In July, we reported that lecanemab (Leqembi) won full FDA approval to treat Alzheimer's disease. In this article, we look beyond anti-amyloid agents like lecanemab to see what other targets are being studied to prevent or treat Alzheimer's in 2024.

2023 was a landmark year for Alzheimer's disease, with lecanemab becoming the first treatment targeted at the disease process to receive full FDA approval.

Reaching this milestone in Alzheimer's treatment was "a long journey," said Babak Tousi, MD, of the Cleveland Clinic in Ohio, an investigator in the lecanemab clinical trials. "We can affect the disease trajectory -- it's a small benefit, but it's still a benefit. We can slow it down."

"This was a big step for us, and it's not just because of the effect of the disease treatment," Tousi pointed out. "We learned more about the disease and learned how to diagnose it more accurately, and how to look at the process of the disease progression and biomarkers."

Another anti-amyloid drug, donanemab, may soon win FDA approval. But the Alzheimer's treatment landscape extends well beyond targeting amyloid-beta, with over 100 different drugs in phase I, II, or III clinical trials.

"A pipeline of potential new treatments offers hope for the Alzheimer's and dementia community," Maria Carrillo, PhD, chief science officer of the Alzheimer's Association, said at the 2023 Alzheimer's Association International Conference (AAIC).

"The progress and approvals we've seen, as well as the diversification of potential new therapies over the past few years, provides hope to those impacted by this devastating disease," Carrillo continued. "The anti-amyloid drugs newly approved by the U.S. Food and Drug Administration are an important first step in Alzheimer's treatment, but there is so much more to be done."

Alternative Targets

In 2023, the Alzheimer's drug development pipeline had 187 trials, the highest number on record, according to Jeffrey Cummings, MD, ScD, of the University of Nevada in Las Vegas, and co-authors in Alzheimer's & Dementia. Of 141 candidate treatments being studied, 79% were for disease-modifying therapies and were aimed not just at amyloid, but tau, inflammation, metabolic dysfunction, cell death, synaptic plasticity, and multiple other aspects of the disease.

"Alternative targets for Alzheimer's disease treatment are being studied, such as tau pathology and biological mechanisms involved in aging," noted Julien Delrieu, MD, of Universite Paul Sabatier in Toulouse, France, and co-authors in a year-end review in Lancet Neurology.

Age is the main risk factor for Alzheimer's and geroscience may offer therapeutic targets, Delrieu and co-authors observed. "Cellular senescence might contribute to Alzheimer's disease and is considered one of the most promising aging targets for the treatment of the disease," they wrote.

A combination senolytic therapy of dasatinib (Sprycel) and the antioxidant quercetin was studied for the first time in patients with mild Alzheimer's disease in a proof-of-concept phase I trial, Delrieu and colleagues said. "This preliminary study showed a good safety profile and promising results on several Alzheimer's disease hallmarks (positive trend in inflammation and amyloid biomarkers) that need to be confirmed," they added. "Other geroscience-based therapies, such as intravenous mesenchymal stem cells, mTOR inhibitors, epigenetic therapies, sirtuins, or telomerase modulators, are also promising."

New therapies aimed at tackling tau pathology also are making headway. "The clinical efficacy of tau-targeting therapies has yet to be established and some trials have failed; however, multiple trials are ongoing and new candidates continue to enter trials," wrote Einar Sigurdsson, PhD, of New York University Grossman School of Medicine in New York City, and co-authors in Nature Reviews: Neurology.

Research suggests antisense oligonucleotides may reduce tau expression in humans, Sigurdsson and colleagues pointed out. Most new tau treatments in ongoing trials are immunotherapies, which can target tau intracellularly or extracellularly, they added.

Repurposing Diabetes Drugs

Ongoing Alzheimer's trials include repurposed diabetes drugs, noted Howard Fillit, MD, of the Alzheimer's Drug Discovery Foundation in New York City, and colleagues in the Journal of Prevention of Alzheimer's Disease.

"Metformin and semaglutide [Ozempic], effective drugs against type 2 diabetes, are ideal candidates for repurposing to address the metabolic dysfunction in [Alzheimer's disease]," Fillit and co-authors wrote.

Metformin is being studied for Alzheimer's dementia prevention in the phase II/III MAP trial. The diabetes drug is also being combined with healthy lifestyle changes in a novel trial called MET-FINGER, which aims to extend the success of the multidomain FINGER lifestyle study.

In two phase III studies -- EVOKE and EVOKE Plus -- the effects of the glucagon-like peptide 1 receptor agonist semaglutide on the brain is being evaluated in early Alzheimer's disease. Another trial is assessing whether semaglutide can change tau accumulation in people with or without diabetes who are amyloid-positive and have no or mild cognitive impairment.

CRISPR Gene Editing

At the 2023 AAIC, researchers presented two early studies using CRISPR gene editing to potentially treat Alzheimer's disease. One study targeted the amyloid precursor protein (APP) gene that encodes amyloid-beta. The other used CRISPR technology to target the epigenome and reduce APOE4 expression in stem-cell-derived neurons and mouse models.

"Studies such as these two that focus on the most advanced technologies -- in this case, CRISPR -- on moving Alzheimer's treatment and prevention forward are enthusiastically welcomed, and need to be multiplied many times over," Carrillo said at the conference.

No single solution will likely solve Alzheimer's, she observed.

"We envision a future where multiple treatments address every aspect of this most complex disease," Carrillo noted. "And that, once proven, the treatments can be combined in ways that complement and enhance each other to reduce risk, treat effectively, stop the progression, and eventually cure Alzheimer's disease and all other dementia."