Most cases of late-onset Alzheimer’s disease (AD) would not occur without the contribution of a single gene, apolipoprotein E (APOE), making it a prime target for future prevention and treatment strategies.

In a study of 470,000 people of European descent, researchers discovered that the vast majority — up to 90% — of AD cases may be driven by variations in the APOE gene. While the APOE4 variant is a well-known risk factor, investigators found that the common APOE3 variant also significantly increases the risk. Combined, these two variants are associated with nearly half of all cause dementia cases.

These findings position APOE as a central driver of AD risk, at a time when most drug development efforts have concentrated on removing amyloid plaques and tau tangles — the hallmark proteins that accumulate in the brains of patients with AD.

“The results of our study indicate that some aspect of APOE function is a necessary component for a large majority of late-onset Alzheimer’s disease,” lead author Dylan Williams, PhD, a genetic epidemiologist at University College London, London, England, told Medscape Medical News. “This highlights a powerful but underrecognized target for prevention and treatment,” he added.

The study was published online on January 9 in npj Dementia.

Genetic Risk in Context

APOE has long been implicated in AD, which represents roughly 60%-80% of all dementia cases and affects more than 7 million Americans aged 65 years or older. Individuals inherit two copies of the gene, one from each parent, resulting in combinations of three common variants: APOE2, APOE3, and APOE4. The APOE4 variant confers the highest individual risk, APOE2 is relatively protective, and APOE3 — the most prevalent — has historically been treated as neutral.

Prior estimates of APOE’s contribution to AD have varied widely, in part because many studies focused narrowly on APOE4. In contrast, the current investigators examined how much disease arises across populations when both APOE3 and APOE4 are considered.

To conduct the analysis, researchers compared AD risk across APOE genotypes and designated individuals with two copies of the protective APOE2 variant as a low-risk reference group. The approach enabled them to estimate overall disease burden rather than individual relative risk alone.

The investigation showed that although APOE4 confers greater individual risk, much of the overall AD burden is driven by the APOE3 allele, which is carried by a far greater proportion of the population.

A key aspect of the study, the investigators noted, was treating APOE3, the most common variant, as a risk allele relative to the protective APOE2 variant, rather than as a neutral baseline.

Therapeutic Potential

For the study investigators drew on data from four large cohorts. These included electronic health record data from the UK Biobank and FinnGen, which together captured AD and all-cause dementia diagnoses in nearly half a million older adults.

In addition, they analyzed amyloid PET data from participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease study, along with neuropathologically confirmed cases from the Alzheimer’s Disease Genetics Consortium.

The researchers combined clinical diagnoses, brain imaging, and postmortem pathology to capture AD and dementia using different criteria, ranging from medical records to biological markers. This approach clarified why previous studies have produced widely divergent estimates of APOE’s impact.

The researchers argue that APOE-related risk, particularly mechanisms linked to the APOE4 variant, has been underprioritized as a therapeutic target relative to its apparent importance in AD biology.

“The extent to which APOE has been researched as a drug target has not been proportionate to its importance,” Williams said.

He added that the findings point to multiple potential therapeutic strategies, including approaches that directly target APOE-related pathways or aim to mimic the protective effects of the APOE2 variant.

However, the investigators noted that APOE is not the sole driver of AD. Carrying APOE risk variants does not make dementia inevitable as genetic susceptibility interacts with aging, lifestyle, cardiovascular health, and environmental factors.

No Clinical Implications — Yet

Commenting on the findings for Medscape Medical News, Scott Small, MD, director of the Alzheimer’s Disease Research Center at Columbia University, New York City, said the study reinforces prior genetic and experimental evidence without changing current clinical practice.

“Among the many genes linked to Alzheimer’s disease risk, APOE4 stands out as the most strongly associated,” said Small, who was not involved in the study. “But based on human genetics and mouse models, APOE4 is not a deterministic gene.”

For a gene to be considered causative, Small explained, it must be present only in affected individuals and shown in experimental systems to independently trigger key features of the disease, criteria that APOE does not meet. As a result, routine APOE testing remains unjustified in most clinical settings.

“There is no point in testing unless there is an APOE-based intervention,” he said. “For diagnosis, we already have much better biomarkers.”

Several experts also weighed in on the research in a statement from the UK-based nonprofit and independent Science Media Centre.

Timothy Frayling, PhD, a professor of human genetics at the University of Geneva, Geneva, Switzerland, said the estimates align with prior research but could be misleading if interpreted too literally.

“People should not worry if they have the risk versions of the gene because 99.4% of us do,” Frayling said, likening the finding to saying that most road traffic deaths would not occur without the contribution of cars.

Richard Oakley, PhD, associate director of research and innovation at Alzheimer’s Society in the UK, emphasized that genetic risk does not amount to a diagnosis and that people can still take steps to reduce dementia risk. “We must not lose sight of the risk factors that remain within our control,” he said.

This study was supported by funding from the UK Medical Research Council. Williams reported being supported by an Alzheimer’s Research UK Senior Fellowship. Other co-authors were funded by grants from the Norwegian Research Council, UK Research and Innovation, the Research Council of Finland, the Sigrid Juselius Foundation, and the University of Eastern Finland. Williams and Small reported no relevant financial relationships. Frayling and Oakley reported no relevant disclosures.