Possible Fraud Suggests a Setback in Alzheimer’s Research

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Pharmaceutical companies are exploring drugs to treat or prevent Alzheimer’s disease with increasing urgency. About 6.5 million Americans who have reached the age of 65 are living with Alzheimer’s. That number is expected to double by 2050.

Research continues to expand knowledge of Alzheimer’s, potentially opening the door to effective treatment. Unfortunately, as the National Institute on Aging reports, researchers “don’t yet fully understand what causes Alzheimer’s disease in most people.” 

Unfortunately, drugs that appear promising in animal tests are unsuccessful in drug trials. Genentech spent a decade developing crenezumab, a medication that was intended to slow or prevent Alzheimer’s in patients who carried a specific gene that is thought to cause an early onset of the disease. Recent drug trials failed to establish that the drug is effective.

Crenezumab is not unique in that regard. About 99% of Alzheimer’s drugs fail clinical trials. 

A drug that could cure or prevent Alzheimer’s, slow its progress, or diminish its symptoms would give hope to millions. Such medications would also be enormously profitable. At the beginning of 2022, 143 Alzheimer’s drugs were being tested in clinical trials. To date, the Food and Drug Administration has approved a half dozen drugs that target Alzheimer’s.

The Aduhelm Controversy

One of the drugs approved by the FDA is Aduhelm. Aduhelm is the trade name used by Biogen to market the generic drug aducanumab. The FDA approved Aduhelm in an accelerated process that allows promising drugs to be prescribed for patients with serious diseases despite uncertainty about the drug’s effectiveness. Retaining approval is conditioned upon verification that the drug has a clinical benefit.

Aduhelm reduces amyloid beta plaque. Amyloid plaques are formed when misfolded proteins called beta amyloids collect in the spaces between nerve cells. One beta amyloid is “stickier” than others and is more likely to join with other amyloids to form plaque. 

Since amyloid plaques are found in the brains of Alzheimer’s patients, researchers have theorized that amyloid plaques cause Alzheimer’s when they develop in areas of the brain that are responsible for memory and other cognitive functions. Neuroscience professor Sylvain Lesné is the lead author of an influential paper published in 2006 that found a causal link between amyloid plaques and Alzheimer’s. However, researchers have not identified how amyloid plaques damage nerve cells. 

Potential Fraud in the Lesné Study

  The Lesné study was based on mice that had been genetically altered to create beta amyloids. The mice were developed by neuroscientist Karen Ashe. The mice appeared to suffer from symptoms associated with Alzheimer’s.

A recent review of the brain scan images published with Lesné’s paper raised questions about Ashe’s mice. The images purport to show a relationship between memory issues and the presence of beta amyloid. Neuroscientist Matthew Schrag determined that the images appear to have been altered. Schrag notified the National Institute of Health, a federal agency that funds Alzheimer’s research. When he could not interest the NIH in his findings, he shared his concerns with colleagues.

The journal Science hired an image analyst to conduct an independent review of the images. Science then shared the analyst’s findings with leading neuroscience researchers. The experts agreed that the images had been altered and suggested that the alterations were intended to change the evidence to conform with the results that Lesné and Ashe wanted.

While Schrag was careful to avoid labeling the images as fraudulent, the scientists who reviewed the images for Science have been less circumspect. One referred to the analyst’s findings as proof of “shockingly blatant” image tampering. Science referred to the results as evidence of fabricated data.

Back to the Drawing Board

Most Alzheimer’s drug research has been premised on the presumed relationship between amyloid plaques and the disease. If amyloid plaques are not responsible for the development of Alzheimer’s, tens of billions of dollars spent on drug research for more than a decade has been misdirected.

Aduhelm may have failed clinical trials because it treats a condition that is not responsible for Alzheimer’s. Aduhelm is a very expensive drug, although Biogen reduced the price at the end of 2021. Still, Medicare officials pointed to the high price of Aduhelm to justify a 14.5% increase in the Part B premium. Medicare’s subsequent decision to cover the drug for only a limited number of beneficiaries will likely result in a premium reduction in 2023.

Alzheimer’s researchers are shifting their focus from amyloid plaque buildup. While plaques may play a role in Alzheimer’s, researchers now suspect that attacking plaque alone is not an effective treatment. Multiple factors may contribute to Alzheimer’s, making drug development or other treatment particularly challenging. Drug therapy might not even be the best approach. Some researchers suggest that increasing exercise may delay cognitive decline in Alzheimer’s patients. Unfortunately, scientists may be years or decades away from understanding the disease well enough to develop effective treatments.

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