With the anticipation of a third Alzheimer’s drug, donanemab, likely to be approved by the FDA, advancements are being made in treating the early stages of Alzheimer’s disease.
However, further therapies are still needed to aid those with advanced disease, according to Gil Rabinovici, MD, director of the UCSF Alzheimer’s Disease Research Center.
This is merely the beginning of a new era of molecular therapies for Alzheimer’s and related neurodegenerative disorders, Rabinovici wrote in a JAMA editorial.
Monoclonal Antibodies and Alzheimer’s
Like the two earlier drugs, aducanumab (Aduhelm) and lecanemab (Leqembi), donanemab is a monoclonal antibody that targets plaques in the brain composed of a protein called amyloid, which disrupts cell function and leads to the rapid spread of another protein, tau.
Both amyloid and tau are key contributors to the development of Alzheimer’s disease.
The trial results indicated that donanemab slowed cognitive decline by 35% compared to a placebo in patients with low-to-intermediate levels of tau in the brain, similar to outcomes reported with Leqembi.
Additionally, patients on donanemab experienced a 40% lower risk of progressing from mild cognitive impairment to mild dementia or from mild to moderate dementia.
Donanemab also showed better efficacy in removing amyloid plaques compared to Aduhelm and Leqembi.
Considerations for Serious Disease and Side Effects
While these results are promising, Rabinovici highlighted that patients with advanced Alzheimer’s showed little to no benefit compared to placebo recipients.
In light of this, and considering the potentially severe side effects, the focus should be on developing more effective and safer treatments. R
abinovici recommended that donanemab should be administered only to patients with low-to-intermediate levels of tau, indicating milder disease stages.
Risk Factors and Ethical Concerns
Like the two other Alzheimer’s drugs, donanemab was associated with ARIA, amyloid-related imaging abnormalities, which could include brain swelling and microbleeds.
Serious ARIA occurred in 3.7% of patients, including three deaths. The risk was higher among patients with the APOE4 gene, which is linked to an increased risk for Alzheimer’s.
Additionally, the trial had a significant limitation due to its lack of racial and ethnic diversity, with just 8.6% of participants being non-white.
This raises ethical concerns about the general applicability of the results, given that studies have shown higher rates of dementia in Black and Latino populations.
Cost and Accessibility of Treatment
Given the expected high cost of donanemab and high patient demand, Rabinovici suggested that treatment duration might be limited to the time required to clear amyloid plaques from the brain, which could significantly enhance the feasibility of treatment for patients, clinicians, insurers, and health systems.
Despite these advances, the treatment of Alzheimer’s remains a complex challenge, with further research needed, especially for those in advanced stages of the disease.
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The study was published in JAMA.
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