For decades, scientists have searched for answers to Alzheimer’s disease. Billions of dollars have flowed into research labs. Drug companies have poured resources into treatments targeting sticky brain plaques and tangled proteins. Yet a cure remains elusive, and even the newest medications offer only modest benefits at best. But what if researchers have been looking in the wrong place all along?
A new study suggests they might have been. And the implications could reshape everything we thought we knew about preventing and treating Alzheimer’s disease.
A Gene Hiding in Plain Sight
Back in the early 1990s, scientists discovered something interesting about a gene called APOE. People carrying certain versions of it seemed far more likely to develop Alzheimer’s disease later in life. It was a promising lead, one that should have sparked intense research interest.
Instead, something strange happened. Most of the scientific community moved on. Researchers became fascinated with two proteins found in the brains of Alzheimer’s patients. Beta-amyloid forms sticky plaques between brain cells. Tau creates tangles inside neurons. For years, scientists debated which protein mattered more and which one drugs should target. Meanwhile, APOE faded into the background.
Dr. Dylan Williams, who led new research from University College London, has a theory about why APOE got overlooked. “The full importance of APOE has probably not been sufficiently recognised by dementia researchers,” he told IFLScience.
Williams also points to practical challenges. Targeting APOE with drugs meant reaching it inside the central nervous system, not just in the bloodstream. Earlier pharmaceutical technology simply was not up to that task.
But times have changed. Gene therapy has advanced dramatically. And Williams’ team decided it was time to give APOE another hard look.
Understanding Your Genetic Hand
Before diving into what researchers found, it helps to understand how APOE works. Everyone carries two copies of the APOE gene, one inherited from each parent. Three common versions exist, called ε2, ε3, and ε4. Since you have two copies, you end up with one of six possible combinations.
For years, scientists understood the basics. Carrying ε4 raised your Alzheimer’s risk. Carrying ε2 seemed protective. But ε3, the most common version carried by about 95 percent of people worldwide, was considered neutral. Neither good nor bad. Just average.
Williams and his colleagues suspected that the assumption was wrong. Labeling ε3 as neutral only made sense if you compared it to itself. When measured against ε2, a different picture emerged.
Williams used an analogy to explain the problem with previous research. Imagine studying lung cancer risk by looking only at heavy smokers. You would conclude that heavy smoking causes lung cancer, which is true. But you would miss the risk posed by moderate smoking if you never compared smokers to non-smokers. Scientists studying APOE had essentially been ignoring the non-smokers.
Risk actually falls along a gradient. Carriers of ε2 face the lowest risk. Carriers of ε3 face intermediate risk. Carriers of ε4 face the highest risk. By treating ε3 as the baseline instead of ε2, researchers had been underestimating how much APOE actually contributes to Alzheimer’s disease.
Crunching Numbers Across Continents
Williams and his team set out to quantify APOE’s true impact. Working with colleagues at UCL and in Finland, they analyzed data from roughly 470,000 participants across four major studies.
UK Biobank provided data on over 171,000 participants aged 60 and older. FinnGen contributed information on nearly 290,000 people from Finnish biobanks. Researchers also examined brain scans from about 4,400 participants in a clinical trial called the A4 Study. Finally, they reanalyzed data from the Alzheimer’s Disease Genetics Consortium, which included over 5,000 cases confirmed through postmortem brain examinations.
Each dataset offered a different window into Alzheimer’s disease. Some relied on electronic medical records and clinical diagnoses. Others used brain imaging to detect amyloid buildup before symptoms appeared. The ADGC data provided the gold standard of neuropathological confirmation at autopsy.
Across all these sources, researchers calculated something called population attributable fractions. In plain terms, they estimated what percentage of Alzheimer’s cases would not exist if people did not carry ε3 or ε4.
Numbers That Demand Attention
When the results came in, Williams found himself pleasantly surprised. “Expectations and findings seldom align really well in research, so it was a nice surprise in that sense!” he told IFLScience.
In the UK Biobank data, ε3 and ε4 together accounted for about 76 percent of Alzheimer’s cases. FinnGen showed a similar figure at roughly 72 percent. When researchers looked at cerebral amyloidosis in the A4 Study, the number climbed to about 85 percent.
But the most striking finding came from the Alzheimer’s Disease Genetics Consortium, where cases had been confirmed through brain examination after death. In that dataset, nearly 93 percent of Alzheimer’s disease was attributable to ε3 and ε4. Put another way, without those two gene variants, almost all Alzheimer’s cases simply would not occur.
For all-cause dementia, which includes Alzheimer’s and other forms of cognitive decline, the numbers were somewhat lower but still substantial. About 45 percent of dementia cases in both UK Biobank and FinnGen traced back to carrying ε3 or ε4.
Some of these findings surprised even Williams. A small number of careful researchers had suspected something like this for over 20 years. But nobody had been able to prove it with direct empirical data until now.
When the team separated the contributions of each gene variant, they found that ε4 accounted for roughly 57 percent of neuropathologically confirmed Alzheimer’s burden. But ε3, long dismissed as neutral, was responsible for about 36 percent. A gene variant carried by nearly everyone was quietly driving more than a third of all Alzheimer’s cases.
Why Current Drugs Fall Short
These findings cast a long shadow over recent pharmaceutical developments. Several anti-amyloid drugs have reached the market in recent years, generating both excitement and controversy. In theory, clearing beta-amyloid plaques from the brain should slow Alzheimer’s progression. In practice, results have been underwhelming.
Williams did not mince words when discussing these treatments. He noted that recently licensed anti-amyloid drugs show limited effectiveness at slowing disease, even though they successfully clear beta-amyloid from patients’ brains. What they are designed to do in molecular terms, they accomplish brilliantly. Yet patients do not improve much.
Even worse, Williams pointed out that reasons still exist to doubt whether these drugs work at all. Clearing plaques might be treating a symptom rather than a cause.
If APOE variants account for nearly all Alzheimer’s cases, focusing solely on amyloid plaques starts to look like addressing smoke while ignoring fire. Williams called APOE a natural target, crying out for much more research activity.
New Tools for an Old Problem
Here is where the story takes a hopeful turn. Gene therapy has transformed over the past decade. Editing, silencing, and transfer approaches that once seemed like science fiction now work in clinical settings. Treatments for conditions like sickle cell disease and certain cancers have already proven that modifying genes inside living patients is possible.
APOE sits squarely in the crosshairs of these new capabilities. If the gene variants driving Alzheimer’s risk can be edited or silenced, prevention might become reality rather than aspiration.
Yet an odd disconnect exists between APOE’s importance and research attention. Only one therapy targeting APOE directly at the gene or protein level, called LX1001, has entered human trials for Alzheimer’s disease. Fewer than one percent of registered Alzheimer’s trials involve APOE-targeting approaches.
Scientists have not ignored APOE entirely. Researchers have explored immunotherapy approaches and small-molecule drugs aimed at correcting APOE protein function. But given that this single gene appears responsible for the vast majority of Alzheimer’s cases, the level of investment seems strangely low.
Williams hopes his research will change that calculus. Vast improvements in gene therapy have made APOE a realistic target in ways that were not possible before. What was once a problem too difficult to solve may now have solutions within reach.
Questions Still Unanswered
No single study answers every question, and Williams’ research leaves important gaps to fill. Most participants in these studies came from European backgrounds. APOE affects Alzheimer’s risk differently across ethnic groups, so findings might not apply equally to everyone. Williams and his team plan to investigate APOE’s role in more diverse populations.
Another puzzle remains unsolved. Not everyone carrying high-risk APOE variants develops dementia. Something protects certain people despite their genetic hand. Environmental factors, lifestyle choices, and other genes likely interact with APOE in ways scientists do not yet fully understand. Unpacking those relationships could reveal additional targets for prevention.
Alzheimer’s Research UK has stepped up to support continued investigation. Dr. Sheona Scales, the organization’s Director of Research, expressed enthusiasm about supporting Williams as he investigates how genetics, environmental factors, and societal conditions influence dementia risk.
A Shift in Focus
For too long, Alzheimer’s research has resembled a search for lost keys under a streetlight, not because the keys are there, but because the light is better. Beta-amyloid and tau were visible and measurable. APOE seemed too complicated, too hard to target, too embedded in basic human biology.
Williams and his colleagues have now shone a bright light on what was hiding in plain sight. A single gene, carried in some form by nearly everyone, appears to underlie almost every case of Alzheimer’s disease and nearly half of all dementia cases.
Drug companies and research institutions face a choice. They can continue pouring resources into approaches that have yielded disappointing results. Or they can pivot toward APOE and the promising tools now available to target it.
Millions of families worldwide have watched loved ones slip away to Alzheimer’s disease. They deserve research strategies based on where the evidence actually points. Right now, that evidence points squarely at APOE, a natural target that has waited far too long for its moment in the spotlight.
