A growing body of evidence suggests that a single gene, APOE, may play a far more dominant role in Alzheimer’s disease than previously recognized.
A single gene may play a much larger role in Alzheimer’s disease than scientists once thought.
In a new analysis led by researchers at UCL, the APOE gene was linked to an estimated 72% to 93% of Alzheimer’s cases, depending on how the disease was measured. The team also found that roughly 45% of all dementia cases may be tied to the same gene. The study, published in npj Dementia, argues that APOE deserves far more attention as a target for future treatments.
What is particularly startling is that APOE is not a rare mutation carried by only a small number of people. It is a common gene found in everyone, and most people carry forms of it that appear to raise Alzheimer’s risk.
APOE comes in three common versions (alleles): ε2, ε3, and ε4. Each person inherits two copies, creating six possible combinations of these variants. For decades, scientists have known that ε4 raises Alzheimer’s risk and that ε2 appears to be more protective. The ε3 version, which is the most common, has often been treated as neutral by comparison.
This study challenges that idea.
The researchers say Alzheimer’s risk has likely been underestimated because scientists have focused so heavily on ε4 while paying less attention to ε3. When both ε3 and ε4 are considered together, APOE appears to be involved in most Alzheimer’s cases.
Rethinking the Role of “Neutral” Variants
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.”
Why This Study Stands Out
To estimate APOE’s overall impact, the researchers combined evidence from four very large datasets using different ways of tracking Alzheimer’s and dementia.
Two of the datasets, UK Biobank and FinnGen, included more than 460,000 people ages 60 and older whose diagnoses could be tracked through health records. A third dataset, the A4 Study, looked at amyloid positron emission tomography (PET) brain scans in 4,415 participants to measure amyloid buildup before symptoms appeared. A fourth, from the Alzheimer’s Disease Genetics Consortium, compared people with neuropathologically confirmed Alzheimer’s at autopsy with cognitively healthy controls.
This design matters because Alzheimer’s can be defined in different ways — through clinical diagnosis, imaging, or brain tissue analysis. Combining these approaches provides a more complete picture of APOE’s role.
The researchers also used a rare but important comparison group: people with two copies of ε2, considered lowest risk. Large datasets made this possible, allowing clearer estimates of how much risk is linked to the more common ε3 and ε4 variants.
Striking Estimates of Genetic Influence
The researchers estimate that 72 to 93% of Alzheimer’s cases may be tied to the ε3 and ε4 variants of APOE. For dementia overall, the gene may account for about 45% of cases.
These figures are higher than earlier estimates, largely because this study considered the combined effects of both ε3 and ε4 rather than focusing mainly on ε4 alone.
Differences between the four datasets reflect how each study defined and measured Alzheimer’s and dementia. Some relied on clinical diagnoses, while others used brain imaging to detect amyloid pathology. Variations in follow-up time and participant selection may also have influenced results.
Overall, the combined evidence suggests APOE is responsible for at least three out of four Alzheimer’s cases, and possibly more.
The findings indicate that APOE should be a central focus in research on disease mechanisms and drug development.
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.”
Genetic Risk Is Not Destiny
APOE does not act alone in causing Alzheimer’s or other dementias. Even among people with two ε4 copies, the highest risk group, the lifetime risk of developing Alzheimer’s remains 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. 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.”
Broader Research Context
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 than 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 are linked to dementia
Earlier research suggests 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 may also interfere with fat and energy use in brain cells and promote inflammation. Over time, these effects can damage neurons and increase vulnerability to Alzheimer’s and related dementias. More research is needed to confirm these processes and to explain why the ε3 variant also carries higher risk than ε2.
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
The study was supported by funding from Alzheimer’s Research UK, the Medical Research Council and others.
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