Despite the fact that the prevalence of Alzheimer’s disease is growing, with 6 million cases in the United States alone, expected to rise to 13 million by 2050, it is still unclear to scientists how the disease manifests to cause the symptoms that it does.
Current thinking is based on the idea that certain forms of a protein called beta-amyloid clump together in between neurons in the brain in a way that impairs memory and causes the symptoms of Alzheimer’s disease.
This model was first confirmed in 2006 with a paper published in NatureTrusted Source, which used a mouse model to demonstrate the existence of beta-amyloid clumps in the brain, caused by a particular subtype of the protein.
This has remained the prevailing model of how Alzheimer’s disease develops, despite a limited understanding of the underlying causes, both genetic and environmental.
Then, an investigation published in Science, in July 2022 alleged that some images had been manipulated in the paper published in 2006.
The original paper is now currently the focus of an investigation by the editorial team at Nature, which promises an editorial response to the allegations in due course. To date, the paper has been cited in over 2,200Trusted Source scientific papers and accessed more than 50,000 times.
No matter what the outcome of the investigation, there is no doubt the paper was a highly influential one in Alzheimer’s science and has impacted future research into treatments.
This was not the only controversy to hit Alzheimer’s science last year, however. Dr. Matthew Schrag, a neuroscientist and physician at Vanderbilt University, who raised the alarm over the images in the paper, did so after having been approached by the lawyers of two prominent neuroscientists.
AllegedlyTrusted Source, they could have profited financially if a Texas-based biotech company — Cassava Sciences — lost money if it was unsuccessful in its development of an Alzheimer’s drug, Simufilam.
The drug is currently in trials, and the company claims it improves cognition by repairing a protein that can block brain deposits of beta-amyloid.
On the basis of Dr. Schrag’s investigation into the images, it was requested that trials be halted through a petition to the Food and Drug Administration (FDA). The company also came under investigation from the U.S. Justice Department, Reuters revealed in July 2022.
Though the FDA did not halt the trial, Reuters reported that the company’s shares dropped 30% following the launch of the criminal investigation. In January 2023, Cassava Sciences posted mid-trial results without figures for significance, which were mixed. It is expected they will publish further results over the coming 2 years.
Schrag had also been outspoken about the FDA’s accelerated approval of the Alzheimer’s drug Aduhelm in June 2021, which claims to improve cognition by clearing beta-amyloid.
Among the various controversies and the toing and froing between lawyers, biotech companies, the FDA, and even the U.S. Justice Department, there is one group that is no better off: Alzheimer’s patients.
This point was driven further home when in January 2023 the FDA did not approve pharmaceutical company Eli Lilly’s Alzheimer’s drug DonanemabTrusted Source, as expected, as the clinical trial conducted by the company had shown more data were needed to determine efficacy.
This raised the question: What next for finding a treatment for a debilitating disease that is only set to increase in prevalence in coming years?
First, it was important to reflect on the designs of the trials for Alzheimer’s treatments, said Prof. Bruce Albala, director of the Center for Clinical Research responsible for the oversight and implementation of clinical trials at UC Irvine, CA, in an email to Medical News Today.
“One of the biggest challenges to advancing the development of treatments for Alzheimer’s disease has been in identifying, recruiting, and retaining the appropriate patients”, he told us.
“What is more the length of the studies is fairly long, lasting years. This is because any treatment that is intended to slow the progression of the disease is dependent on the amount of time for non-treated or usual treatment control group to show worsening in their memory and daily activities compared to those receiving the investigational medication”, Prof. Albala explained.
Differences between the way the disease manifests in different patients also complicates matters, he said: “In addition, because worsening for those with non-inherited, later in life Alzheimer’s disease is relatively slow, it requires large numbers of participants, in the upper hundreds, to show a significant difference between those on the experimental drug and those who do not receive it (i.e., controls)”.
Kath Intson, CEO of Varient — a precision medicine startup — and a PhD candidate at the University of Toronto in Canada agreed that the designs of the trials needed to be analyzed when considering why they were not delivering expected results.
The opportunities for genomics to elucidate treatment options further do not stop there, as sequencing the genomes of people in the trials could help to determine if people with a particular genetic variant could benefit more from one traditional beta-amyloid-targeting drug than others, similar to current research into the value of applying precision medicine approaches to cancer.
One major problem with treating many neurological conditions is that it is difficult to design drugs that cross the blood-brain barrier.
This means higher doses of drugs are needed to get a relatively small amount to the site of action, which can lead to greater side effects.
A paper published in November 2022 in Proceedings of the National Academy of Sciences suggested designing molecules that could cross this could reduce the impact of side effects on patients as lower doses would be necessary to have an effect.
While the beta-amyloid model remains the dominant theory in Alzheimer’s science, our current understanding of the mechanisms behind the disease is repeatedly proving too blunt to base the development of targeted therapies for this group of patients on.
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