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A large population-level analysis led by researchers at University College London has suggested that common variants of the APOE gene may underpin the majority of Alzheimer’s disease cases and a substantial proportion of all dementias, prompting renewed calls to prioritise the gene as a therapeutic target
A single gene may account for the vast majority of Alzheimer’s disease cases, according to a comprehensive modelling study led by researchers at University College London (UCL), UK. The analysis has suggested that between 72% and 93% of Alzheimer’s disease cases would not have occurred without the contribution of common variants of the apolipoprotein E gene – known as APOE – while close to 45% of all dementia cases were also estimated to depend on the gene’s influence.
The findings have indicated that APOE and the protein it encodes represent a powerful yet under-recognised target for future drug discovery, with potential relevance for preventing or treating a large proportion of dementia worldwide.
APOE has long been linked to Alzheimer’s disease. Three common variants, or alleles, of the gene exist, known as ε2, ε3 and ε4. Each person inherits two copies of APOE, resulting in six possible genetic combinations. Research dating back to the 1990s established that individuals who carry one or more copies of the ε4 variant face a substantially higher risk of Alzheimer’s disease than those with two copies of the more common ε3 variant, while carriers of ε2 generally experience a lower risk. The ε3 variant has often been treated as neutral in relation to Alzheimer’s disease risk.
“We have long underestimated how much the APOE gene contributes to the burden of Alzheimer’s disease,” said Dr Dylan Williams, lead author of the study, from the UCL Division of Psychiatry and the Unit for Lifelong Health and Ageing at UCL.
“The ε4 variant of APOE is well recognised 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 [on] people, we may be able to prevent most disease from occurring,” he added.
The work represents the most extensive modelling to date of the proportion of Alzheimer’s disease and dementia cases that arise across the population because of common variation in APOE. The researchers synthesised evidence on the associations between ε3 and ε4 alleles and the risk of Alzheimer’s disease, any form of dementia, and the biological brain changes that precede Alzheimer’s pathology.
Central to the analysis was the use of data from four very large population studies, together comprising more than 450,000 participants. The scale of these datasets enabled the researchers to identify sufficient numbers of people who carried two copies of the ε2 variant, a relatively uncommon genetic profile. This group was used as a low-risk reference population, allowing the team to estimate disease attribution with greater precision than in previous studies.
On the basis of these data, the researchers concluded that the combined effects of the ε3 and ε4 alleles explained a markedly higher proportion of Alzheimer’s disease cases than earlier estimates, which had largely focused on ε4 alone. Differences between the four contributing studies reflected variation in how Alzheimer’s disease and dementia were defined and measured, including reliance on recorded clinical diagnoses or evidence of amyloid pathology from brain imaging, as well as differences in follow-up duration and potential recruitment biases. When considered together, the evidence suggested that APOE was most likely responsible for at least three-quarters of all Alzheimer’s disease cases, and possibly even more.
The authors argued that these findings strengthen the case to prioritise APOE in mechanistic research and therapeutic development. Recent progress in gene editing and other forms of gene therapy has increased interest in approaches that directly target inherited risk factors. In parallel, genetic insights may also highlight physiological pathways that are amenable to intervention with more conventional medicines.
“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,” Dr Williams said.
Despite the strong genetic signal, the researchers emphasised that Alzheimer’s disease and other dementias do not arise solely because of APOE. Even among individuals in the highest-risk category, those who inherit two copies of the ε4 variant, lifetime risk of Alzheimer’s disease has been estimated to remain below 70%.
“Most people with genetic risk factors like APOE ε3 and ε4 will not get dementia in a typical lifetime, since there are complicated interactions at play with other contributing genetic and environmental risk factors,” Dr Williams explained.
“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.”
The study was conducted by researchers at University College London and the University of Eastern Finland, split between the cities of Joensuu and Kuopio, with funding support from Alzheimer’s Research UK, the MRC and other organisations.
“This study highlights that more Alzheimer’s cases are linked to the APOE gene than previously thought,” said Dr Sheona Scales, Director of Research at Alzheimer’s Research UK.
“However, not everyone with these variants will develop Alzheimer’s, which demonstrates the complex relationship between genetics and other risk factors for dementia.
“Despite APOE being linked to Alzheimer’s disease, very few treatments in clinical trials target this gene directly. Findings from this study show that further research into APOE will be important to develop future prevention and treatment strategies for Alzheimer’s.”
Previous research has proposed that the ε4 variant increases dementia risk because the protein it produces clears amyloid-beta less effectively. Amyloid-beta is a sticky protein that forms plaques in the brain, a hallmark of Alzheimer’s disease. The ε4 protein has also been linked to disrupted lipid and energy metabolism in brain cells and to increased inflammation, changes that may gradually damage neurons and increase vulnerability to neurodegeneration.
For further reading please visit: 10.1038/s44400-025-00045-9
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