New research suggests that most Alzheimer’s cases may rely on the influence of just one gene.
A new analysis led by researchers at University College London suggests that Alzheimer’s disease may depend far more heavily on one gene than scientists once believed. The study estimates that more than 90% of Alzheimer’s cases might not develop without the influence of a single gene called APOE.
The impact appears to extend beyond Alzheimer’s alone. Researchers found that nearly half of all dementia cases may also rely on this gene’s contribution.
Published in npj Dementia, the findings point to APOE and the protein it produces as a major but often overlooked focus for drug development. Targeting this pathway could potentially prevent or treat a substantial share of dementia cases.
How APOE Variants Affect Alzheimer’s Risk
The APOE gene has been linked to Alzheimer’s disease for many years. It exists in three common forms, or alleles, known as ε2, ε3, and ε4. Each person inherits two copies of APOE, which results in six possible combinations[1] of these variants.
Research in the 1990s showed that people who carry one or more ε4 variants face a much higher risk of Alzheimer’s compared with those who have two copies of the more common ε3 variant. People with ε2 generally have a lower risk than ε3 carriers.
Why Researchers Say APOE’s Role Has Been Underestimated
Lead author Dr. Dylan Williams (UCL Division of Psychiatry and Unit for Lifelong Health and Ageing at UCL) said: “We have long underestimated how much the APOE gene contributes to the burden of Alzheimer’s disease. The ε4 variant of APOE is well recognized as harmful by dementia researchers, but much disease would not occur without the additional impact of the common ε3 allele, which has been typically misperceived as neutral in terms of Alzheimer’s risk.
“When we consider the contributions of ε3 and ε4, we can see that APOE potentially has a role in almost all Alzheimer’s disease. Consequently, if we knew how to reduce the risk that the ε3 and ε4 variants confer to people, we may be able prevent most disease from occurring.”
The Most Comprehensive Population Analysis to Date
The study represents the most detailed modeling so far of how common APOE variants contribute to Alzheimer’s and dementia across the population. Researchers combined evidence linking the ε3 and ε4 alleles to Alzheimer’s disease, all-cause dementia, and the brain changes that precede Alzheimer’s.
A critical element of the analysis was access to data from four very large studies involving more than 450,000 participants. This allowed researchers to identify a sizable group of people with two ε2 copies, an uncommon but low risk group, and use them as a reference point in their calculations for the first time in this type of research.
How Much Alzheimer’s and Dementia May Depend on APOE
Based on their analysis, the researchers estimated that 72-93% of Alzheimer’s cases would not have occurred without the ε3 and ε4 variants of APOE. They also found that roughly 45% of all dementia cases might not arise without the gene’s influence.
These estimates exceed earlier assessments of APOE’s impact, largely because the new study evaluated the combined effects of both ε3 and ε4 rather than focusing only on ε4.
Why Study Results Varied
Results differed somewhat across the four studies included in the analysis. These differences reflected how Alzheimer’s and dementia were defined and measured, including whether cases were identified through medical diagnoses, other dementia classifications, or signs of amyloid buildup seen on brain scans.
Variation in follow-up length and possible recruitment biases also contributed. When considered together, the evidence suggests that APOE is likely responsible for at least three quarters of Alzheimer’s cases, and potentially more.
A Strong Case for Drug Discovery Focus
The findings indicate that APOE should receive greater attention in research aimed at understanding disease mechanisms and developing new treatments.
Dr. Williams said: “There has been major progress in recent years in gene editing and other forms of gene therapy to target genetic risk factors directly. Moreover, genetic risk also points us towards parts of our physiology that we could target with more conventional drugs. Intervening on the APOE gene specifically, or the molecular pathway between the gene and the disease, could have great, and probably under-appreciated, potential for preventing or treating a large majority of Alzheimer’s disease.
“The extent to which APOE has been researched in relation to Alzheimer’s or as a drug target has clearly not been proportionate to its full importance.”
Genetics Is Not Destiny
Despite its strong influence, APOE is not the sole cause of Alzheimer’s or other dementias. Even among people with the highest genetic risk, those who carry two ε4 variants, lifetime risk of Alzheimer’s disease is still estimated to be below 70%.
As Dr. Williams explained: “Most people with genetic risk factors like APOE ε3 and ε4 won’t get dementia in a typical lifetime, since there are complicated interactions at play with other contributing genetic and environmental risk factors. Understanding what modifies the risk people inherit from their APOE genes is another crucial question for dementia researchers to grapple with.
“For instance, other research has suggested that perhaps half of dementia incidence could be prevented or delayed by improving many modifiable risk factors such as social isolation, high cholesterol or smoking, across populations.[2] With complex diseases like Alzheimer’s and other diseases that cause dementia, there will be more than one way to reduce disease occurrence. We should explore many options by which we might modify Alzheimer’s and dementia risk, including but not limited to strategies related to APOE.
“Nonetheless, we should not overlook the fact that without the contributions of APOE ε3 and ε4, most Alzheimer’s disease cases would not occur, irrespective of what other factors are inherited or experienced by carriers of these variants throughout life.”
Funding and Expert Response
The study was carried out by researchers at UCL and the University of Eastern Finland and was supported by Alzheimer’s Research UK, the Medical Research Council, and other funders.
Dr. Sheona Scales, Director of Research at Alzheimer’s Research UK, said: “This study highlights that more Alzheimer’s cases are linked to the APOE gene that previously thought. However, not everyone with these variants will develop Alzheimer’s, demonstrating the complex relationship between genetics and other risk factors for dementia.
“Despite APOE being linked to Alzheimer’s, very few treatments in clinical trials target this gene directly. Findings from this study show that further research into APOE will be important for developing future prevention and treatment strategies for Alzheimer’s.
“Alzheimer’s Research UK is delighted to support Dr. Williams as he continues to investigate how genetics alongside environmental and societal factors influence dementia risk, which will ultimately bring us closer to a cure.”
Why APOE Variants Increase Dementia Risk
Earlier studies suggest that the ε4 variant may raise dementia risk because the protein it produces is less effective at clearing amyloid-beta (a sticky protein that forms plaques). It also interferes with fat and energy processing in brain cells and promotes inflammation, which can gradually damage neurons and increase vulnerability to Alzheimer’s and related dementias. Further research is needed to confirm these processes and to explain why ε3 increases dementia risk compared with ε2.
Notes
- The six combinations of the APOE gene are: ε2+ε2; ε2+ε3; ε2+ε4; ε3+ε3; ε3+ε4; ε4+ε4. The variants are referred to as APOE2, APOE3, APOE4 in relation to APOE protein type.
- The Lancet Commission on dementia prevention, intervention, and care 2024 (also on UCL News)
Reference: “The proportion of Alzheimer’s disease attributable to apolipoprotein E” by Dylan M. Williams, Sami Heikkinen, Mikko Hiltunen, FinnGen, Neil M. Davies and Emma L. Anderson, 9 January 2026, npj Dementia.
DOI: 10.1038/s44400-025-00045-9
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