Dr. Juan Fortea discusses his groundbreaking research redefining APOE4 homozygosity as a genetic cause of Alzheimer's and his upcoming webinar

WASHINGTON, Oct. 21, 2025 /PRNewswire/ -- APOE4 Alzheimer's Alliance Board Member Perry S. Chen discusses Dr. Fortea's groundbreaking research 
in advance of APOE4 Alzheimer's Alliance Webinar discussing the root causes of Alzheimer's.

Join the APOE4 Alzheimer's Alliance's free virtual webinar to learn more about Dr. Fortea's research on the genetic origins of Alzheimer's disease, advancements in APOE4 research, and Alzheimer's prevention strategies!

Event date: Friday October 24, 2025, 9 AM Pacific Time: 12 PM Eastern Standard Time

Register today at: https://apoe4alzheimersalliance.org/webinar-dr-fortea

Prior to the webinar, Dr. Fortea sat down for an interview to share his perspective on the future of Alzheimer's clinical research and disease treatment – especially for APOE4 homozygotes (people with two copies of the APOE4 gene, widely considered the strongest genetic risk factor for late-onset Alzheimer's disease).

Fortea's career in behavioral neurology and dementia was driven by a keen interest in the brain. "What makes us human is the brain and the higher functions. So, to study the diseases that affect the higher functions, to me, was kind of an obvious choice," he says. "I was fascinated by the brain, so that very early on led me to neurology. And I didn't change my mind after that." After residency, Fortea pursued a Ph.D. studying forms of Alzheimer's disease caused by inheriting specific genetic mutations – including Down syndrome. "When I was starting to think about APOE4 homozygotes, I started to see a lot of commonalities there too," he says, pointing out that people with two copies of the APOE4 gene, much like those with Down syndrome, develop abnormal levels of Alzheimer's biomarkers (molecules in the brain related to disease) at a consistently earlier age than average.

Fortea's research eventually led him to conclude that APOE4 homozygosity may be distinctive enough to be considered a new genetic form of Alzheimer's disease. The NIH estimates that while APOE4 homozygotes account for only 2% of the general population, they represent 15% of Alzheimer's patients. Fortea's study, published in Nature Medicine in 2024, was one of the largest ever to focus on APOE4 homozygosity.

Many researchers find his evidence compelling, but some disagree that APOE4 should be reclassified as a direct cause of the disease. Others have pointed out that people with non-European ancestry are underrepresented in the study cohorts, meaning his data may be less accurate at predicting how APOE4 homozygosity affects them. Fortea acknowledges this issue, and hopes future research can address it. "I have to admit, the people that participated there are not representative of the general population, so we do need population-based studies."

Members of APOE4-related online communities have expressed a variety of opinions and feelings since his paper's release ranging from agreement to criticism, anxiety, despair, and hope. Although his conclusion remains controversial, there is no doubt Fortea's paper has contributed significantly to the broader ongoing conversation about how people's genes affect their chances of developing Alzheimer's disease and what they can do about it.

So, does this mean that all APOE4 homozygotes are guaranteed to get dementia? No, Fortea assures, because even people with abnormal levels of Alzheimer's biomarkers do not always end up developing clinical signs of dementia like memory loss. "The penetrance of the symptoms, we could not assess. That's because we had a bias in the pathological study towards dementia and in the clinical cohorts towards cognitively unimpaired," Fortea acknowledges, pointing out a limitation of his study's scope.

Even so, Fortea maintains that people with two copies of the APOE4 gene should not be lumped in together with those that have one or zero copies when it comes to research and treatment. The FDA requires "black box" safety warnings on amyloid-targeting antibody medications like Kisunla and Leqembi that have been linked to much higher rates of swelling or bleeding in the brains of APOE4 homozygotes. These safety concerns have led the European Union to forbid these drugs from being prescribed to patients with this high-risk genotype.

Ultimately, Fortea expresses optimism about the future of Alzheimer's disease treatment, highlighting promising examples of ongoing research into disease-modifying therapies that may be safer for APOE4 homozygotes – some of which are being developed by companies he consults for. He envisions a world where sophisticated combination therapies are tailored to specific genetic profiles in order to maximize their effectiveness and safety for each individual patient. "One size does not fit all in medicine, almost never. I think that's the whole idea: to personalize medicine," he says, emphasizing the crucial role that research plays in developing effective disease treatments. "Let's not be afraid of science. Let's just follow the data, see where it takes us, do the best we can and learn from our mistakes. I think that's the only way forward."

ApoE4 Alzheimer's Alliance 

The ApoE4 Alzheimer's Alliance (A3) is dedicated to amplifying the voices of ApoE4 Alzheimer's patients and their caregivers by advocating for their needs before the U.S. policy makers and regulatory agencies. Our mission is to drive progress by sharing patient stories and lived experiences to highlight the unmet medical needs faced daily by those affected.

SOURCE ApoE4 Alzheimer's Alliance