New study shows APOE genetics may explain up to 90% of Alzheimer’s risk, which may help in reshaping prevention strategies.
If Alzheimer’s prevention has felt like a moving target, APOE may be the clearest bullseye yet. Now, a new study suggests common variants of the APOE gene may account for up to 90% of Alzheimer’s disease risk at the population level, reframing genetics as a central driver of one of aging’s most feared conditions. Led by researchers at University College London, the findings strengthen the case for prevention strategies that treat Alzheimer’s not as a bolt-from-the-blue diagnosis, but as a risk trajectory that can potentially be altered earlier in life [1].
While understanding APOE doesn’t guarantee protection from Alzheimer’s, it points research toward the areas where intervention could make the biggest difference.
Three forms, very different outcomes
APOE comes in three common versions, called alleles: ε2, ε3 and ε4. Most people carry ε3, considered the standard version. ε4 is the high-risk allele, while ε2 is rare but strongly protective.
Previous studies treated ε3 as “neutral,” but the new research suggests that it isn’t optimal. Even people with ε3 alone may carry a significant Alzheimer’s risk compared to those with ε2.
Dr Dylan Williams, the study’s lead author, explained that the APOE gene’s contribution to the prevalence of Alzheimer’s has been significantly underestimated for a long time. He noted that many cases of the disease might not occur without the added impact of the common $\epsilon3$ allele, which has historically been misunderstood as having a neutral effect on risk [2].
In other words, APOE isn’t just about ε4. The common forms of the gene, which most of us carry, also matter.
Putting the numbers in perspective
The researchers analyzed nearly 470,000 people across four major studies, including the UK Biobank and FinnGen. They focused on participants aged 60 and older with confirmed Alzheimer’s diagnoses and genetic data [1].
They calculated the population attributable fraction (PAF), a measure of how much of a disease could theoretically be prevented if a specific risk factor didn’t exist. Using the rare ε2/ε2 version of the APOE gene as a “gold standard,” researchers looked at how much Alzheimer’s risk comes from the more common ε3 and ε4 versions. They found that between 70% and 90% of Alzheimer’s cases could be linked to these common versions.
Think of it like this: imagine a classroom of 100 older adults. If everyone had the rare protective ε2/ε2 gene, almost none of them would develop Alzheimer’s. But in reality, most people have ε3 or ε4. Because of this, around 70 to 90 students out of 100 who develop Alzheimer’s can trace their risk back to having the more common versions of the gene.
Even when looking at all types of dementia, almost half the cases (about 44–46 out of 100) are tied to these APOE versions.
Put simply, most Alzheimer’s and nearly half of all dementia cases can be traced back to common APOE variants. However, it’s important to note that it’s not the only factor; lifestyle and environment still play a role. Think of APOE as setting the stage: what you do daily can influence how the story unfolds.
The study also highlights a bigger shift in thinking. Medicine often treats “normal” as good enough. But if the standard version of APOE carries measurable risk, maybe “normal” isn’t enough.
This approach aligns with geroscience, which treats aging itself as a process that can and should be managed. By targeting the biggest contributors to risk, like APOE, medicine can aim not just to treat disease, but to prevent decline before it starts.
Williams sees a way forward, noting that significant strides have been made in gene editing and other treatments that directly address genetic risk factors.
“Intervening on the APOE gene, or the molecular pathway between the gene and Alzheimer’s, could have huge potential for preventing or treating a large majority of cases,” he added.
The longevity field would view APOE as a guide, more than a gene. By understanding which molecular pathways drive Alzheimer’s, researchers can develop strategies to extend healthspan.
The study reminds us that the future of aging is about protecting the quality of those years. Genetics can tell us where to focus, lifestyle can tilt the odds in our favor and emerging therapies may offer tools to intervene directly at the molecular level.
[1] https://www.nature.com/articles/s44400-025-00045-9
[2] https://www.alzheimersresearchuk.org/news/apoe4-and-apoe3-gene-variants-linked-to-at-least-7-in-10-alzheimers-cases-study-suggests/
