Moving Away from Alzheimer’s Anti-Amyloid Therapies

Reviewed by Sharyn Rossi, PhD, BrightFocus Foundation

Clearing amyloid from the brain by using targeted antibodies is the foundational approach for the latest slate of approved Alzheimer’s therapies. Amyloid-targeting drugs Aduhelm and Leqembi show little-to-modest effects on Alzheimer’s symptoms in clinical trials. They’ve also brought a new term into the collective consciousness— amyloid-related imaging abnormalities (ARIA). The rare side effect often presents without symptoms but is life-threatening in some cases. Study outcomes now have researchers questioning whether targeting amyloid is best and if these antibody therapies are the most promising strategy.  

“I think these clinical trials had to be done. What I worry about is a lack of willingness to learn from [them],” said Dr. Madhav Thambisetty, an Alzheimer’s expert at the National Institute on Aging. He presented an overlook of the Alzheimer’s treatment pipeline at the 2024 American Association for the Advancement of Science Annual Meeting on February 17. Every year, conference organizers recognize the top 10 breakthroughs in science—choosing this year to highlight the recent therapeutic milestones in Alzheimer’s disease.   

Advances in treatment came with the approval of Leqembi in 2023. “[It] was a landmark in terms of the science and a huge milestone in trying to target one of the defining pathologies in Alzheimer’s disease,” Dr. Thambisetty said. 

In a clinical trial, Leqembi treatment produced a moderate slowing of cognitive decline by 25% at 18 months. However, the widely reported statistic is only a relative difference between treatment groups, Dr. Thambisetty cautioned. It leaves out important information like the variability in decline between participants and measures of uncertainty in assessing responses to treatment.

The benefits to cognition also came at a price for some participants. Those who received Leqembi had a greater risk of ARIA than the non-treated group, especially for participants carrying the Alzheimer’s risk gene APOE4.  

Across amyloid trials, roughly 1 in 100-200 treated patients experienced ARIA, prompting the U.S. Food & Drug Administration to issue a black box warning for this class of medications. Less understood, however, is the brain shrinkage that occurred across treated participants compared to their non-treated counterparts. The long-term consequences of this side effect are unknown and “especially worrying,” Dr. Thambisetty said, considering the loss of brain volume that already takes place in Alzheimer’s. We need better reporting and examination of ARIA and brain shrinkage, he added, including the symptoms of ARIA cases and how this impacts cognitive outcomes for participants.  

The use of antibodies to clear one of the hallmark Alzheimer’s proteins from the brain aims to get right at the heart of the disease. Many therapies only target Alzheimer’s symptoms and do nothing to address the underlying problem. The “controversial approval” of the anti-amyloid drug Aduhelm in 2021 was a “dramatic upheaval after a century of little progress,” Dr. Thambisetty said.  

Earlier this year, Aduhelm and its post-approval ENVISION trial were discontinued by the manufacturer. The study failed to show that the clearance of amyloid from the brain produced a meaningful improvement in symptoms for treated patients. These events have now supercharged a larger conversation on how experts define a meaningful outcome in clinical trials for Alzheimer’s treatment.    

Between controversies and side effects, the Alzheimer’s community has hesitated to embrace the first anti-amyloid therapies. But Dr. Thambisetty remarked that not all is lost if we learn from our mistakes and continue the hunt for more Alzheimer’s treatments.  

“In an era in targeting pathology of neurodegenerative diseases… it’s a very exciting time because we can reliably and accurately target core hallmarks of these diseases,” Dr. Thambisetty said. That means more targeted antibodies on the way, like those fighting against another Alzheimer’s hallmark, tau protein. While clinical trials have produced negative results thus far, Dr. Thambisetty expects to see more anti-tau therapies on the horizon.  

He also anticipates a redefining of Alzheimer’s disease by its biological markers—relying less on the evaluation of clinical symptoms for diagnosis. This approach will be “hugely controversial,” Dr. Thambisetty said.  

Advances in targeted therapies and a narrowed focus on the biological underpinnings of Alzheimer’s disease could spell more combined approaches to treatment. As BrightFocus Foundation’s Dr. Sharyn Rossi shares, “Alzheimer’s is a disease with multiple contributing factors—therefore, treatment will require a combination approach to better address cognitive and behavioral symptoms.” 

That’s why scientists supported by BrightFocus Foundation’s Alzheimer’s Disease Research program are taking a 360° approach to empowering drug discovery for Alzheimer’s treatment. Explore a few of our currently funded research projects below:  

• Novel Molecules to Tackle Toxic Amyloid-Beta Production in Alzheimer's 

• Targeting Brain Immune Cells as a Novel Therapeutic in Alzheimer's Disease  

• A Newly Discovered Version of Toxic Tau as a Therapeutic Target in Alzheimer's Disease 

You may also be interested in:

• What are Alzheimer’s Plaques and Tangles? 

• New Alzheimer’s Drugs: What To Expect Over The Next 3 Years 

• Tau Protein and Alzheimer’s Disease: What’s the Connection? 

About BrightFocus Foundation       

BrightFocus Foundation is a premier global nonprofit funder of research to defeat Alzheimer’s, macular degeneration, and glaucoma. Through its flagship research programs — Alzheimer’s Disease Research, National Glaucoma Research, and Macular Degeneration Research — the Foundation has awarded nearly $290 million in groundbreaking research funding over the past 50 years and shares the latest research findings, expert information, and resources to empower the millions impacted by these devastating diseases. Learn more at brightfocus.org. 

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