Growing numbers of dementia cases are one of the biggest challenges for public health systems, but we still do not have a cure for this condition. Controversies have blighted Alzheimer’s science over the past year, meaning that access to effective treatments looks further off than ever. Do we need to improve our understanding of Alzheimer’s disease before we can cure, or even prevent it?
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
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
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 hving been approached by the lawyers of two prominent neuroscientists.
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
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.
She pointed out that failing to stratify potentially different groups of patients could be affecting results. She told MNT in an interview:
“With this Eli Lilly trial that developed this new Alzheimer’s drug [Donanemab], the exclusion criteria in the trial were for Alzheimer’s patients that had been taking acetylcholine esterase inhibitors, but what this tells us [is] that the patient population that they’re selecting for did not find relief with acetylcholine esterase inhibitors, which are commonly associated with improved cognition and improved function. So already, you know, within the trial design, we’re looking at a population that is acetylcholine [and] esterase treatment-resistant.”
“And that’s really interesting, because there are probably some subtypes that respond to acetylcholine esterase inhibitors treatment, and, and they may not be the same subtypes that respond to [Eli] Lilly’s experimental donanemab,” she added.
Both also pointed out that trialing the drugs on patients who were already symptomatic meant that the impact of the drugs was potentially limited as damage to the brain had already occurred.
Dr. Ramit Ravona-Springer, geriatric psychiatrist, and director of the Psychogeriatric Memory Clinic at Sheba Medical Center, Israel agreed with this.
She told MNT: “Another reason may be that, until recently, most of the clinical trials were carried out in people that already clinically expressed dementia. That is, they were in mild to moderate Alzheimer’s disease patients. And that may be that it’s too late, when the brain is already overwhelmed with pathology.”
“And so maybe we should even go earlier than the recent trials. [These] recent trials were conducted in patients with mild cognitive impairment — that is [the] stage preceding dementia — and in very mild Alzheimer’s disease patients, but maybe if we knew who was the right candidate, and could intervene even earlier, then we would see even greater effects,” she added.
In order to do this researchers needed to find ways to detect Alzheimer’s disease earlier, Dr. Ravona-Springer said:
“So the currently available screening tools are based on either invasive procedures — for example, lumbar puncture — or very costly radiological assessments — for example, amyloid PET or other assessments— and they’re very costly and not necessarily accessible to everyone […] I hope that in the near future, blood biomarkers will be more available. They’re less costly, of course.”
These could even be used for wider-scale population screening if they were cheap enough, she said.
It was also important to better define the subcategories of Alzheimer’s and to determine the role of genetics within this, explained Intson.
It is possible, she suggested, that some people with a particular genetic variant that pre-disposed them to Alzheimer’s could experience accumulations of a particular isoform of beta-amyloid, that some drugs would target and others might not. This would mean different groups of patients would have different outcomes.
“And not to plug Eli Lilly again, but [the company] seems to be recognizing this with other dementias. So they’re developing a gene therapy for specific genetic subtypes of Parkinson’s disease,” Dr. Ravona-Springer noted.
“And we’re going to start to see this happening across the dementias, as we learn more and more about these genetic subtypes of dementia. But that’s a great example of how medicine is, is changing some of the, you know, blockbuster drugs and hopes to cure all patients, to more precision medicine and genetic subtypes of diseases,” she added.
Alzheimer’s could therefore be treated not by targeting beta-amyloid build-up, but instead by targeting genes that express abnormally in people with the condition.
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.
Prof. Albala said:
“A better understanding of the disease is very important so that drug treatments can be targeted against crucial biological mechanisms that actually cause Alzheimer’s disease. Long-term studies such as ADNI [Alzheimer’s Disease Neuroimaging Initiative] have followed people who have a very early form of the disease over many years using both biological — e.g., brain imaging, CSF [cerebrospinal fluid] and blood analysis, pathology, etc. — and cognitive-memory testing to better understand how Alzheimer’s disease progresses.”
“Diagnosing and treating early, long before any behavioral signs or symptoms are evident is what we must make our eventual goal,” he pointed out.
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