Alzheimer’s Risk May Be Driven by a Single Gene
New population-scale data suggest APOE variants account for most Alzheimer’s cases, reshaping how genetic risk is understood
Large-scale genetic and clinical data suggest that common variants of the APOE gene may account for the majority of Alzheimer’s disease cases and nearly half of all dementia, challenging the long-held assumption that only APOE4 meaningfully drives risk.
Study Details
Alzheimer’s disease remains one of the most complex and costly neurodegenerative disorders worldwide. While genetics have long been known to influence risk, attention has focused primarily on the APOE4 variant. This new analysis suggests that APOE3, long considered neutral, may also meaningfully contribute to disease burden.
Researchers at University College London, examined whether APOE variants could explain how much Alzheimer’s disease and dementia occur at the population level, not just individual risk.
The study was published in NPJ Dementia and analyzed data from more than 470,000 older adults across multiple cohorts.
Methodology
The investigators combined data from four complementary sources to capture both clinical diagnosis and biological confirmation:
Electronic health records from UK Biobank and FinnGen to assess clinically diagnosed Alzheimer’s disease and all-cause dementia
Amyloid PET imaging from the A4 Study to identify Alzheimer’s pathology before symptoms
Autopsy-confirmed cases from the Alzheimer’s Disease Genetics Consortium to reduce diagnostic uncertainty
The team estimated the proportion of disease cases attributable to APOE variants by comparing risk relative to APOE2, a protective allele
Key Findings
APOE3 and APOE4 variants together were associated with 71.5% to 92.7% of Alzheimer’s cases across cohorts
Nearly 45% of all-cause dementia cases were linked to these same variants
In autopsy-confirmed Alzheimer’s disease, APOE4 accounted for about 57% of cases, while APOE3 accounted for about 36%
APOE3, the most common allele, may not be biologically neutral as previously assumed
APOE variants appear necessary for most Alzheimer’s cases at the population level, but insufficient on their own to cause disease in most individuals.
Implications for Practice
For patients, these findings reinforce that genetic risk does not equal genetic destiny. Most people carry APOE3 or APOE4, yet the majority will never develop dementia in their lifetime. Lifestyle and environmental factors still matter.
For clinicians and researchers, the results suggest a broader role for APOE biology in Alzheimer’s disease than previously recognized. This may help explain why therapies targeting amyloid or inflammation alone have shown limited success.
The study also renews interest in APOE-focused interventions. Early-stage approaches such as gene therapy designed to increase APOE2 expression in high-risk individuals are already being explored, though these remain experimental.
Importantly, experts caution against overinterpretation. Modifiable risk factors such as cardiovascular health, education, hearing loss, physical activity, and metabolic disease remain critical targets for prevention and risk reduction, even in genetically susceptible individuals.