Alzheimer’s disease has resisted every major drug thrown at it for over 30 years. Billions of dollars in research funding have targeted sticky brain plaques and tangled proteins, with results that range from disappointing to controversial. But what if the biggest clue to preventing Alzheimer’s has been sitting in the scientific literature since the 1990s, largely overlooked? A new study from UCL researchers has delivered a finding that could redirect the entire field. Two common variants in a single gene called APOE appear to be responsible for up to 93% of Alzheimer’s cases and nearly half of all dementia. The number is so high that even the researchers were surprised. And the reason it took this long to see the full picture comes down to a simple but costly misunderstanding about one of those gene variants.
APOE: The Gene Almost Everyone Carries
APOE stands for apolipoprotein E, a gene that produces a protein involved in fat transport and metabolism in the brain. Everyone inherits two copies of APOE, one from each parent. Three common versions (called alleles) exist: ε2, ε3, and ε4. Since you carry two copies, there are six possible combinations.
Scientists identified a strong link between APOE and Alzheimer’s risk in the early 1990s. People carrying one or two copies of ε4 face a much higher risk of developing Alzheimer’s. People with ε2 appear to have some protection. And ε3, the most common variant (carried by about 95% of the global population), was considered neutral, neither helpful nor harmful. That assumption turned out to be wrong.
The Mistake That Held Back Alzheimer’s Research
For three decades, dementia researchers treated ε3 as the baseline, the “normal” version of the gene. Studies compared people with ε4 to people with ε3 to measure how much extra risk ε4 created. Nobody compared either group to people carrying two copies of ε2, the lowest-risk combination, because ε2/ε2 individuals are extremely rare (less than 1% of most populations).
Dr. Dylan Williams, the study’s lead author from UCL’s Division of Psychiatry, explained the problem using a smoking analogy. Looking only at ε4 and Alzheimer’s is like studying only heavy smokers and lung cancer while ignoring moderate smokers and non-smokers. You miss the full picture.
In reality, Alzheimer’s risk from APOE exists on a spectrum. Carriers of ε2 sit at the low end. Carriers of ε3 sit in the middle. Carriers of ε4 sit at the top. By lumping ε2 and ε3 carriers together as the reference group, previous studies masked the fact that ε3 itself confers meaningful risk.
Williams noted that a small number of astute researchers had inferred this at least 20 years ago, but they lacked the large datasets needed to prove it with direct evidence.
The Numbers Are Staggering
The UCL team, working with colleagues at the University of Eastern Finland, analyzed data from more than 450,000 participants across four major studies: UK Biobank, FinnGen, the A4 Study, and the Alzheimer’s Disease Genetics Consortium (ADGC).
For the first time in a study of this scale, they used people with two copies of ε2 as the low-risk baseline. Then they calculated how much Alzheimer’s disease and dementia in the other groups could be attributed to carrying ε3, ε4, or both.
Results across the four datasets were consistent and striking. Between 72% and 93% of Alzheimer’s cases would not have occurred without the contributions of ε3 and ε4. Approximately 45% of all-cause dementia cases would not have arisen without these two alleles.
In the ADGC analysis, which used neuropathologically confirmed Alzheimer’s cases (verified by brain examination after death), the figure reached 92.7%. When researchers broke that number into separate contributions, ε4 accounted for about 57% of the burden, and ε3 alone accounted for roughly 36%.
Williams told IFLScience that expectations and findings seldom align well in research, but these numbers matched what a handful of earlier scientists had predicted, making it a reassuring and surprising result.
Why Has APOE Been Overlooked?
Given the strength of the APOE connection, it seems baffling that the gene has received so little attention as a drug target. Williams identified three reasons.
First, since the mid-1990s, the Alzheimer’s research field has been dominated by two competing theories: the amyloid hypothesis (blaming sticky beta-amyloid plaques between brain cells) and the tau hypothesis (blaming tangled tau proteins inside brain cells). Enormous funding and scientific careers have been built around understanding and targeting these two proteins. APOE got pushed to the side.
Second, even among researchers who recognized APOE’s importance, the full scale of its contribution was not appreciated. The misclassification of ε3 as neutral meant that published estimates of APOE’s role in Alzheimer’s were far too low.
Third, past pharmaceutical technology may not have been capable of targeting APOE effectively. The protein operates primarily in the central nervous system, making it harder to reach with conventional drugs. Earlier attempts to develop APOE-targeted therapies ran into technical walls.
Williams noted that vast improvements in gene therapy over the past decade, including gene editing, gene silencing, and gene transfer approaches, have changed the landscape. What was once intractable may now be achievable.
Anti-Amyloid Drugs Have Not Delivered
The timing of this study matters. In recent years, new anti-amyloid drugs like lecanemab and donanemab have received regulatory approvals and generated major headlines. But their clinical benefits remain limited and debated.
Williams was candid: the recently licensed anti-amyloid drugs show, at best, limited effectiveness at slowing disease in Alzheimer’s cases, despite being brilliant at doing what they are supposed to do in molecular terms, which is clearing beta-amyloid from the brain. He added that there are still reasons to doubt whether these drugs are effective at all.
If removing amyloid plaques does not stop Alzheimer’s from progressing, the field needs new targets. APOE, according to this research, is a natural target crying out for much more research activity.
Currently, only one therapy targeting APOE directly at the gene or protein level (called LX1001) is being tested in human clinical trials. That represents less than 1% of all therapies in registered Alzheimer’s trials. Given that APOE may account for up to 93% of the disease, that imbalance is difficult to justify.
APOE Is Not the Whole Story
An important clarification: Alzheimer’s disease is not caused by a single gene. Even people with the highest-risk combination (two copies of ε4) have an estimated lifetime Alzheimer’s risk below 70%. Most people who carry ε3 or ε4 will not develop dementia in a typical lifetime.
Other genetic and environmental risk factors play roles. Social isolation, high cholesterol, smoking, head injuries, hearing loss, and many other modifiable factors influence dementia risk. Some research suggests that roughly half of all dementia cases could be prevented or delayed by addressing these lifestyle and environmental contributors.
Williams emphasized that with complex diseases like Alzheimer’s, there will be more than one way to reduce disease occurrence. Targeting APOE does not mean ignoring everything else. But without the underlying risk from ε3 or ε4 that most people inherit, the vast majority of Alzheimer’s cases would not occur, regardless of what other risk factors people experience.
In other words, APOE sets the stage. Other factors determine whether the disease actually develops. Remove the stage, and most of the disease disappears.
How APOE ε4 and ε3 May Damage the Brain
Previous research has suggested several biological mechanisms by which APOE variants increase Alzheimer’s risk. The ε4 protein appears to be less effective at clearing harmful beta-amyloid from the brain, allowing plaques to build up faster. It also disrupts fat and energy processing in brain cells and promotes inflammation, changes that gradually damage neurons and make the brain more vulnerable.
Less is known about why ε3 confers intermediate risk compared to ε2. Understanding the specific functional differences between ε2 and ε3 proteins is now a research priority, since ε3 is carried by such a large proportion of the population.
Interestingly, the APOE gene also showed up as a top risk locus for coronary artery disease in a comparison analysis. But no other single genetic locus for Alzheimer’s or heart disease came close to matching APOE’s contribution to Alzheimer’s. No other gene accounted for more than 36% of disease burden for either condition.
Where Research Goes from Here
Williams and his team are now planning studies in more ethnically diverse populations. The current analysis included primarily people of European descent, and APOE associations with Alzheimer’s risk are known to differ by ancestry. Confirming these findings across populations is essential before global treatment strategies can be developed.
There is also much to learn about the environmental and genetic modifiers that interact with APOE. Not everyone with a high-risk genotype develops Alzheimer’s. Understanding what protects some carriers from disease while others succumb could reveal additional prevention strategies.
Alzheimer’s Research UK is supporting this continued work. Director of Research Dr. Sheona Scales noted that the findings show further research into APOE will be important for developing future prevention and treatment strategies.
For a disease that affects more than 55 million people worldwide and currently has no cure, a gene responsible for up to 93% of cases is as close to a master switch as science has found. Whether the field is ready to flip its priorities toward APOE may determine how soon that switch gets turned off.
My Personal RX on Protecting Your Brain and Reducing Alzheimer’s Risk
Alzheimer’s disease develops over decades before symptoms appear. While you cannot change the APOE genes you inherited, you can take daily steps to reduce inflammation, support brain function, and address the modifiable risk factors that interact with genetic risk. I tell my patients that brain protection starts now, not when memory problems begin. Here is what I recommend:
- Prioritize Deep, Restorative Sleep: Your brain clears toxic waste proteins, including beta-amyloid, through the glymphatic system during deep sleep. Sleep Max combines magnesium, GABA, 5-HTP, and taurine to calm your mind, balance neurotransmitters, and promote restorative REM sleep so your brain can perform its nightly cleanup.
- Know Which Supplements Your Brain Needs After 40: Declining nutrient absorption weakens brain defenses over time. Download my free guide, The 7 Supplements You Can’t Live Without, to learn which supplements protect cognitive function, which “healthy” foods may be misleading you, and how to identify quality products worth your investment.
- Exercise for at Least 30 Minutes Daily: Physical activity increases blood flow to the brain, stimulates the release of brain-derived neurotrophic factor (BDNF), and reduces inflammation. Walking, swimming, cycling, and resistance training all contribute to healthier brain aging.
- Manage Chronic Stress Before It Damages Your Brain: Prolonged stress raises cortisol, which shrinks the hippocampus and weakens memory. Practice daily stress management through breathwork, meditation, time in nature, or any calming activity.
- Stay Socially Connected: Social isolation is a recognized modifiable risk factor for dementia. Regular, meaningful contact with friends, family, or community groups keeps your brain active and emotionally regulated.
- Reduce Sugar, Processed Food, and Alcohol: High-sugar diets promote insulin resistance and brain inflammation. Excess alcohol shrinks brain volume. Replacing processed foods with whole, nutrient-dense alternatives protects brain cells from chronic damage.
Source: Williams, D. M., Heikkinen, S., Hiltunen, M., FinnGen, Davies, N. M., & Anderson, E. L. (2026). The proportion of Alzheimer’s disease attributable to apolipoprotein E. Npj Dementia, 2(1), 1. https://doi.org/10.1038/s44400-025-00045-9
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