Challenges in Treating Genetically Predisposed Alzheimer Disease: Insights from APOLLOE4

Emer MacSweeney, MD

Finding effective treatments for Alzheimer disease (AD) has been a challenge thus far, and is even more difficult for patients with the apolipoprotein (APOE) ε4 allele, the most significant genetic risk factor for developing late-onset AD. Research has shown that carrying 1 ε4 allele increases the risk of AD by approximately 2-3 times, while carrying 2 ε4 alleles (ε4/ε4) increases the risk by about 8-12 times.

APOLLOE4, a phase 3, double-blind, placebo-controlled study testing valiltramiprosate (Alzheon), is among the few trials evaluating potential therapeutics in this predisposed, at-risk population. At the 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, held April 1-5 in Vienna, Austria, the first dataset from APOLLOE4 was presented, a 325-patient study lasting 78 weeks of treatment. Overall, the study did not meet its primary end point of change in Alzheimer’s Disease Assessment-Cognitive (ADAS-Cog13) subscale in the entire cohort; however, did show more pronounced effects in a subgroup of patients with less progressed AD, considered mild cognitively impaired.

Emer MacSweeney, MD, a trial investigator representing the largest enrolled cohort of patients from the European Union, sat down at the meeting to give her perspectives on the study and its findings. In the interview, she discussed the unique challenges of treating AD in APOEε4/ε4 carriers, highlighting their heighted genetic risk and earlier onset of symptoms compared with others. The conversation also underscored the importance of early diagnosis and action, given the faster progression of the disease in these individuals, and how evolving imaging techniques, like detecting amyloid-related imaging abnormalities (ARIA) early, are crucial in managing treatment risk. MacSweeney, a consultant neuroradiologist, also advocated for increased education and tools, such as alter bracelets, to improve patient safety and awareness among healthcare providers.

Can you describe your experience as a trial investigator for the study, especially given your role in recruiting the highest number of participants in the EU?

Of course. One of the things that made this study different from many others was that it was exclusively for people with the APOE e4/e4 genotype. This group of individuals tends to be highly educated about studies and the emerging drugs in development. Much of this awareness stems from their personal connection to the disease. They have about a 15% lifetime risk of developing Alzheimer’s, and many have seen direct relatives suffer from it over the years. This creates a dual dynamic: they’re both motivated and well-informed—not just about the disease but also about the opportunities for new medications, thanks to the vast amount of information available online and interviews like this one.

Why has it been so challenging to find treatments for patients who are APOE e4/e4 carriers?

There are two main factors. First, many clinical trials to date have focused on monoclonal antibodies targeting amyloid protein. These treatments work by accelerating the removal of amyloid from the brain. However, people with the e4/e4 genotype have the highest risk of developing a side effect called ARIA, or amyloid-related imaging abnormalities. This made the APOLLOE4 study particularly significant, as it was specifically designed for this population. The expectation was a lower risk of ARIA with the study’s drug—an expectation the results have supported.

This population often presents with symptoms at a younger age—typically in their 40s, 50s, or early 60s. Without disease-modifying treatments, the disease progresses faster. Early action is crucial for everyone, but even more so for these individuals. Unfortunately, most people don’t know their APOE status, which makes early intervention all the more critical. My message would be: if you’re worried about your memory or cognitive function, seek evaluation as soon as possible.

While the study didn’t meet its primary endpoint, what were your key takeaways from APOLLOE4?

The biggest takeaway is that early action is critical. The results showed that, while the combined mild AD and MCI population didn’t meet the endpoint, separating out the MCI group revealed very exciting and favorable outcomes. On the other hand, the mild AD dementia group did not show the same benefit. Anecdotally, during the study, we observed individuals with very mild symptoms doing remarkably well. Although we didn’t know who was on active medication during the trial, the outcomes post-randomization weren’t surprising.

Recruiting these patients is challenging. Only about 3% of the general population is e4/e4. Once symptoms develop, genotype testing becomes crucial. For those who test positive, finding and enrolling in studies is essential. Across the board, whether for APOLLOE4 or other treatments, the milder the symptoms at treatment onset, the better the outcome. This is consistent across all studies and available drugs.

How has radiology evolved in the Alzheimer field over the last decade?

The most significant advancement has been in detecting ARIA. This is crucial for identifying it early in patients on treatment and ensuring they’re not given further doses if ARIA is present. One challenge we’ve faced is educating radiologists unfamiliar with ARIA. For example, ARIA-E can be mistaken for an acute ischemic event, which could lead to inappropriate anticoagulation treatment.

In our clinics, we’ve implemented measures to mitigate this risk. Patients are encouraged to wear medical alert bracelets indicating they’re on monoclonal antibodies. This allows emergency clinicians to identify the treatment and contact us if needed. Educating patients and their partners about potential risks is vital. We’re in a new era where we’re treating the underlying disease, but the focus must remain on managing and mitigating risks—with unrecognized ARIA being one of the biggest challenges.

Transcript edited for clarity. Click here for more AD/PD 2025 coverage.