for about 5% of disease liability. Those figures describe different measures: heritability estimates the contribution of genetic differences within a population, while SNP-based estimates focus on variation captured by particular genetic markers and methods. They should not be treated as directly interchangeable.
The new work matters because a better account of genetic associations could help researchers identify disease mechanisms and, over time, improve risk prediction. Its results reinforce interest in brain immune responses as well as amyloid, rather than suggesting that Alzheimer’s has a single genetic or biological cause. The study does not show that genetic testing can currently predict an individual’s outcome, nor does it establish a treatment based on the newly identified loci.
The researchers highlighted five possible drug targets—RRM2B, SYK, KEAP1, CACNA1S and AXL—through gene-prioritization analyses. These are research leads, not therapies validated by this study. The authors’ review of prior experimental work included mixed findings, and the present analysis did not test any of the targets as treatments.
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From Twin Studies to Genetic Mapping
Alzheimer’s is the most prevalent type of dementia. Previous genome-wide association studies had identified about 80 risk loci, while estimates based on common single-nucleotide polymorphisms suggested a comparatively small share of disease liability. The new study expands the catalogue of associated loci and compares approaches to estimating genetic contribution.
To investigate the gap between heritability estimates and SNP-based estimates, the team used SBayesRC and linkage disequilibrium score regression, alongside simulations using UK Biobank data. The study’s design also included proxy cases based on a reported parental diagnosis, which increased the available data but differs from analyzing only people with confirmed diagnoses. Some cohorts used clinical diagnoses or ICD-10 codes, including unspecified dementia codes.
Current disease-modifying Alzheimer’s treatments primarily target amyloid-beta aggregates, and the source report notes that their ability to relieve symptoms has been limited. The study also prioritized QPCT at a previously known genetic locus, connecting it to an amyloid-beta modification targeted by donanemab. That genetic association is not evidence that the study evaluated donanemab or established its effectiveness.
“The study investigated how inherited risk relates to changes in the brain’s immune cells and neurons, and whether existing methods underestimate the genetic contribution to Alzheimer’s disease.”
— The study authors, as summarized in the News-Medical report
Limits of the Genetic Findings
The results identify statistical associations, but they do not by themselves prove how each locus affects Alzheimer’s risk. The report does not provide a single revised estimate showing exactly how much common genetic variation contributes to disease liability compared with earlier estimates. The size of any change depends on the method and dataset used.
Some biological findings also remain unresolved. After adjustment for average differences in gene expression across cell types, the microglial association remained significant, while neuronal associations became nominal rather than statistically significant. The study could not determine whether observed expression differences in neurons contribute to Alzheimer’s or occur as a consequence of neurodegeneration. No individual inflammatory microglial state reached statistical significance.
Because the effective sample was predominantly European ancestry, the findings are less precise for other groups. The study also did not test the proposed drug targets as treatments or establish that the associated genes can be used to guide care. Clinical usefulness and treatment effects remain unproven.
Research Needed Before Clinical Use
Further work will be needed to replicate the associations, clarify how particular genes influence brain cells, and test whether the proposed targets affect disease processes in laboratory and clinical research. Larger and more balanced datasets across ancestry groups could improve the precision and reach of genetic estimates.
For now, the findings add to the research map of Alzheimer’s genetics rather than changing diagnosis or treatment. The next key developments will be independent validation of the loci and evidence showing whether any of the suggested biological targets can lead to safe, effective interventions or more useful risk prediction.
Key Questions
What did the study find?
It identified 127 genetic loci associated with Alzheimer’s, including 48 described as newly identified, and linked genetic signals to pathways involving microglia, neurons, immune activity and other processes.
Does the study prove genes account for more than 5% of Alzheimer’s risk?
No single updated percentage is reported in the supplied study summary. The researchers compared methods for estimating the contribution of common variants, but heritability and SNP-based estimates measure different aspects of genetic contribution.
Are the proposed genes new Alzheimer’s treatments?
No. RRM2B, SYK, KEAP1, CACNA1S and AXL were highlighted as possible research targets. The study did not test them as treatments, and the findings do not establish that targeting them would help patients.
How well did the study represent different ancestries?
It included five ancestry groupings, but about 91% of the effective sample size was European ancestry. The report says results were less precise in groups with smaller samples.
Source: news-medical.net
