Hope in Alzheimer’s disease

After decades of frustration and failure, the development of drug drugs (MA) is beginning to evolve beyond anti-amyloid treatments. Meanwhile, Fueled by an increasing number of experimental agents. Consequently, a larger range of therapeutic targets and a record number of active clinical trials, a prudent but increasing optimism is felt.

The 2025 report on the pipeline of development drugs against Alzheimer’s disease indicates that 138 new drugs are currently. Furthermore, evaluated in 182 clinical trials – an increase of 9 % compared to 2024. Moreover, launched by the Dr Jeffrey L. Nevertheless, Cummings And its colleagues in 2016. However, this year’s annual report reveals that these clinical trials are conducted in more than 4,500 sites around the world and involve more than 50,000 participants.

“There are good reasons to be optimistic. However, It is not only the growing number of clinical trials. hope alzheimer’s disease Furthermore, but also the targeted therapies that are studied, “said Jeffrey L. Furthermore, Cummings, of the Health Service of the Faculty of Medicine Kirk Kerkorian, University of Nevada.

The Dr Howard Fillitco -founder and scientific director of Alzheimer’s Drug Discovery Foundation, share this opinion.

“What’s going on is really remarkable. For example, We have the first drugs modifying the disease on the market. Therefore, which is incredible, and I think that the development portfolio has radically changed for five years, “he said to Medscape Medical News.

James Roweprofessor of cognitive neurology at the University of Cambridge, England, also says he is impressed by the last report. Therefore, “What strikes me is not only the number of new drugs. Additionally, Therefore, but also the diversity of their targets, which gives us several possibilities of success,” he commented at a press conference on the report.

The next big step?

Twelve hope alzheimer’s disease phase 3 trials should publish their results this year. Similarly, In an interview with Medscape Medical NewsDr. Similarly, Cummings stressed that “the most interesting results” come from two trials. For example, Evoke and Evoke+, on the antagonist of GLP-1 receptors, Sémaglutide, in patients with a light cognitive disorder (MCI) or a light dementia due to the MA.

“Sumaglutide is an approved drug for diabetes and obesity. Therefore, What is important is that it is an oral drug – it would be fantastic if we had an oral alternative as treatment. “said Dr. Cummings.

Phase 3 data on the Xanoméline + Trospium combination. an approved medication for adult schizophrenia tested here for MA psychosis, are also eagerly awaited.

“There is currently no treatment approved for psychosis in the MA. so it will be a particularly interesting result,” he noted.

Dr. Cummings has also highlighted the BIIB080. an oligonucleotide antissens experimental biogen hope alzheimer’s disease targeting the Tau protein, as another promising molecule in early phase. This treatment obtained a designation Fast Track of the FDA in Avril.

During the first tests. the BIIB080 reduced the soluble TAU in cerebrospinal fluid (LCR), reduced the pathology of aggregated tau in the brain, and shown favorable trends in exploratory clinical results. New data is expected in 2026.

Hopes are also raised for the Trontinémab (Roche). a modified version of the antiamyloid monoclonal antibody Ganénumab, which uses brain shuttle technology to better cross the blood-brain barrier.

“This so -called brain shuttle technology is exciting. as it allows many more antibodies to pass in the brain and reach the target. This technology could also allow other drugs to enter the brain, “said Dr. Cummings.

Overview

We currently count:

• 48 trials evaluating 31 drugs in phase 3;

• 86 trials evaluating 75 drugs in phase 2;

• 48 trials hope alzheimer’s disease evaluating 45 drugs in phase 1.

Among the 182 trials, 16 have long -term extensions of agents tested previously.

Since the beginning of 2024, 56 new tests have been added to the pipeline, including 10 new phase 3. In 2025, 12 agents should complete their phase 3 tests, and 29 their phase 2.

Targeted therapies on the disease always dominate pipeline. Therapies directly targeting biological disease represent 30 %, and small molecules 43 %.

Medicines for cognitive improvement represent 14 % of the pipeline, these targeting the neuropsychiatric symptoms of the 11 %. Reused agents (repurposed) represent 33 % of the total. In addition, biomarkers are used as main criteria in 27 % of active trials.

Beyond amyloids: new targets

Lecanemab. Donanemab anti-amyloid agents were the first drugs targeting the MA directly, marking “major progress in our understanding and our ability to treat the disease,” said Sheona hope alzheimer’s disease Scalesdirector of research within the charity association Alzheimer’s Research UK.

She pointed out that one of the major objectives of antiamyloid research is to increase brain exposure. reduce side effects.

Beyond amyloids, this year’s report shows not only digital growth, but also greater biological diversity among the molecules studied.

“Research reveals an increasing complexity in the way in which the MA begins. progresses, and it goes beyond the amyloid. The current pipeline targets more varied mechanisms than in previous years, ”insisted the pre -Scales.

As in 2024, only 18 % of drugs targeting amyloid linked pathophysiology, compared to 11 % for processes related to TAU protein.

“Neuroinflammation. in particular, is a very active field of therapeutic development,” said Emma Meadinterim scientific director at theOxford Drug Discovery Institute.

“Neuroinflammation is the brain’s response to an injury, infection or illness. Research suggests that in neurodegenerative diseases. microglies-immune cells of the brain-become dysfunctional hope alzheimer’s disease and contribute to the damage linked to the MA, “she explained.

Thirty drugs (22 %) target neurotransmitters receptors, 24 (17 %) neuroinflammation and the immune system, and 6 %aim for synaptic plasticity and neuroprotection.

Combined therapies. prevention

Given the complexity of the MA, it is clear that an effective treatment will require act on several complementary pathological mechanisms. The 2025 pipeline includes 20 combined therapy trials, or 11 % of the trials. Ten of them target both inflammation and the amyloid.

For example, two trials test dasatinib with quercetin as a senolytic therapy against dementia. Senescent cells accumulate with age and could contribute to diseases like MA.

Six trials evaluate dextromethorphane + CYP2D6 inhibitor to reduce the agitation linked to dementia. Four tests test xanoméline + trospium.

“Given the complexity of Alzheimer’s disease. the variability of pathologies over time, future treatments are likely to target specific mechanisms depending hope alzheimer’s disease on the stage of the disease,” said PRE Mead.

Professor Rowe added that one of the most striking advances is the increase in the number of advanced prevention. phase tests. These trials aim to intervene before the appearance of symptoms. in high -risk individuals (genetics, biomarkers, early pathological changes) to delay or prevent clinical appearance.

“The aspiration to be warned. not only to treat, begins to reflect itself in the figures, and it is very exciting,” he said.

Reuse of existing drugs?

About a third of the agents studied are drugs already approved for other indications. which could accelerate their access to patients. This includes agonists of GLP-1 receptors used for diabetes and obesity. In addition to the semaglutide. another agonist in the incretinated receptors, the Liraglutide, has shown a 50 % reduction in brain atrophy and an 18 % slowdown in cognitive decline in the trial You hope alzheimer’s disease live phase 2b. The Metformin anti -Diabetique drug is also in phase 3, with expected results in 2026.

Antihypertensive drugs, enzyme inhibitors of angiotensin conversion and angiotensin receptor blockers (ARA) are also being studied for their neuroprotective effects. A randomized trial of candesartan has shown positive neurocognitive effects, regardless of its effects on blood pressure.

In addition. a low dose of levetiracetam, an antiepileptic, has shown potential to treat MCI and the early forms of MA, by targeting the hyperactivity of the hippocampus, characteristic of the disease.

Research also suggests that certain antibiotics. antivirals, vaccines and anti-inflammatory drugs could protect against dementia by attenuating neuro-induced inflammation by pathogens.

Towards a remedy?

Innovation in clinical trials is also notable in 2025, with an increasing role in plasma biomarkers for the diagnosis of MA.

Recent studies show that the P-TU 217 plasma has diagnostic precision equivalent to BIMB BIOMARQUEURS. Several hope alzheimer’s disease new trials use this marker to confirm the diagnosis and as an inclusion criterion. In an essay. the eligibility was based on the Aβ 42/40 + P-TU 217/Tau non phosphorylated ratio; Another was based on blood biomarkers or previous CSF/PET data. The TAU243 levels in the LCR. which corrèle with the insoluble tau detected by PET, are used as the main criterion in a trial of anti-tau antibodies.

“The use of biomarkers as an inclusion. monitoring criterion shows their growing role in the development of treatment against the MA”, write Cummings and its colleagues.

In conclusion, they indicate that the 2025 pipeline shows a robust impulse towards the discovery of new treatments.

“When I see the extent of current scientific research. I am extremely optimistic: we have never been so close to finding treatment for Alzheimer’s disease,” said Dr. Cummings in a press release.

Article translated and adapted from the Portuguese edition of Medscape.com

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