The foundation of Alzheimer’s disease research
To alter any disease course in a targeted way, you first need to understand the underlying mechanism at the molecular level and how this leads to symptoms in patients. Fundamental research on Alzheimer’s disease (AD) and advancements in genetics have partly unraveled this intricate web of factors leading to neurodegeneration. The identification of genetic variations predisposing people to AD and related dementias have yielded tremendous insight into the mechanisms leading to neurodegeneration. In particular, the identification of mutations in genes that facilitate the development of the pathological hallmarks of this serious disease: amyloid beta plaques and neurofibrillary tau tangles. “In the last 20 or 30 years, our understanding on what’s actually going wrong in Alzheimer’s diseased neurons has substantially progressed,” says Gerard Griffioen, CSO at reMYND, a biotech company developing treatments for neurodegenerative disease including Alzheimer’s.
A starting point for drug discovery
These findings marked the beginning of disease-modifying drug research for AD. One route to slowing disease progression is through targeting amyloid beta plaques with antibody therapies. With some current antibody therapies – Lecanemab and the recent FDA approved Donanemab – disease progression can be slowed down by approximately 27% and 35% respectively. In other words, neuronal decline over the course of three years could be prolonged to four years. Although this is a clear therapeutic effect, it is modest, and there are no observable symptomatic improvements. “This therapy targets the amyloid beta pathology, which is one pathophysiological element of many others . So, it’s not surprising that the effect is limited,” highlights Griffioen. Furthermore, there are serious side effects to be considered. Swelling and bleedings in the brain are associated with Lecanemab, leading to its disapproval by EMA the 25th of July. “However, this is the first time a treatment shows that it is possible to modify AD,” emphasizes Griffioen. “This is great news, it’s the first sign of hope for patients. Now, we have to build on these results to make potential new therapeutics better, safer and more affordable.” Current research also indicates that many other cellular changes, including mitochondrial dysfunction, neural inflammation, and aberrant calcium signaling, are drivers of neurodegeneration, opening new avenues for AD drug discovery.
“In the last 20 or 30 years, our understanding on what’s actually going wrong in Alzheimer’s diseased neurons has substantially progressed,” – Gerard Griffioen, CSO at reMYND
The hurdles of Alzheimer’s drug research
However, these avenues come with their own challenges. First, the right target must be identified and later, the right modality needs to be developed to tackle it. Before discovery of the current anti-amyloid beta therapies, researchers tried to inhibit secretases involved in amyloid beta production. This resulted in undesirable side effects due to the role of the secretase enzyme in numerous other cellular functions. “This indicates a very important challenge: finding the right way to achieve disease modification – not only from an effectivity point of view but also from a safety perspective,” emphasizes Griffioen.
Secondly, because AD is a complex and heterogenous disease, it is difficult to set up clinical trials. “Every patient has a unique constellation of risk factors, resulting in patient-specific onset and progression of the disease,” explains Griffioen. Risk factors include increasing age, genetic predispositions, head injuries, high blood pressure, diabetes, and more. This plethora of variables leads to a very heterogenous population and any clinical trial thus requires many patients to accommodate that variation. Furthermore, when studying disease-modifying therapies, it takes a long time to see the effect of the treatment compared to the placebo. Consequently, clinical trials for AD are generally long and very expensive. Fortunately, a lot of knowledge has already been gained from the anti-amyloid beta trials. “The development of amyloid beta-lowering therapies has been highly instructive for the field,” confirms Griffioen.
Discovering new frontiers in the Alzheimer’s drug landscape
These challenges don’t stop researchers from exploring new frontiers. At reMYND, Griffioen’s research team developed a compound able to normalize calcium homeostasis in Alzheimer’s-diseased cells. “It’s important to identify a common denominator as to how AD risk factors lead to neurodegeneration. We believe impaired calcium homeostasis is such a process,” states Griffioen. Calcium is known to regulate synaptic function, neuronal integrity, tau phosphorylation, and the processing of proteins leading to amyloid beta plaques, all important mechanisms gone awry in AD.
By screening compounds for their capacity to counter tau neurotoxicity, researchers at reMYND found effective compounds that bind to septin filaments, proteins controlling the activity of store-operated calcium channels and thus the perfect starting point for further drug development. “Calcium dyshomeostasis is a central element in the Alzheimer’s disease cascade. If you are able to restore this it in a safe way, the effects will be notable, with fast symptomatic benefits as well as disease modification,” explains Griffioen. Administration of their optimized compound to tau- or amyloid-beta diseased mouse models restored normal neuronal function and slowed down disease progression, further supporting their hypothesis.
“Every patient has a unique constellation of risk factors, resulting in patient-specific onset and progression of the disease,” – Gerard Griffioen, CSO at reMYND
Bright minds shaping a bright future
With our improved understanding of the AD pathology, research is now also aiming for other disease elements apart from amyloid beta, such as targeting tau. This could eventually lead to the development of combination therapies. “Combination therapy is also used in other indications such as the treatment of HIV. Because when you target the disease in different ways, you may have a higher treatment effect size,” says Griffioen.
Apart from reMYND, other Belgian research teams are also working hard to improve outcomes for AD patients.
Muna Therapeutics is blazing new trails by studying resilience to neurodegeneration. Even in the presence of misfolded proteins, some patients seem to be protected against cognitive decline. With MiND-MAP, they search for new therapeutic targets by using single cell spatial multi-omics and bioinformatics to identify proteins involved in this resilience. Their microglial-focused drug program is now being prepared for clinical testing.
Learn more about Muna Therapeutics’ hopeful solutions for memory loss.
In addition, research by Prof. Bart De Strooper and his team at VIB opens new possibilities for treating AD. With their groundbreaking research, they found that amyloid beta plaques and tau tangles initiate a type of programmed cell death called necroptosis. Furthermore, they were able to prevent necroptosis, rescuing cells from death. Already being investigated for cancer and ALS, necroptosis is now also a promising target for drug development in AD.
Another important focus is to treat patients earlier on in disease progression, even before symptoms occur. At Johnson & Johnson, researchers are developing an investigational, sensitive blood test to detect phosphorylated tau in AD patients at an early stage. There is currently a clinical trial running for their antibody-based therapeutic targeting tau toxicity in early-stage AD patients.
There’s still a lot to be done to find the long-awaited cure, but current advancements are boosting confidence and creating hope in researchers as well as patients. This might incentivize pharma companies to invest more in Alzheimer’s disease, helping us on our way to saving minds.
