New Trials, New Targets: New Hope for Alzheimer's

Medscape

7 hours ago

After decades of frustration and failure, the landscape of drug development for Alzheimer's disease (AD) is starting to shift beyond anti-amyloids. Fueled by a growing pipeline of investigational agents, a broader range of therapeutic targets, and a record number of active clinical trials, a growing, but cautious, optimism is taking hold.
The Alzheimer's Drug Development Pipeline 2025 reported there are currently 138 novel drugs under evaluation in 182 clinical trials — up 9% from 2024. Initiated by Jeffrey L. Cummings, MD, and colleagues in 2016, this year's annual report showed these clinical trials are being conducted at more than 4500 sites worldwide and included more than 50,000 participants.
'There's great reason for optimism. It's not just the increased amount of clinical trials, but the targeted therapies being studied,' said Cummings, Department of Brain Health, Kirk Kerkorian School of Medicine, University of Nevada, Nevada, in a statement.
Howard Fillit, MD, cofounder and chief science officer of the Alzheimer's Drug Discovery Foundation, agreed.
'What's going on is really quite remarkable. We have the first disease-modifying drugs on the market, which is amazing, and I think the portfolio of drugs in development has changed dramatically from even 5 years ago,' Fillit told Medscape Medical News .
James Rowe, PhD, professor of cognitive neurology, University of Cambridge, Cambridge, England, was equally impressed by the latest report.
'What strikes me is not just the number of new drugs but their range of targets in which they work, giving us multiple shots on goal,' Rowe commented during a media briefing on the report.
The Next Big Thing?
Currently 12 phase 3 trials are expected to report results this year. In an interview with Medscape Medical News , Cummings noted that 'one of the most interesting and probably most influential of the readouts that will occur this year' involves two trials evoke and evoke+ of the GLP-1 receptor antagonist semaglutide in patients with mild cognitive impairment (MCI) or mild AD dementia.
'Semaglutide is a drug approved for diabetes and obesity, and it has epidemiologic and laboratory support for testing in Alzheimer's disease. And what's important is that this is an oral medication and it would just be fabulous if we had an oral alternative for treatment,' said Cummings.
Phase 3 data on the combination of xanomeline plus trospium, a medication approved for schizophrenia in adults, which is being tested for psychosis in AD, is also highly anticipated, Cummings said.
'There are no approved treatments for psychosis in Alzheimer's disease, so this is going to be a particularly interesting readout,' he noted.
Cummings also highlighted BIIB080, Biogen's investigational antisense oligonucleotide targeting tau, as another promising compound for early-stage AD. The therapy received Fast Track designation from the FDA in April.
In early testing, BIIB080 reduced soluble tau protein in cerebrospinal fluid (CSF), decreased aggregated tau pathology in the brain and showed favorable trends in exploratory clinical outcomes. New data on BIIB080 is expected in 2026.
Hopes are also high for trontinemab (Roche), a modified version of the anti-amyloid monoclonal antibody gantenerumab. The therapy uses brain shuttle technology to improve its ability to cross the blood-brain barrier.
'This so-called brain shuttle technology is exciting because they've found a way to get much more of the antibody across the brain barrier and into the brain and engage the target. And this technology could be used to get other drugs into the brain,' Cummings said.
The Big Picture
There are currently 48 trials assessing 31 drugs in phase 3; 86 trials assessing 75 drugs in phase 2; and 48 trials assessing 45 drugs in phase 1. Of the 182 trials, 16 are long-term extensions of agents in prior trials.
Since the beginning of 2024, 56 new trials entered the pipeline across all phases, including 10 new phase 3 trials. A total of 12 therapeutic agents are expected to complete phase 3 trials and 29 are scheduled to complete phase 2 in 2025.
Disease-targeted therapies (DTTs) continue to dominate the AD drug pipeline. Biological DTTs comprise 30% of the pipeline and small molecule DTTs account for 43%.
Drugs targeting cognitive enhancement make up 14% of the pipeline and drugs aimed at ameliorating AD neuropsychiatric symptoms comprise 11%. Repurposed agents represent 33% of the pipeline agents. In addition, biomarkers are among the primary outcomes of 27% of active trials.
Beyond Amyloid: New Targets
Anti-amyloid agents, lecanemab and donanemab, became the first disease-targeting medications for AD and represented a 'huge leap forward in our understanding and ability to treat AD,' Sheona Scales, PhD, director of research, Alzheimer's Research UK, told reporters attending the press briefing.
Scales noted that a key focus of ongoing anti-amyloid research is to find ways to increase brain exposure and reduce the side effects of these agents.
Beyond anti-amyloids, the latest pipeline report showed not only numerical growth but also increased biological diversity among the agents under investigation.
'Research is revealing even more complexities around how Alzheimer's disease starts and progresses, and this goes beyond amyloid. The current therapeutic pipeline has more diverse targets than in previous years,' Scales said.
Similar to 2024, this year only 18% of drugs in the pipeline target amyloid-related pathophysiology, whereas 11% target tau-related processes.
'Neuroinflammation, in particular, is a highly active area of therapeutic development,' Emma Mead, PhD, interim chief scientific officer, Oxford Drug Discovery Institute, told reporters.
'Neuroinflammation is the brain's response to injury, infection or disease, and research has suggested that in neurodegenerative conditions, microglia, the immune cells of the brain, become dysregulated and this contributes to the damage associated with Alzheimer's disease,' Mead explained.
Thirty drugs (22%) in the pipeline target neurotransmitter receptors, 24 (17%) address neuroinflammation/immune processes and 6% address synaptic plasticity/neuroprotection.
Combination Therapies and Prevention
Given the complexity of AD, it's become clear that targeting a single pathway may not be sufficient for effective treatment. Combination therapy targeting multiple complementary pathologic mechanisms will be necessary to maximize therapeutic effects.
The 2025 AD drug pipeline includes 20 trials of combination therapies, comprising 11% of all current trials. Ten of these trials target aspects of both inflammation and amyloid.
For example, two trials are testing dasatinib, in combination with quercetin, as a senolytic therapy for dementia. Senescent cells accumulate with age and are believed to contribute to age-related diseases like dementia.
Six trials are assessing combinations of dextromethorphan and a CYP2D6 inhibitor for reducing agitation associated with dementia.
Four trials are assessing the combination of xanomeline plus trospium.
'Because Alzheimer's disease is so complex and different pathologies develop at different times across the disease course, it's likely that in the future, patients are going to be offered specific treatments that target distinct mechanistic pathways depending on their disease stage,' Mead said.
Rowe said one of the most compelling findings in the latest pipeline reported as the notable increase in late-phase trials focused on prevention. These AD prevention trials aim to intervene before symptoms appear — targeting individuals at high risk due to genetics, biomarkers, or early pathological changes — to delay or even prevent clinical onset.
'The aspiration to prevent, not just treat, is starting to be seen in the figures and that's very exciting,' he told the briefing.
Repurposing Current Medications?
About a third of the agents currently under investigation are repurposed medications — drugs originally approved for other conditions — which may offer a faster path to patient access. They include the GLP-1 receptor agonists (RAs) used to treat diabetes and obesity.
In addition to semaglutide, another GLP-1 RA, liraglutide, demonstrated a 50% reduction in brain atrophy and 18% slower cognitive decline in the phase 2b ELAD clinical trial of adults with mild to moderate AD. The diabetes medication metformin is also in phase 3 testing for AD with results expected in 2026.
Antihypertensive medications — including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs) — are also being studied for their potential neuroprotective effects.
A randomized trial of the ARB candesartan showed positive neurocognitive effects independent of, and in addition to, their blood-pressure lowering effects.
Further, a low dose formulation of the antiepileptic levetiracetam has also shown potential in the treatment of MCI and early AD by targeting hippocampal hyperactivity, a hallmark of AD.
Research has also hinted that antibiotics, antivirals, some vaccines, and anti-inflammatory medications may protect against dementia, possibly by mitigating pathogen-induced neuroinflammation.
Closer to a Cure?
'Trial innovation' is also evident in the 2025 AD drug development pipeline, the report's authors noted, with plasma biomarkers playing a greater role in AD diagnosis.
Recent studies have suggested that plasma p-tau 217 measures are equivalent in diagnostic accuracy to CSF biomarkers of AD pathology. Several trials entering the pipeline this year are using plasma p-tau 217 to confirm AD diagnosis and serve as an eligibility criterion for clinical trial participation.
In one trial, eligibility was based on Aβ 42/40 plus the ratio of p-tau 217/nonphosphorylated tau 217; a separate trial used 'blood biomarkers' or past CSF or PET evidence of Aβ abnormalities for eligibility.
CSF levels of microtubule-binding region tau243 have been shown to correlate with insoluble tau detected by tau PET imaging and are being used as a primary outcome measure in an anti-tau antibody trial.
'The use of biomarkers to determine eligibility and as outcomes in clinical trials shows the increasingly important role that biomarkers play in AD drug development,' Cummings and colleagues wrote.
Summing up, they said the 2025 AD drug pipeline report demonstrates 'robust' momentum toward identifying new therapies for the treatment of AD.
'Seeing the broad range of scientific research that's taking place, I am extremely hopeful that we are closer than ever to finding a cure for Alzheimer's,' Cummings said in the news release.