Takeaways from CTAD 2025: Continued Evolution of AD Therapeutics

Highlights included attendees reacting to the readout of large Phase 3 trials studying the effects of the GLP-1 agonist semaglutide in early AD patients, learning more about the impacts of lifestyle interventions on the risk of cognitive impairment, and reviewing a comparative analysis of the benefits of continuous versus fixed treatment with lecanemab or donanemab.

New year's resolution: Get ahead of AD

An introductory lecture by Paul Aisen, MD, of the University of Southern California quickly set the tone for CTAD25. Noting that AD was thought to be untreatable 20 years ago, Dr. Aisen took a retrospective look at the immense progress made by the field in developing effective disease-modifying therapies for AD. He emphasized that recent clinical trials suggest the greatest impact on disease progression is achieved when treatment is given as early as possible. It is now well accepted that neuropathological changes in the brain, including amyloid and tau aggregation, precede clinical symptoms by many years. In turn, the field is looking ahead to the possibility of treating pre-symptomatic patients, ie, individuals with confirmed neuropathology but normal cognitive function.

Dr. Aisen predicted that treating pre-symptomatic patients with the 2 approved anti-amyloid treatments before irreversible brain damage occurs could slow disease progression by as much as 50% to 60%, compared to about 30% average slowing achieved in early symptomatic patients. Together with the availability of blood biomarker tests sensitive enough to detect amyloid pathology well before the onset of clinical symptoms, treatment of pre-symptomatic patients could become a reality in only a few years. Eisai and Lilly are conducting active studies of their FDA-approved anti-amyloid treatments in these patients, scheduled for primary completion in 2027 to 2028. Dr. Aisen further theorized on the future establishment of a primary prevention campaign, where beginning at age 50 all individuals would be tested annually and results predicting amyloid accumulation would prompt initiation of anti-amyloid treatment. While only a hypothesis contingent on the success of multiple future clinical studies, Dr. Aisen theorizes that his model might one day result in 100% prevention of AD.

GLP-1s couldn't weigh in on slowing dementia

Topline findings of the EVOKE and EVOKE+ Phase 3 clinical studies of the efficacy and safety of the GLP-1 receptor agonist semaglutide in early AD patients were not what many in the field had hoped for. Semaglutide, a widely used drug approved in the United States for the treatment of type 2 diabetes in 2017 and obesity in 2021, did not achieve a statistical difference from placebo in either EVOKE study's primary or secondary endpoint measures of cognitive decline. While select AD biomarkers declined about 10% relative to placebo, and inflammation in the periphery was significantly reduced, these treatment-favoring biochemical effects failed to translate into a slowing of cognitive decline.

Novo Nordisk, the sponsor of both studies, moved to discontinue the 1-year extension periods, signaling the closure of this early chapter of clinical research into GLP-1s as potential AD treatments. Yet, questions remain that may be answered next year when the full results of both studies are released. For example, were patients enrolled in the trials already too progressed to benefit from treatment, despite the exclusion of those progressed beyond mild dementia due to AD? As repeatedly emphasized by Jeffrey Cummings, MD, of the University of Nevada, Las Vegas, the AD field learns from every clinical trial, whether reading out a positive or negative result. These trials definitively demonstrated that GLP-1 agonists do not slow AD progression in the studied patient population. With as many as 31 different agents investigated in phase 3 trials in 2025, this negative readout helps the field shift its focus.

Patient-tailored combination therapies

With anti-amyloid treatments established as the new standard of care for AD patients with early disease, clinicians have been looking ahead to combination therapies to address the sheer complexity of neuropathological processes underlying the disease. A panel chaired by Dr. Cummings articulated the opportunities, clinical scenarios, and future challenges for clinicians considering combination therapies tailored to individual patients' needs. Indeed, many were looking ahead to the possibility of a newly emergent GLP-1 treatment class to add on to the anti-amyloid standard of care for their patients. However, with the negative result of the phase 3 trials, what treatments should clinicians consider adding to anti-amyloid treatments? Dr. Cummings outlined the possible combinations, including anti-amyloid plus anti-tau treatments and anti-amyloid plus targeted treatments for co-pathologies, such as in patients with vascular risk factors. He also pondered the timing of introducing a novel treatment. Suzanne Schindler, MD, PhD, of Washington University emphasized the critical importance of blood biomarker panels for measuring targeted co-pathologies to appropriately tailor combination therapies.

In a panel discussion, Fred Grossman, DO, of Coya Therapeutics remarked that it shouldn't be challenging to design clinical trials to test the benefit of a novel add-on medication combined with an established treatment. He noted, "Large pharma companies are looking to hit a homerun and we don't need that; the mindset needs to change." His implication seemed to be that clinical trials should focus on demonstrating added efficacy on top of the standard of care, rather than creating a new blockbuster. Ultimately, such a shift in mindset seems to already be underway—as demonstrated by the many presentations suggesting the benefit of personalized precision medicine approaches for patients with AD.

POINTing to effective lifestyle modifications

Results of the US POINTER trial, initially released this past summer, showed that lifestyle changes can significantly improve cognitive function (especially executive functioning) in older adults. At CTAD25, the POINTER findings were updated with new readouts on the impact of lifestyle modifications on AD-related imaging biomarkers. POINTER compared 2 distinct programs of lifestyle modification: 1) a structured regimen that included participants' regular check-ins with and monitoring by clinical specialists and the development of a personalized health plan, and 2) a self-guided program where participants were encouraged to follow a general health plan and establish their own goals, involving less frequent check-ins.

POINTER is not specifically studying the effects of these lifestyle modifications in AD patients, but actually a cross-section of 60- to 79-year-old Americans, so the new readout at CTAD was eagerly anticipated to connect the exciting topline finding with biomarkers associated with AD pathology. The findings showed no difference in biomarker changes between the structured and self-guided regimens but did demonstrate that a subset of participants with lower baseline hippocampus volume (a brain region key to learning and memory that is especially vulnerable to AD-related atrophy) benefited more from the structured regimen. Furthermore, participants with higher accumulation of pathological tau in the entorhinal cortex benefited more from the structured regimen relative to the self-guided program. Finally, respiratory disturbances during sleep declined more in the structured versus self-guided groups. While data collection and analysis from the study is ongoing, the interim updates demonstrated that the lifestyle interventions shown to improve cognitive function in older adults also improve other health trajectories that impact brain function and resilience related to AD. These findings are a welcome reinforcement to clinicians' holistic strategies for mitigating the impacts of AD for patients and their families.

Treat-and-stop versus treat continuously, part deux: treat past plaques

This past summer, Eisai and Lilly shared results of long-term extension studies of their pivotal Phase 3 trials, Clarity AD and TRAILBLAZER-ALZ2, respectively. Their findings showed benefit for participants treated with lecanemab and donanemab for 4 years and 3 years, respectively, relative to control groups. The 2 studies and the drugs' labels differ in one key aspect: continuous treatment past amyloid plaque removal is recommended for lecanemab whereas the donanemab label gives clinicians the option to discontinue treatment once plaque removal has been confirmed. However, the question of whether one treatment regimen benefits patients more than the other has not been answered. Given the expense and potential safety risks associated with both treatments, an answer to this question is urgently needed.

At CTAD25, Suzanne Hendrix, PhD, of the Pentara Corporation presented a study, funded by Eisai, utilizing statistical modeling to generate a simulated dataset from publicly available data from both trials. This simulation enabled a comparison of disease progression following plaque removal among participants continuously treated with lecanemab and those treated acutely with donanemab relative to a common placebo trajectory. The results were provocative: discontinuing donanemab treatment after 12 months resulted in 17% slowing of disease progression, whereas continuous treatment with lecanemab slowed disease progression by 29% compared to the simulated placebo group.

Not surprisingly, the presentation elicited robust questioning among the CTAD25 audience. Dr. Hendrix emphasized the limitations of her group's analysis but stood by the findings and called for both Eisai and Lilly to release full data sets to enable a more rigorous comparison of the trials' efficacy data. While a definitive conclusion can't be drawn, evidence in favor of a continuous anti-amyloid treatment regimen has now been shown. However, it remains to be seen if clinicians shift their decision-making around long-term therapy. Together with Eisai's presentation of modeling data to be submitted to the FDA for evaluation of subcutaneous initiation dosing (potentially giving patients an at-home option to start treatment), evolution within the class of approved anti-amyloid therapies shows no sign of slowing down.

What's on the horizon for AD therapeutics?

Progress in understanding and intervening in AD, as in other areas of medicine, is incremental and non-linear. The field certainly left CTAD25 with plenty to think about as 2026 approaches: negative readout of a major therapy trial, continued advancements in blood biomarker testing, improved understanding of the long-term benefits of anti-amyloid treatment, and building momentum toward pre-symptomatic disease intervention and perhaps even prevention.

We at the HWP Group are excited for what's to come and continue to relish the opportunities to communicate emerging advancements on behalf of our clients.