Cochrane Review: Amyloid-Beta Targeting Monoclonal Antibodies for Alzheimer’s Disease Ineffective, Risky

A Cochrane review of 17 randomized controlled clinical trials with 20,342 participants concluded that monoclonal antibody drugs targeting amyloid-beta have “trivial” effects on cognitive function and dementia severity at 18 months and “probably result in a small increase” in the risk of brain swelling.[1]

“Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease,” the authors of the 2026 systematic review concluded.

“Future research on disease-modifying treatments for Alzheimer’s disease should focus on other mechanisms of action.” The Cochrane Library, which publishes the reviews, is an established international, non-profit source of collaborative, evidence-based studies and databases on health and health care.[2]

The Food and Drug Administration (FDA) has approved three amyloid-beta-targeting monoclonal antibodies for Alzheimer’s disease: aducanumab (ADUHELM), donanemab (KISUNLA) and lecanemab (LEQEMBI).[3],[4] Public Citizen’s Health Research Group has classified all of these drugs as Do Not Use.

Aducanumab was withdrawn from the market in 2024. Donanemab[5] and lecanemab[6] are approved for the treatment of Alzheimer’s disease in persons with mild cognitive impairment (predominantly difficulties with memory) or mild dementia (early-stage dementia that interferes with daily activities), the populations in which treatment was initiated during the clinical trials. The prescribing information for both drugs includes a boxed warning, the FDA’s strongest warning, for amyloid-related imaging abnormalities (ARIA), which are associated with brain swelling and brain bleeding. Although ARIA does not usually cause symptoms, it can lead to serious and life-threatening events and can be fatal.

Sales of donanemab and lecanemab have been lower than anticipated because of concerns about their effectiveness and safety.[7] Initially, it was projected that Medicare would spend billions of dollars a year on lecanemab alone. In fact, Medicare spent $139 million on lecanemab and $74 million on donanemab during the first three quarters of 2025, and the program does not forecast significant spending on either drug in 2026 or 2027.[8]

Amyloid-beta

Amyloid-beta is a portion of a transmembrane protein on the surface of neurons.[9] Its clustering in the brain tissue surrounding neurons forms plaques that are characteristic of Alzheimer’s disease. However, whether amyloid plaques are benign, reflect past cell death or trigger ongoing cell degradation remains unclear. One hypothesis is that amyloid-beta deposits disrupt connections (synapses) between neurons, leading to malfunction and neuronal death. Researchers have also observed that amyloid-beta plaques can accumulate during normal aging[10] or that with dementia the plaques may reflect irreversible rather than treatable brain damage.

The Cochrane review

The Cochrane review searched five biomedical databases through Aug. 7, 2025, including two clinical trial registries, for randomized trials of at least 12 months duration that compared monoclonal antibodies targeting amyloid-beta with placebo or no treatment in persons with mild cognitive impairment or mild dementia due to Alzheimer’s disease. The drugs considered were aducanumab, donanemab, lecanemab and four others that are not approved for use in the United States.

Participants in the 17 studies had a mean age ranging from 70 to 74 years; the mean duration of impairment before enrollment was 17 to 52 months. The studied drug was usually administered intravenously every two to four weeks. Eleven of the studies lasted 18 months; six lasted 24 months or longer.

At 18 months, “little or no difference” was found between drug and placebo on standardized measures of cognitive function, dementia severity and functional ability. For example, on a 70-point standardized cognitive function scale, persons receiving the drug scored an average of 0.85 points better than those on placebo. Though statistically significant, that difference is markedly below the 2-to-4-point change considered clinically meaningful. On an 18-point standardized dementia scale, the mean difference between drug and placebo was 0.29 points, barely statistically significant and below the 1-to-2-point change considered clinically meaningful. Splitting the analysis by drug confirmed the overall results; differences for aducanumab, donanemab and lecanemab were similar to the overall results for both the cognitive and dementia measures.

A “small increase” was observed in scans showing any brain swelling (edema), with an absolute risk difference of 107 per 1,000 participants; symptomatic brain swelling was observed to increase by 29 per 1,000 participants, and brain microbleeding by 4 per 1,000 participants. At 18 months, the monoclonal antibody treatment was not associated with an increase in serious adverse events.

The authors noted that all the studies were partially biased toward favorable results. Some participants may have correctly guessed that they were receiving the drug rather than placebo, and all trials were sponsored by pharmaceutical companies. Some studies were small and not widely representative of people with Alzheimer’s disease.

What You Can Do

Public Citizen’s Health Research Group recommends that monoclonal antibodies targeting amyloid-beta not be used by people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. The findings of the Cochrane review reinforce our concerns and underscore the importance of developing alternative treatments. Dementia is sometimes preventable, however. Approaches to reduce the risk of cognitive decline include: shingles vaccination,[11] protecting hearing and vision, healthy nutrition, maintaining friendships and reducing alcohol use.[12]
 

References

[1] Nonino F, Minozzi S, Sambati L, et al. Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease. Cochrane Database Syst Rev. 2026;4(4):CD016297.

[2] Cochrane. About us. https://www.cochrane.org/about-us. 2026. Accessed June 3, 2026.

[3] Worst Pills, Best Pills News. Updates on new Alzheimer’s disease drugs. May 2024. https://www.worstpills.org/newsletters/view/1596. Accessed June 1, 2026.

[4] Worst Pills, Best Pills News. Donanemab (KISUNLA): A bad choice for Alzheimer’s disease. https://www.worstpills.org/newsletters/view/1626. Accessed June 1, 2026.

[5] Elil Lilly. Label: donanemab-azbt (KISUNLA). July 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761248s004lbl.pdf. Accessed June 3, 2026.

[6] Eisai. Label: lecanemab-irmb (LEQEMBI). January 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761269s011lbl.pdf. Accessed June 3, 2026.

[7] Herman B. Medicare is spending far less than expected on new Alzheimer’s drugs. STAT. May 11, 2026. https://www.statnews.com/2026/05/11/medicare-spending-less-than-expected-alzheimers-drugs-leqembi-kisunla/. Accessed June 1, 2026.

[8] Ibid.

[9] Abdulkhaliq AA, Kim B, Almoghrabi YM, et al. Amyloid-β and tau in Alzheimer's disease: pathogenesis, mechanisms, and interplay. Cell Death Dis. 2026;17(1):21.

[10] Goldman B. One step back: why the new Alzheimer’s plaque-attach drugs don’t work. March 13, 2024. Stanford Medicine News Center. March 13, 2024. https://med.stanford.edu/news/insights/2024/03/why-alzheimers-plaque-attack-drugs-dont-work.html. Access June 3, 2026.

[11] Worst Pills, Best Pills News. Study: vaccine for herpes zoster (shingles) may help prevent or Delay Dementia. August 2025. https://www.worstpills.org/newsletters/view/1676. Accessed June 7, 2026.

[12] Worst Pills, Best Pills News.  Lancet Commission: nearly half of dementia cases are preventable. January 2025. https://www.worstpills.org/newsletters/view/1637. Accessed June 7, 2026.