Gut Check is a periodic look at health claims made by studies and by newsmakers. We ask: Should we believe this?

The Claim: Drugs that target beta-amyloid, the molecule widely considered the cause of Alzheimer’s disease, make neurons function worse — at least in mice — explaining why anti-amyloid compounds have failed to improve memory or cognition in clinical trials.

The Backstory: For nearly a quarter-century, the leading explanation of Alzheimer’s disease has been that a protein called beta-amyloid (written β-amyloid) is deposited around brain neurons, forming sticky “plaques” that eventually kill cells, destroy synapses, erase memory, and cripple cognition. The amyloid hypothesis has been so dominant — virtually every pharmaceutical and biotech company trying to develop an Alzheimer’s drug is on the amyloid warpath — that scientists pursuing other explanations have warned that “The Church of the Holy Amyloid” has choked off research on competing ideas.

The real tragedy has been the repeated failures of experimental compounds targeting amyloid: They often clear away amyloid but don’t help symptoms. In 2014, for instance, Phase 3 trials of bapineuzumab (from Pfizer and Johnson & Johnson) and of solanezumab (Eli Lilly) both failed to improve cognition in Alzheimer’s patients, continuing a sorry pattern. Although Biogen and Lilly reported somewhat more encouraging results this summer, the results were far from triumphs. On Wall Street, which always finds humor in tragedy, there’s a rule of thumb for a company about to report results from an Alzheimer’s trial: short its stock.

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Second Take: In a new study, scientists injected a form of the Pfizer-J&J anti-amyloid antibody, or a similar one from Novartis, into mice whose brains were riddled with β-amyloid plaques. The Pfizer-J&J compound sopped up amyloid in the mice; Novartis’s had less effect. But the shocker was that both antibodies made neurons become hyperactive, reported Marc Busche of Technical University of Munich and colleagues (including two from Novartis) on Monday in Nature Neuroscience.

“Hyperactive neurons don’t function properly,” Busche said. “And with time, hyperactive neurons go silent. They burn themselves out.” That hyperactivity occurred in both older mice with lots of amyloid plaques and younger ones with little plaque accumulation. “Antibodies targeting amyloid not only didn’t improve brain function,” Busche said, “they made it worse.” One explanation: By attacking plaques, antibodies mobilize amyloid, which is toxic to neurons, making things even worse than when amyloid is bound up in plaques.

STAT’s first call was to John Hardy of University College London, a father of the amyloid hypothesis, expecting he’d tell us not to believe this study. “This is a very, very good group and I think that this paper is almost certainly right,” he said. (Hardy was en route to Silicon Valley to receive a $3 million Breakthrough Prize.) Although he thinks the amyloid hypothesis is still “basically right,” Hardy said, “we don’t understand how amyloid causes neuronal death.” The assumption had been that amyloid itself is toxic to brain cells. But, instead, it might affect, say, the brain’s glial cells (support structures), whose collapse might in turn wreck neurons. Or amyloid might be almost a bystander, with the real culprit the loss of synapses. The new study “should be taken together with all of the past findings that indicated Alzheimer’s cognitive deficits are more likely due to synaptic loss and not to plaques,” said Dr. Daniel Alkon, scientific director of the Rockefeller Neurosciences Institute. The new study, he said, offers another reason “for questioning the utility” of anti-amyloid drugs, “in addition to the universal failure of that therapy” in patients.

The Takeaway: There is growing evidence, from both clinical trials and mouse experiments, that targeting β-amyloid doesn’t stop, let alone reverse, the neuronal apocalypse of Alzheimer’s. If so, the world has spent 25 years and countless billions of dollars pursuing Alzheimer’s drugs that won’t work.

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