Alzheimer’s Drug Review Ignites Backlash From Experts

A systematic review suggested that drugs targeting amyloid beta appeared to have no clinically meaningful positive effects, sparking swift backlash from Alzheimer’s disease experts.

The review assessed 17 trials conducted between 2014 and 2024, reported Francesco Nonino, PhD, of the IRCCS Institute of Neurological Sciences of Bologna in Italy, and colleagues in Cochrane Database of Systematic Reviews.

Twelve trials evaluated drugs that did not meet their primary endpoints — bapineuzumab, crenezumab, gantenerumab, and solanezumab. Three studies examined aducanumab (Aduhelm), which failed one of its two pivotal trials and was later withdrawn from the market. Two trials — a lecanemab (Leqembi) study and a donanemab (Kisunla) study — assessed Alzheimer’s treatments now approved in the U.S. and other countries.

Results of all 17 trials were pooled. Compared with placebo, the treatments “probably result in little to no difference in cognitive function” measured by the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog), with a mean standardized difference (SMD) of -0.11 points (95% CI -0.16 to -0.06), Nonino and colleagues noted.

The treatments also “may result in little to no difference in dementia severity” measured by the Clinical Dementia Rating Sum of Boxes (CDR-SB), with an SMD of -0.12 (95% CI -0.24 to -0.00), they added.

“The risk of adverse events, most notably amyloid-related imaging abnormalities (ARIA), is high. Although symptomatic ARIA is uncommon, the long-term consequences of cerebral edema and recurrent (micro) bleedings are uncertain,” the researchers wrote.

Future Alzheimer’s treatments should focus on other targets besides amyloid removal, Nonino and co-authors stated.

The seven drugs in the review “all target the same protein,” said co-author Edo Richard, PhD, of Radboud University Medical Center in the Netherlands, during a press conference. “The fact that some trials showed no effect and other trials did show an effect is, in fact, a very good and strong scientific reason to perform a meta-analysis to avoid overinterpretation of positive studies while ignoring negative studies.”

“Anti-amyloid antibodies are not one uniform group of medicines,” wrote Bart De Strooper, MD, PhD, of University College London, on the U.K. Science Media Centre website. “They are different molecules, developed at different times, directed against different forms of amyloid, and associated with very different trial outcomes.”

When failed and successful trials are combined into a single pooled estimate, “the average will inevitably look weaker than the best performing agents. That is not a biological insight; it is simply the arithmetic consequence of mixing negative and positive studies together,” added De Strooper, who was not involved with the analysis.

On the same website, Dag Aarsland, MD, PhD, of King’s College London, wrote that “while all of these therapies aim to reduce amyloid, they do so through different mechanisms and target different epitopes. These differences may be clinically meaningful, both in terms of effectiveness and safety.”

In comments to MedPage Today, Suzanne Schindler, MD, PhD, of Washington University in St. Louis, pointed out that “because 15 of the 17 trials included in the review were with early treatments that are not used in the clinic, the combined results do not accurately reflect the two treatments that are now approved and clinically used.”

“There is considerable variability within the class of amyloid-targeting treatments and clinicians should evaluate information on the treatments they are actually providing,” she added.

The Cochrane review included 17 clinical trials with 20,342 participants. Four studies evaluated bapineuzumab, four examined gantenerumab, three assessed aducanumab, two each studied solanezumab and bapineuzumab, and one study each tested lecanemab and donanemab.

All studies used placebo as a comparison. Eleven studies lasted 18 months, four ran for 24 months, and two extended beyond 24 months. The review reported the results of the studies at 18 months.

Mean age of participants ranged from 70 to 74 years. Seven studies included only people with mild dementia; one trial enrolled only those with mild cognitive impairment. The others involved mixed populations. The average duration of cognitive impairment ranged from 17 to 52 months.

The external validity of the study results for the wider Alzheimer’s disease population is limited, the researchers noted. “Due to the strict inclusion criteria, estimates of the Alzheimer’s disease population potentially eligible for this treatment range from 5% to 15%,” they wrote.

“Given the relatively short follow‐up in available studies and considering the long disease course of Alzheimer’s disease, more information on the long‐term safety profile of amyloid beta‐targeting monoclonal antibodies is needed,” they added.