A verdict from a top global evidence-based medicine institution has once again thrust the core theories of Alzheimer's disease, which have dominated the field for over two decades, into the eye of the storm.

In the history of Alzheimer's disease (AD) drug development, the β-amyloid (Aβ) hypothesis has long been the undisputed "absolute main thread." Global pharmaceutical companies have invested billions of dollars in clearing Aβ plaques from the brain, launching numerous blockbuster drugs and even influencing FDA approval rules. However, a new report from Cochrane on April 16th presented a revolutionary conclusion:

Antibody drugs targeting Aβ offer almost no clinically meaningful benefit to patients and may increase the risk of brain hemorrhage and swelling.

Edo Richard, professor of neurology at Radboud University Medical Center and senior author of the paper, even suggested that researchers should abandon the amyloid hypothesis and turn to other targets.

Ironically, this report, intended to put an end to decades of controversy, not only failed to quell the debate but also instantly ignited fierce confrontation across the industry. Pharmaceutical companies, clinical experts, and patient organizations quickly retaliated, arguing that Cochrane's conclusions were too general, its methodology flawed, and that they seriously misled the assessment of the true value of Aβ drugs.

From its initial acclaim to repeated questioning, from its successive approvals to its current controversies, the Aβ path for Alzheimer's disease is experiencing an unprecedented crisis of trust.

Is the Aβ hypothesis a beacon of hope for a cure, or a dead end proven to be impassable? This debate will not only determine the fate of several drugs, but may also rewrite the course of global AD research and development over the next decade.

01
Complete rejection

As a globally recognized top evidence-based medicine institution, Cochrane's systematic reviews are generally regarded as the "gold standard" for evidence-based clinical practice and health decision-making. This time, it focused on the most core area in the entire Alzheimer's disease field—Aβ monoclonal antibodies—and gave a conclusion that it completely rejected them.

To ensure the objectivity of the conclusions, the research team reviewed 17 randomized controlled clinical trials covering seven different Aβ antibody drugs, including over 20,000 patients with mild cognitive impairment or mild dementia. These included approved drugs such as lencanezumab (Leqembi) and kassuzumab (Kisunla), as well as discontinued commercialization drugs like aducarumab (Aduhelm), and several investigational drugs that failed in clinical trials. All data came from high-quality placebo-controlled trials.

Following a rigorous meta-analysis, Cochrane's report concluded very simply: after an 18-month intervention, Aβ monoclonal antibody had negligible effects on patients' cognitive function, daily living abilities, and the severity of dementia, with effects far below the clinical threshold.

Francesco Nonino, a neurologist and epidemiologist at the IRCCS Neuroscience Institute in Bologna, Italy, stated that evidence suggests these drugs have no meaningful effect on patients. “There is now compelling evidence to conclude that there is no clinically meaningful effect. While early trials showed statistically significant results, it is important to distinguish this from clinical relevance. Statistically significant results found in trials do not typically translate into meaningful clinical differences for patients.”

In addition to the lack of clinically meaningful effects, the review found that Aβ monoclonal antibody drugs may increase the risk of brain swelling and hemorrhage in patients.

In other words, even if the medication successfully clears amyloid plaques from the patient's brain, it doesn't translate into tangible benefits for the patient. There is no significant improvement in cognition, no marked improvement in daily living abilities, no meaningful slowing of disease progression, and it may even cause side effects.

Based on this, Edo Richard directly suggested in his report that future research on the treatment of Alzheimer's disease should abandon the Aβ hypothesis and turn to other mechanisms of action.

This clearly challenges the central position of the Aβ hypothesis.

Since its formal proposal in 1991, the theory that "abnormal Aβ plaque deposition leads to Alzheimer's disease" has long held a dominant position, almost defining the research and development direction of the entire industry. Over the past 20 years, major global pharmaceutical companies have invested heavily in the Aβ hypothesis, with thousands of studies conducted around it, involving tens of billions of dollars in funding.

Despite repeated setbacks in clinical trials, the Aβ hypothesis remained strong thanks to its extensive research and industrial investment, ultimately leading to the FDA approval of three drugs.

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