After decades of false starts, Alzheimer’s disease research is finally gaining momentum. Leqembi and Kisunla, approved in 2023 and 2024, are gaining commercial traction after slow launches, while the 2026 pipeline includes 158 drug candidates across 192 clinical trials, according to a recent review.
“The Alzheimer’s space, for the first time in a very long time, has really got a fire under it. It's really bubbling away,” said Ivo Carre, a senior business analyst at Lifescience Dynamics.
But better drugs are critically needed. In trials, Leqembi and Kisunla produced modest average slowing of cognitive and functional decline in people with early symptomatic Alzheimer’s disease, fueling debate over whether clearing amyloid alone can deliver enough benefit.
That has intensified interest in targets such as tau and neuroinflammation. Other researchers argue that amyloid may still be the right target, but the wrong stage of disease or with the wrong modality.
Five questions could help determine how Alzheimer’s treatment evolves in the coming years.
Can treating Alzheimer’s earlier delay symptoms?
As the saying goes, timing is everything, and that may also hold true for Alzheimer’s treatment. Some experts believe Leqembi and Kisunla haven’t shown more substantial benefits because they are being used too late in disease progression.
Researchers are testing whether amyloid-targeting drugs work better when given before or near symptom onset. Results beginning next year could start to show whether this earlier treatment can delay clinical decline or the emergence of symptoms in people who already have Alzheimer’s pathology.
Eli Lilly’s late-stage Trailblazer 3 trial, expected to conclude in 2027, is testing donanemab in people with preclinical Alzheimer’s disease who are at risk of cognitive and functional decline. Blood biomarkers are helping make such studies feasible. Roche and Lilly’s recently FDA-cleared Elecsys pTau217 test can aid assessment of people 55 and older who already show signs or complaints of cognitive decline.
Separately, p-tau217 is also being used in research to identify Alzheimer’s pathology before symptoms arise. Roche, meanwhile, plans to recruit cognitively unimpaired people with Alzheimer’s biomarkers into the phase 3 PrevenTRON study of trontinemab. If the trials show a benefit, they could shift treatment earlier.
Does faster amyloid plaque clearance translate into greater clinical benefits for patients?
The approvals of Leqembi and Kisunla have shown that the two drugs can slow progression in early Alzheimer’s disease, but will speedier clearance translate into bigger effects?
Roche’s trontinemab study could provide that answer. A phase 1b/2a study of the drug showed that it rapidly cleared amyloid plaques in the brain. The treatment uses Roche’s Brainshuttle technology, which is designed to ferry the medication across the blood-brain barrier, potentially allowing for lower systemic doses.
“What we see consistently is that this brain shuttle platform is working. It's getting more antibody into the brain with lower rates of the side effect known as ARIA,” Carre said. ARIA, or amyloid-related imaging abnormalities, can include brain swelling or bleeding.
In the trial, some 91% of participants in the 3.6 mg/kg treatment group saw amyloid levels reduced below a target threshold after 28 weeks. However, the key question remains: Will this rapid clearance translate into clinical improvements for patients?
It could be answered in an ongoing phase 3 trial, which is expected to conclude in 2028.
Can tau approaches build on a mixed signal?
Like amyloid plaques in the brain, tau tangles have also been linked to disease progression in Alzheimer’s patients.
A number of drugs in the pipeline target tau, and the approach showed promise when Biogen presented phase 2 results for diranersen, or BIIB080, from its Celia trial, which showed signs of clinical benefit. But while the drug appeared to slow disease progression, the trial was not a clear win for the drug. The trial did not meet its primary objective, which was to show that a higher dose of the medicine would outperform lower doses. In fact, the lower-dose group saw the strongest results, which were modest overall, compared with placebo.
“There's a lot of questions that still remain around the asset, but it does, in part, validate the approach,” Carre said. “It’s the first time we’ve seen anything beyond amyloid have an effect.” Now, the question is whether future research will offer further evidence that the tau approach works and whether the benefits will extend to other drugs in this category.
Can researchers find the right balance to tamp down neuroinflammation?
Some observational studies have associated certain anti-inflammatory drugs used for autoimmune conditions with lower rates of Alzheimer’s disease, although the evidence is mixed and does not establish a protective effect. There are several anti-inflammatory drugs in the pipeline. But will they prove effective and overcome safety challenges after a series of setbacks?
Among these setbacks were Novo Nordisk’s phase 3 trials of its blockbuster GLP-1 drug. Some experts suspected that the drug could reduce inflammation in the brain. Novo’s drug did improve some biological markers linked to Alzheimer’s, but ultimately couldn’t delay disease progression.
“It’s an area where there is still interest. It’s just about turning it into the right target,” Carre said. “You don’t want to completely remove neuroinflammation. It has a fundamental role in protection of the brain. But too much of it, the chronic neuroinflammation, is what we’re worried about. It’s about finding that balance and unfortunately it’s not been found or validated just yet.”
Can the TREM2 approach make a comeback?
Some experts have high hopes for TREM2, a receptor on the brain’s immune cells that has been linked to Alzheimer’s disease risk and is associated with pro-inflammatory responses. “The conversation around TREM2 is that we do know that it's going to be important,” Carre said. The challenge is finding the most efficient way of targeting it, he said.
Efforts so far have struggled to show a clinical benefit. Past programs have been discontinued because of safety concerns or problems with the molecules themselves rather than the TREM2 target, Carre said. One TREM2 drug from Alector, AL002, for example, failed in phase 2 because it was unable to slow disease progression. Even so, Alector said at the time that it planned to continue its TREM2 research.
And new candidates, including an investigational drug from Sanofi, could revalidate TREM2 as a target if successful, Carre said. The drug, SAR448851, which is now in phase 2, is designed to improve brain penetration compared with other antibody-based TREM2 approaches. The study is expected to wrap up in 2029.
Ultimately, the next few years may bring answers to these five questions. “It’s a very interesting time and a very busy time,” Carre said. “What we’re really looking for is just seeing, hopefully a lot of positive data,” he said.
