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An international study published in Nature identified 127 genetic loci associated with Alzheimer’s disease, including 48 not previously reported. The researchers say commonly used methods may underestimate the contribution of common genetic variants, while noting that the results do not establish that genes account for a specific share of an individual’s risk or provide a clinical test.
An international research team identified 127 genetic loci associated with Alzheimer’s disease, including 48 newly reported loci, in a study drawing on genetic data from nearly 2.8 million people. Other genetic research has explored factors that may protect against Alzheimer’s risk. Published in Nature, the analysis also found that some existing methods may underestimate how much common genetic variation contributes to Alzheimer’s risk, a finding that could reshape research into the disease’s biology and risk prediction.
The researchers combined de-identified data from 30 cohorts, including people diagnosed with Alzheimer’s, participants whose parent had Alzheimer’s or dementia, and control participants. The effective sample size was 416,493. In the multi-ancestry analysis, the team found 118 significant loci; a further nine were identified in an analysis restricted to people of European ancestry. Together, these made up the 127 loci, of which 48 were new.
The study examined how genetic associations connect to genes, biological pathways and cell types. Its analyses highlighted processes involving microglia, the brain’s immune cells, as well as neurons. The researchers also identified gene sets linked to lipid binding, immune activation, amyloid breakdown and cell adhesion. These findings point to several biological systems associated with inherited risk; they do not, on their own, show that any one pathway causes Alzheimer’s.
The team highlighted five potential drug targets: RRM2B, SYK, KEAP1, CACNA1S and AXL. The study did not test medicines aimed at these targets. The researchers also prioritized QPCT at a previously known locus and connected it to an amyloid-beta modification targeted by donanemab. These are genetic and computational findings, not evidence that the proposed targets will work as treatments.
Why Genetic Risk Estimates May Change
The findings matter because earlier estimates based on common genetic variants suggested they explained only about 5% of Alzheimer’s disease liability, even though twin studies have estimated the heritable component of susceptibility at 60% to 80%. Those figures come from different approaches and describe different aspects of genetic contribution. The new analysis suggests that the apparent gap may partly reflect limitations in how genetic effects have been measured, rather than proving a new precise heritability figure.
A clearer account of genetic risk could help researchers identify biological mechanisms for further study and improve future risk-prediction models. It may also broaden research beyond amyloid-beta: current disease-modifying treatments primarily target amyloid aggregates, and the source report says their effectiveness in relieving symptoms has been limited. The study does not establish that its findings will lead to improved prediction or new treatments, but it offers candidates for follow-up work.
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From Earlier Loci to 127 Signals
Alzheimer’s disease is the most prevalent type of dementia, and dementia from all causes is projected to affect 153 million people worldwide by 2050, according to the study’s background. Earlier genome-wide association studies had identified about 80 Alzheimer’s risk loci. The new analysis expands that catalogue, while using multiple methods to prioritize genes and examine how genetic signals may relate to biological function.
The study combined people with diagnosed Alzheimer’s and proxy cases, defined as participants who reported that a mother or father had Alzheimer’s or dementia. People with Alzheimer’s themselves were excluded from the proxy-case analysis. The researchers analyzed ancestry groups separately and then combined results, but approximately 91% of the effective sample size was of European ancestry. The study therefore adds data from several ancestry groups without providing equally precise evidence for each.
“The researchers investigated 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 Evidence
The study does not provide a single revised percentage for how much Alzheimer’s risk is genetic. Its conclusion that some methods may underestimate the contribution of common variants is based on comparisons of estimation approaches and simulations, not proof that genes explain a particular share of risk for every person. Heritability estimates describe patterns in populations and do not determine an individual’s outcome.
Some biological interpretations also remain unsettled. The researchers found enrichment among several neuronal populations, but said it is unclear whether those expression differences contribute to Alzheimer’s or occur as a result of neurodegeneration. After adjusting for average differences in gene expression across cell types, the microglial association remained significant, while neuronal associations became only nominally significant. No individual microglial state reached statistical significance.
Evidence was less precise for ancestry groups with smaller samples, and the European-ancestry group made up most of the effective sample size. The study’s proposed drug targets were not tested as treatments in this work. It is not yet clear whether follow-up studies will validate the signals across more diverse populations or whether any target will lead to a useful therapy.
Validation and Treatment Research Ahead
The next steps are to test the genetic signals and biological interpretations in independent samples, with larger and more balanced datasets across ancestry groups. Further research will also be needed to determine which prioritized genes and pathways directly influence disease processes, and which associations reflect changes that occur after disease begins.
The proposed targets could inform laboratory and clinical research, but the study itself did not evaluate their safety or effectiveness as Alzheimer’s treatments. Researchers would need additional evidence before any target could be considered a treatment option. Work on risk prediction would likewise need validation in independent populations before the findings could support clinical use.
Key Questions
What did the study find?
The researchers identified 127 Alzheimer’s-associated genetic loci, including 48 they reported as new. They also found evidence that some methods may underestimate the contribution of common genetic variants.
Does the study show that genes cause Alzheimer’s?
No. It found genetic associations and prioritized biological pathways for further investigation. The results do not prove that a particular gene or pathway causes Alzheimer’s in an individual.
Does this mean genes explain a specific percentage of Alzheimer’s risk?
No revised percentage is reported in the supplied study summary. Earlier estimates based on common variants and estimates from twin studies use different methods and measure different aspects of genetic contribution.
Are the five highlighted genes treatments?
No. RRM2B, SYK, KEAP1, CACNA1S and AXL were proposed as potential drug targets based on the analyses. The study did not test treatments aimed at them.
How well does the study represent different ancestries?
The analysis included European, African, East Asian, admixed American and South Asian ancestry groups, but about 91% of the effective sample size was European ancestry. Results were less precise in groups with smaller samples.
Source: news-medical.net
