This one gene may explain most Alzheimer’s cases

The researchers also found that the gene’s impact extends beyond Alzheimer’s alone. Their analysis indicates that nearly half of all dementia cases may also rely on APOE’s contribution.

Published in npj Dementia, the findings point to APOE and the protein it produces as a major yet often overlooked target for drug development. Targeting this gene could open the door to preventing or treating a large share of dementia cases worldwide.

Understanding the APOE Gene and Its Variants

Scientists have known for decades that APOE is linked to Alzheimer’s disease. The gene comes in three common forms, or alleles, called ε2, ε3, and ε4. Each person carries two copies of the gene, which results in six possible combinations* of these variants.

Research dating back to the 1990s showed that people who carry one or two copies of the ε4 variant face a much higher risk of developing Alzheimer’s compared with those who inherit two ε3 copies. By contrast, people with ε2 generally have a lower risk than ε3 carriers.

Why Scientists 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 Largest Modeling Study of APOE’s Population Impact

This research represents the most comprehensive modeling effort so far to estimate how many Alzheimer’s and dementia cases across the population are tied to common APOE variants. The team combined evidence linking ε3 and ε4 to Alzheimer’s, broader dementia diagnoses, and the brain changes that precede the disease.

A key strength of the analysis was access to data from four very large studies, totaling 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 baseline for comparison for the first time in this type of study.

How Much Alzheimer’s and Dementia May Depend on APOE

Using this approach, the researchers estimated that between 72% and 93% of Alzheimer’s cases would not have occurred without the ε3 and ε4 variants of APOE. They also concluded that about 45% of all dementia cases may rely on the gene’s influence.

These figures are higher than earlier estimates of APOE’s role, largely because this analysis accounted for the effects of both ε3 and ε4 rather than focusing on ε4 alone.

Why Results Differed Across Studies

The four studies included in the analysis did not all produce identical results. Differences arose from how Alzheimer’s and dementia were defined and measured, such as whether diagnoses were based on medical records, other dementia classifications, or amyloid buildup seen in brain scans. Variation in follow-up time and recruitment methods also played a role.

Taken together, the combined evidence suggests that APOE is likely responsible for at least three quarters of Alzheimer’s cases, and possibly more.

Implications for Drug Development and Prevention

The findings indicate that APOE should become a higher priority 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 Powerful but Not the Whole Story

Despite APOE’s strong influence, it is not the sole cause of Alzheimer’s or other dementias. Even among people in the highest risk group, those with two ε4 copies, lifetime risk of Alzheimer’s disease 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.”

Study Support and Expert Reaction

The study was carried out by researchers at UCL and the University of Eastern Finland and received funding from Alzheimer’s Research UK, the Medical Research Council, and other organizations.

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 Raise Dementia Risk

Earlier research suggests 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 how brain cells manage fats and energy and promotes inflammation, which may gradually damage neurons and increase vulnerability to Alzheimer’s and related dementias. More research is needed to confirm these processes and to explain why ε3 raises 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