New Trials, New Targets: Alzheimer’s Treatment

After years of limited success, Alzheimer’s disease (AD) drug research is entering a transformative era. The focus is expanding beyond anti-amyloid therapies, driven by a surge in clinical trials, new drug candidates, and a wider range of therapeutic targets. This momentum is building cautious optimism in the scientific community.

A Growing Pipeline of Therapies

According to the Alzheimer’s Drug Development Pipeline 2025, there are now 138 new drugs being tested across 182 clinical trials — a 9% increase from 2024. Spearheaded by Dr. Jeffrey L. Cummings and colleagues since 2016, this report highlights more than 4,500 global trial sites with over 50,000 participants.

“This isn’t just about more trials — it’s about better-targeted ones,” said Dr. Cummings from the University of Nevada. Dr. Howard Fillit, cofounder of the Alzheimer’s Drug Discovery Foundation, echoed this sentiment, noting a major shift in the nature and goals of current drug development.

Professor James Rowe of the University of Cambridge emphasized the diversity of treatment targets, calling it “multiple shots on goal” — a crucial development in such a complex disease.

What’s on the Horizon?

Twelve phase 3 trials are expected to deliver results in 2025. Among the most anticipated are the EVOKE and EVOKE+ studies testing semaglutide — an oral GLP-1 receptor agonist currently used for diabetes and obesity — in patients with mild cognitive impairment (MCI) and early-stage AD.

Additionally, a phase 3 trial of xanomeline plus trospium — previously approved for schizophrenia — could lead to the first treatment for Alzheimer’s-related psychosis. Another promising candidate is Biogen’s BIIB080, an antisense therapy targeting tau, which has shown early signs of reducing tau pathology and received FDA Fast Track status.

Roche’s trontinemab, a modified anti-amyloid antibody using “brain shuttle” technology to cross the blood-brain barrier more effectively, also represents a breakthrough.

Snapshot of the Current Pipeline

There are currently:

• 48 trials testing 31 drugs in phase 3,

• 86 trials testing 75 drugs in phase 2, and

• 48 trials testing 45 drugs in phase 1.

In total, 56 new trials were launched in 2024 alone, with 12 phase 3 and 29 phase 2 trials projected to conclude in 2025.

Therapies that target Alzheimer’s biology remain dominant, with biological drugs making up 30% of the pipeline and small molecules 43%. Cognitive enhancers and treatments for neuropsychiatric symptoms represent 14% and 11% respectively. About one-third of all candidates are repurposed drugs, and 27% of active trials use biomarkers as primary outcomes.

Beyond Amyloid: Broader Biological Targets

Lecanemab and donanemab, the first disease-modifying anti-amyloid drugs, marked major progress, but researchers are now looking beyond amyloid alone. Only 18% of pipeline drugs target amyloid, while 11% focus on tau. The rest reflect increased diversity in approach, including agents aimed at:

• Neuroinflammation (17%)

• Neurotransmitter receptors (22%)

• Synaptic protection and plasticity (6%)

Neuroinflammation has become a key area, particularly the role of microglia — the brain’s immune cells — in disease progression.

Combining Treatments for Better Outcomes

Due to the multifaceted nature of AD, combination therapies are gaining traction. Currently, 20 trials are testing drug combinations, including those that address both amyloid and inflammation. For example:

• Dasatinib with quercetin (senolytic therapy)

• Dextromethorphan with a CYP2D6 inhibitor for agitation

• Xanomeline plus trospium for neuropsychiatric symptoms

Experts believe that treatment in the future will be tailored to individual disease stages, with multiple therapies addressing distinct biological mechanisms.

The Shift Toward Prevention

There’s growing emphasis on preventive strategies, with more late-stage trials targeting individuals at high genetic or biomarker-based risk — before symptoms arise. Professor Rowe called this pivot “very exciting,” as researchers aim not only to treat but to prevent AD.

Repurposing Existing Medications

Roughly 33% of drugs in the pipeline are repurposed agents. This includes:

• GLP-1 receptor agonists (e.g., liraglutide and semaglutide), shown to reduce brain atrophy and slow cognitive decline.

• Metformin, now in phase 3 testing.

• Antihypertensives, like candesartan, which demonstrated cognitive benefits.

• Levetiracetam, an antiepileptic drug, targeting hippocampal overactivity.

Other repurposed candidates include antibiotics, antivirals, and even vaccines, being studied for their potential to mitigate neuroinflammation caused by pathogens.

A New Era of Diagnostics and Innovation

The 2025 pipeline also highlights major innovation in trial design. Plasma biomarkers such as p-tau 217 are increasingly used to diagnose AD and determine clinical trial eligibility — potentially replacing more invasive CSF or PET scans. For example:

• One trial uses Aβ 42/40 plus p-tau 217/non-phosphorylated tau ratios.

• CSF tau243 is being used to monitor tau-targeted treatments.

Dr. Cummings and colleagues emphasized how biomarkers are becoming central to both diagnosis and trial outcomes, enhancing precision and efficiency in drug development.

Looking Ahead

In summary, the 2025 Alzheimer’s drug pipeline offers robust progress across many fronts: from increased trial numbers and biological diversity to innovative combination therapies and prevention efforts.

“I’m more hopeful than ever that we’re nearing a cure,” Dr. Cummings said.

This research is supported by the Alzheimer’s Association, the Alzheimer’s Drug Discovery Foundation, the National Institute on Aging, and the National Institute of General Medical Sciences.