The drugs do exactly what they were designed to do. They clear amyloid plaques from the brain — you can see it on the scans. And then, by every measure that matters to a patient, nothing happens.

A sweeping Cochrane review published Thursday analyzed 17 clinical trials involving more than 20,000 people with mild cognitive impairment or early Alzheimer’s disease. Seven different anti-amyloid drugs were tested. The conclusion: the drugs’ effects on cognitive decline and dementia severity were “absent or trivial,” falling well below the threshold for anything a patient or caregiver would notice.

This isn’t a story about a drug that failed. It’s a story about a theory that has directed Alzheimer’s research for decades — and the growing body of evidence that it may have been the wrong one.

Billions on a Single Bet

The amyloid hypothesis dates to the 1980s, when researchers identified amyloid-β protein accumulating in the plaques found in Alzheimer’s patients’ brains. The logic was intuitive: remove the plaques, slow the disease. Pharmaceutical companies poured billions into developing drugs to do exactly that.

Two of those drugs — lecanemab (sold as Leqembi by Eisai and Biogen) and donanemab (sold as Kisunla by Eli Lilly) — were approved by regulators in the US and EU after trials showed statistically significant slowing of cognitive decline. The emphasis on “statistically” is doing a lot of work there. The actual benefit amounted to roughly a four-to-six-month delay in decline over 18 months — a difference so small that critics questioned whether patients could perceive it.

The Cochrane review, widely regarded as the gold standard for evaluating clinical evidence, looked at the full picture. It found that while anti-amyloid drugs reliably clear amyloid from the brain, this biological achievement does not translate into meaningful clinical improvement.

“Unfortunately, the evidence suggests that these drugs make no meaningful difference to patients,” said Francesco Nonino, the review’s lead author and a neurologist at the IRCCS Institute of Neurological Sciences of Bologna. “While early trials showed results that were statistically significant, it is important to distinguish between this and clinical relevance.”

The drugs also carry real risks. Brain swelling and bleeding — detected on scans in a meaningful number of participants — were more common in treatment groups than in placebo groups. Long-term consequences remain unclear.

A Field Divided

The review has sparked sharp disagreement among researchers, and the fault lines are revealing.

Critics argue that pooling results from seven different drugs — some older compounds known to have failed alongside the newer approved treatments — diluted the signal from lecanemab and donanemab. John Hardy, the British biologist who first developed the amyloid hypothesis in the 1990s, was blunt: “This is a silly paper which should not have been published.” Hardy has consulted for Eli Lilly, Biogen, and Eisai.

Bart De Strooper, a group leader at the UK Dementia Research Institute at UCL, argued that the review “blurs” the evidence by mixing failed drugs with those that have “changed clinical practice.” The arithmetic of averaging positive and negative results together, he said, inevitably produces a muted picture.

The review’s authors stand by their methodology. Co-author Edo Richard, professor of neurology at Radboud University Medical Centre, noted that while the drugs may differ in specifics, they all share the same target: amyloid-β proteins. If the central claim of the amyloid hypothesis were correct, the signal should emerge across the class. It does not.

Robert Howard, professor of old age psychiatry at UCL, pointed to emerging data from extended trials. When patients who started treatment early were compared with those who began 18 months later, there was no meaningful difference after three years. “This suggests that the drugs do not modify disease course,” Howard said, “and appear much more likely to be acting as a symptom-improving treatment.”

Follow the Money

The financial stakes are enormous. Donanemab costs approximately $32,000 per year in the US. In the UK, private providers quote £87,507 for an 18-month treatment package including monitoring. NICE, the body that evaluates cost-effectiveness for England’s NHS, initially refused to cover either drug. It is now reassessing that decision under new cost-effectiveness thresholds agreed as part of the US-UK trade deal.

The pharmaceutical companies behind these drugs have a clear interest in the review being dismissed as methodologically flawed. Alzheimer’s charities and advocacy groups are caught between wanting to offer hope and confronting evidence that the hope may be misplaced. As Howard put it: “It’s very difficult being the person who says these things, but I don’t think it’s fair on patients to have expectations raised.”

What Comes Next

The review’s authors recommend that future research shift away from amyloid removal and toward other mechanisms — tau proteins, neuroinflammation, metabolic pathways. Several such studies are already underway. Australian neuroscientist Bryce Vissel, who was not involved in the review, summarized the finding carefully: the current generation of anti-amyloid drugs is “not delivering the promise that has surrounded it,” but that does not rule out future therapies targeting amyloid differently or at earlier stages of disease.

The amyloid hypothesis has directed the overwhelming majority of Alzheimer’s research funding for a generation. This review does not kill it. But it raises a question the field can no longer dodge: when the plaques disappear and the patient stays the same, what exactly are we treating?

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