DEGENERATION STRUGGLES OP-ED
Despite promising signs, the search for Alzheimer’s treatment is ongoing and complex
The drug company Eli Lilly made world headlines a month ago when it was reported that the drug Donanemab slowed the progression of Alzheimer’s disease by up to 35%. But it is important to interpret these findings cautiously.
“Dementia” is an umbrella term used to describe Major Neurocognitive Disorder with many causes. Alzheimer’s disease is a progressive degenerative brain condition that is responsible for 60-80% of all dementia cases in older persons.
Depending on the stage of the disease, the pathology can be characterised by factors that eventually progress to hinder performance in daily activities such as memory loss, poor judgement, depression and anxiety, disorientation, impaired communication and movement.
The progressive decline seen in patients is thought to be due to two key hallmarks. Both involve proteins which are normally found in human brains. When protein production, distribution and removal go wrong, the disease state may arise.
Within the medical research world, supporters of the theories of the two-protein pathologies are colloquially referred to as the “Baptists” and the “Taoists”. The “Baptists” believe that beta-amyloid protein forms clumps or plaque in brain tissue, impairing normal nerve functioning. The “Taoists” hold that tau protein, found inside nerve cells, loses its structure, resulting in the formation of non-functional tangles.
With advancing age, both problems are not uncommonly found even in people with typical cognitive function. However, there appears to be a complex relationship between amyloid plaques and tau tangles that may lead to the clinical disease known since 1911 as Alzheimer’s disease.
Amyloid and tau have both been the focus of many clinical trials as prime targets for disease-modifying treatments. The main approach to amyloid plaque clearance in these trials has been through the administration of monoclonal antibodies; these are clones of your body’s antibodies that are made in a laboratory, meant to stimulate your immune system.
These antibodies are injected into the human study participants at regular intervals. They produce an immune response which labels the amyloid plaque as abnormal. The body then clears the amyloid out.
This process is, however, not without side effects. Previous antibody trials have met with a mixture of celebration (resulting in rushed US Food and Drug Administration, FDA, approvals), and scepticism (leading to FDA member resignation due to the rushing of approvals).
In a trial led by Dr Mark Mintun from Eli Lilly, a pharmaceutical company based in the United States, in partnership with the Departments of Neurology, of Radiology and Imaging Sciences, and of Medical and Molecular Genetics and the Indiana Alzheimer Disease Center, Indiana University School of Medicine published in the New England Journal of Medicine in 2021, one such monoclonal antibody – Donanemab – was investigated.
Donanemab is an antibody that was developed from a mouse, and modified for use in humans. The discovery of this drug came with a lot of excitement as previous treatments have only been able to prevent the collection of new plaques, as opposed to clearing out old ones.
The Eli Lilly-sponsored trial took place in the US and Canada. Most of the current trials have taken place in high-income countries, and there is a recognition that cohorts from other settings are needed.
The group recruited 257 participants between the ages of 60 and 85. They were randomly assigned to either the intervention group (receiving Donanemab) or the placebo, a biologically inactive substance. While the trial generated excitement, it is important to approach the results with caution due to some limitations and nuanced findings.
In this particular study, researchers investigated whether Donanemab improved cognitive performance and daily functioning in people with Alzheimer’s. They used a widely accepted rating scale called the Integrated Alzheimer’s Disease Rating Scale (iADRS) and measured participants’ score at the start of the study and then again just over a year later.
Participants treated with Donanemab and placebo both scored 106 on the iADRS at the study’s start. It is important that all participants’ original scores or “baseline measures” are somewhat equal before starting the trial. This means that the researchers can assume that any change thereafter is due to the intervention.
One expects that people with dementia will decline in both cognitive performance and activities of daily living over time. Therefore, a lower rate of decline in the treatment group would be a favourable outcome. Considering this, the investigators did not set out to cure the participants of Alzheimer’s disease, but to slow down its progression by half.
After 76 weeks in the trial, participants treated with Donanemab declined by 6.86 points, while those in the placebo group declined by 10.06 points. In absolute terms, this is a difference of about 3.2 points, and in percentage terms, about 30% less decline.
While this was a statistically significant difference in the rate of decline, the investigators note that this did not achieve the study’s goal to slow disease progression by half. Additionally, they noted that the clinical significance of this small improvement remains to be established.
The potentially small benefit of the treatment was contrasted with the development of amyloid-related brain imaging abnormalities in the intervention group: a quarter of whom developed issues, with 22% of those being symptomatic.
Furthermore, although there was a significant decrease in amyloid plaque levels, this reduction did not translate into improved clinical symptoms related to mental decline or cognitive difficulties.
The study also did not find a significant difference in brain tau load between the intervention and control groups.
Significantly more research needed
These findings raise questions about the direct relationship between amyloid reduction and overall disease progression in Alzheimer’s therapy. In other words, we still don’t really know whether abnormal amyloid plaques are the cause or the effect of Alzheimer’s disease.
Two limitations were noted by the authors, namely a relatively small sample size and a lack of representation within the sample. The majority of participants were American and white; eight participants were black, three Asian and another three identified as other.
This further brings into question how applicable the findings are considering that the sample does not match that of the South African population, and ethnic differences have been reported to play a role in Alzheimer’s disease progression.
In summary, while the study on Donanemab’s efficacy in Alzheimer’s disease treatment provided some promising results, it is crucial to interpret these findings cautiously.
Further research is needed to establish the clinical significance, explore potential long-term effects, and determine whether these findings can be applied to various populations. Ultimately, the search for effective disease-modifying treatments for Alzheimer’s disease continues to be an ongoing and complex endeavour. DM
Morgan Watson holds a BSc Honours in Psychology, is currently completing her MPhil in Behavioural Medicine and is a Content Developer in the HIV Mental Health Research Unit, Department of Psychiatry and Mental Health, University of Cape Town.
Jessica Henn holds a BSocSc Honours in Psychology, is currently completing her MA in Psychological Research and is a clinical intern in the HIV Mental Health Research Unit, Department of Psychiatry and Mental Health, University of Cape Town.
Professor John Joska is Head of Clinical Services (psychiatry) at Groote Schuur Hospital and Director of the University of Cape Town HIV Mental Health Research Unit.