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Despite Alzheimer’s Research Fraud Allegations, Amyloid Beta Dx Tests on Solid Footing


NEW YORK – Following a report published last week in Science highlighting potential fraud in a number of influential papers on Alzheimer's disease, scientists in the field and observers outside it have been trying to assess what the development might mean for Alzheimer's research.

In particular, there are concerns that if the research in question is, in fact, fraudulent, it could weaken the evidence for the "amyloid hypothesis" that underpins much of the work done on drugs and diagnostics for the disease.

However, with regard to Alzheimer's diagnostics, at least, there's no reason to think the revelations detailed in the Science article have any implications for tests currently used or under development for diagnosing the condition, said Jeffrey Cummings, a neurologist and Alzheimer's researcher at the University of Nevada, Las Vegas.

The Science report described alleged data fabrication in papers authored by Sylvain Lesné, a neuroscientist at the University of Minnesota. Among the papers called into question was a 2006 study in Nature, in which Lesné and his colleagues reported evidence of a form of the protein amyloid beta called Aβ*56 that appeared to cause dementia in rats.

The paper was significant in that it bolstered the notion — long influential in Alzheimer's research — that the amyloid plaques observed on the brains of Alzheimer's patients are key drivers of the disease and potential therapeutic targets. If the paper and other publications by Lesné on Aβ*56 are proved to be fraudulent, it would undermine a notable piece of evidence that has been used to make the case of the amyloid hypothesis — a hypothesis that has come under increasing pressure in recent years as numerous anti-amyloid Alzheimer's drugs have failed.

That's of little relevance to the diagnostics space, though, Cummings suggested. Aβ molecules — most commonly Aβ-42 and Aβ-40 — are commonly measured in cerebrospinal fluid (CSF) and, more recently, in plasma, to help determine whether a patient has the amyloid brain plaques characteristic of Alzheimer's, and while amyloid's usefulness as a therapeutic target may be in question, the presence of amyloid plaques is an essential characteristic of the disease.

"The use of amyloid plaques diagnostically is very firm," Cummings said. "They were among the first observations that [Alois] Alzheimer made in 1906. We have studied those plaques for 125 years, and they are part of all diagnostic criteria."

Cummings said that he regularly uses Athena Diagnostics' ADMark laboratory-developed test for Alzheimer's evaluation, which measures markers including Aβ-42, total tau protein, and phosphorylated tau (p-tau) in CSF.

In May, Fujirebio Diagnostics received US Food and Drug Administration classification for its Lumipulse G β-Amyloid Ratio (1-42/1-40) test, making it the first in vitro diagnostic available in the US for detection of the amyloid plaques associated with Alzheimer's disease.

Blood-based tests for Aβ-42, Aβ-40, and other Alzheimer's markers are also an area of major interest as blood draws are less invasive and more convenient than the spinal taps required to obtain CSF samples.

Quanterix has developed research-use-only assays for blood-based measurements of Aβ-42 and several phosphorylated forms of tau.

St. Louis-based Alzheimer's testing firm C2N Diagnostics offers a blood-based test, PrecivityAD, for assessing brain amyloid status. The company launched the assay as an LDT in October 2021.

Italian diagnostics firm Diadem is also developing blood-based tests for Alzheimer's. In January, it received FDA breakthrough device designation for its AlzoSure Predict test.

C2N CEO Joel Braunstein echoed Cummings comments in asserting that the questions about the Aβ*56 research have "no impact" on the validity of Aβ-based diagnostics for the disease.

"At the end of the day, we know that amyloid plaques are a pathological hallmark of Alzheimer's disease," he said. "It is observed in all patients with Alzheimer's disease. So I don't think there is any dispute as to whether one finds it pathologically. It's another question to say, well, is it causative? That's a totally different question."