Science & technology | Neuroscience

Critical research on the causes of Alzheimer’s may have been falsified

Scientists could have been led down blind alleys for more than a decade

Illustration of amyloid plaques in Alzheimer's disease.

Alzheimer’s disease is by far the most common cause of dementia, a progressive decline in brain function most common among the elderly. In America more than 6m people live with the disease, at a cost of over $300bn a year. Despite such vast sums, no single cause for Alzheimer’s has yet been identified.

With so much at stake, it is striking that a landmark paper in the field of Alzheimer’s research has been accused of containing fabricated data, as Science reports this week. In 2006 Nature published a study titled “A specific amyloid-β protein assembly in the brain impairs memory”. It described the work of a team including Sylvain Lesné, a neuroscientist at the University of Minnesota medical school, which backed a theoretical explanation of the origins of the disease known as the “amyloid hypothesis”.

According to this hypothesis, the clumping together in the brain of amyloid-beta peptides, long molecules consisting of chains of amino acids, can trigger the sort of neurological breakdown associated with Alzheimer’s. Though the exact causal connections remain unclear, patients with the disease are almost always found to have plaques in the brain that are formed by amyloid proteins.

The paper claimed that rats injected with one such peptide, called Aβ*56, displayed a dramatic decline in cognitive ability. This looked like a rare oasis of causation in a desert of correlation, and so the publication reignited interest in the amyloid hypothesis. Sixteen years and thousands of citations later, Science estimates that the American National Institutes of Health has devoted $1.6bn of research funding to amyloid research projects this year. This amounts to nearly half of the federal funds devoted to Alzheimer’s as a whole.

All the more reason, then, to worry. Matthew Schrag, a neurologist at Vanderbilt University, raised the alarm when he analysed images from the 2006 paper and identified signs that suggested that experimental results had been fabricated. Most egregious were images of blot tests—in which protein molecules found in a sample are separated to appear as blots on a membrane—where certain identical blots inexplicably appeared in multiple places.

Dr Lesné did not respond to a request for comment from Science, and a spokesperson for the University of Minnesota told the magazine that it was reviewing complaints about the work.

Whether this potential evidence of fabrication is enough to topple the primacy of the amyloid hypothesis remains to be seen. Sara Imarisio, head of research at Alzheimer’s Research uk, a charity, called the allegations “concerning” but stressed that Aβ*56 is only one of many amyloids researchers were investigating. “These allegations do not compromise the vast majority of knowledge built up during decades of research into the role of this protein in the disease,” she said.

Georg Meisl, an Alzheimer’s researcher at the University of Cambridge, agrees that the hypothesis is built on sturdier foundations than Dr Lesné’s paper. All the same, he says, “we should appreciate the complexity of the problem and that many factors, such as inflammation, may play together. The field is increasingly moving toward such more nuanced models of the disease.”

The amyloid hypothesis has been accused of looming too large before. In June 2021 the American Food and Drug Administration (fda) approved an Alzheimer’s drug called Aduhelm produced by pharmaceutical company Biogen, on the basis of evidence that it reduced amyloid in the brain. This decision was widely criticised, not least by the fda’s own advisory committee for nervous system therapies, ten of whose 11 members voted against approving the drug and three of whom subsequently resigned in protest. (The fda subsequently asked Biogen to conduct a clinical trial of Aduhelm to bolster the evidence for its efficacy if it wanted to retain the drug’s approval.)

Researchers backing other theoretical horses may be keen to seize on this moment of instability for the amyloid hypothesis. One alternative avenue of investigation concerns tau proteins, which are also found to build up in the brains of Alzheimer’s patients. Drugs designed to target tau are a comparatively recent development, with major trials now in progress.

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