Six advancements in Alzheimer’s research over the past year

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Alzheimers disease

The most common cause of dementia, Alzheimer’s disease, is a brain disorder that is characterized by cognitive decline which often manifests itself through memory loss, feelings of disorientation and difficulty making decisions.

Alzheimer’s occurs when there is an excessive accumulation of proteins in the brain, a hallmark feature of the disease. These proteins, namely, amyloid – which forms plaques around brain cells – and tau – the deposits form tangles in brain cells – that affect the brain, lead to a decline in chemical messengers known as neurotransmitters, which are key to proper brain functioning.

A common misconception about Alzheimer’s is that only people in their 70s are diagnosed with the disease. While it is true that most people develop symptoms later on in their lifetime, early onset Alzheimer’s – although rare – is experienced by those younger than 65. 

As various drug targets have been discovered overtime, therapeutic options have advanced as well.

For the treatment of Alzheimer’s, lecanemab, a monoclonal antibody that targets amyloid plaques, was developed by Japanese pharmaceutical Eisai in collaboration with American biopharma Biogen. It was granted accelerated approval by the European Medicines Agency (EMA) earlier this year. The drug has also been authorized to treat early-stage Alzheimer’s by the Food and Drug Administration (FDA), amid safety and cost concerns.

Other treatment measures include acetylcholinesterase (AChE) inhibitors – which improve levels of the neurotransmitter acetylcholine, essential for nerve cell communication – memantine – works by regulating glutamate levels in the brain – as well as cognitive stimulation therapy and rehabilitation techniques. And lately, artificial intelligence has been up-and-coming in the drug discovery process for treating Alzheimer’s. 

As we observe Alzheimer’s & Brain Awareness Month in June, here are six recent advancements that could transform Alzheimer’s research. 

Table of contents

    Coya Therapeutics shows Treg cells can tackle disease progression

    While much therapeutic research has gone into targeting the proteins associated with Alzheimer’s, inflammation due to nerve damage is another factor that is being studied with regard to neurodegeneration. Leveraging this knowledge, U.S.-based clinical stage company Coya Therapeutics is developing a drug to treat mild to moderate Alzheimer’s disease.

    The drug candidate COYA 301 is a low dose, interleukin two (IL2) therapy which is designed to enhance the function of Treg cells in the body. Ramping up the Treg cells can hinder an inflammatory cascade and thereby ameliorate the condition, explained Howard Berman, chief executive officer of Coya Therapeutics.

    “The synapses – the area between, where the neurons fire, that allows you to think properly – is compromised because of inflammatory mediators, cytokines, microglia, and it prevents these neuronal signals from firing,” said Berman who believes that COYA 301 has great therapeutic potential. 

    In an eight-patient study published in June, COYA 301 demonstrated a diminished expression of proinflammatory cytokines. The drug was administered as a five day-course for four months. Cognitive function was observed to have improved, which was measured through MMSE scores – an assessment for dementia.

    Furthermore, one of the patients underwent a positron emission tomography (PET) scan before and after treatment. Post-therapy, a marked reduction in inflammation throughout the brain, including the hippocampal regions was observed.

    “Alzheimer’s is a disease of the family. It’s a disease that impacts not just the individual; the person doesn’t really have the wherewithal to understand what they’re going through because of the dementia, but the family is majorly impacted. And it’s a tragedy because the family sees what the personality is stripped of. So, we believe this is a therapy that may inform the way that patients are taken care of, and alleviate many of the burdens that we all have seen in these patients,” said Berman, who added that Alzheimer’s is increasing in incidence owing to an aging population.

    Focused on Treg cell therapies, the company is also advancing in clinical trials for the neurological condition amyotrophic lateral sclerosis (ALS), which it hopes to commercialize by 2025 upon approval from the FDA.

    New research uncovers promising drug target for Alzheimer’s disease

    Researchers at Rensselaer Polytechnic Institute in New York have found a new drug target that could slow the progression of Alzheimer’s disease.

    They observed interactions between apolipoprotein E (ApoE) and heparan sulfate (HS). ApoE is a protein that binds to fats in order to transport cholesterol throughout the body, while heparan sulfate is a sugar molecule that is present on cell surfaces and plays a key role in cellular communication. Variants of ApoE, ApoE3 and ApoE4 – inheriting the latter gene elevates the risk of Alzheimer’s by three-fold, and two copies of it by eight- to 12-fold – were observed to bind with the sulfate bond in heparin sulfate. Moreover, the stronger the bond, the higher the likelihood of developing Alzheimer’s. This binding pattern was noted to be rather similar to that occurring with the Tau protein, which are misfolded in the brains of people with Alzheimer’s.

    As heparan sulfate 3-O transferase is the enzyme that catalyzes the sulfation process in the sugar molecule, it points to a potential drug target to delay disease progression.

    “Ultimately, we want to prevent or mitigate enough of the symptoms of Alzheimer’s disease so people can continue to live independently,” said Dylan Mah, first author of the study and doctoral student at Rensselaer. “Understanding how the disease works on a molecular basis is really critical to finding new treatments.”

    The research team aims to create a 3D structural model of ApoE-HS and further monitor the interplay in cell cultures and animal models.

    Could sleeping pills halt Alzheimer’s progression?

    On average, adults require seven to nine hours of sleep every day. But about 10% of the world’s population struggle with insomnia, meaning that they don’t get adequate sleep on a regular basis. While changing sleeping habits are encouraged to tackle sleep disorders, in extreme and rare cases, sleeping pills are prescribed. Suvorexant is one such medicine that has been approved by the FDA for the treatment of insomnia. Now, research suggests that it could slow or even hamper the development of Alzheimer’s. 

    Belonging to a class of drugs known as orexin antagonists, suvorexant blocks orexin, a biomolecule associated with wakefulness. Therefore, obstructing orexin promotes sleep. 

    Although Alzheimer’s is a neurodegenerative disease that is known to lead to memory loss, many people who have been diagnosed with the condition experience sleep disturbances early on. As poor sleep accelerates detrimental changes to brain functioning, this is a vicious cycle. But a drug like suvorexant could prevent this from happening, according to research conducted by Washington University School of Medicine in St. Louis in the U.S.. 

    In a small two-night proof-of-concept study, researchers at the university found that in people who had received a high dose of the pill, amyloid levels dropped by 10% to 20%. In the Alzheimer’s brain, there is a build up of plaques of the amyloid protein. Furthermore, there was a decline in the levels of the tau protein in the cerebrospinal fluid withdrawn from participants.

    Recognizing that extensive research is essential to understand the effect of the drug better, Brendan Lucey, senior author of the research and director of Washington University’s Sleep Medicine Center, said: “We don’t yet know whether long-term use is effective in staving off cognitive decline, and if it is, at what dose and for whom. Still, these results are very encouraging. This drug is already available and proven safe, and now we have evidence that it affects the levels of proteins that are critical for driving Alzheimer’s disease.”

    New research suggests molecule that blocks neurodegeneration-causing enzyme could reverse Alzheimer’s

    The hyperactivity of the enzyme CDK5 in Alzheimer’s is not newfound knowledge. It has been long understood that when the enzyme interacts with the modified protein P25 – causing a structural change in CDK5 – it enables CDK5 to more easily influence the tau protein to form neurofibrillary tangles, a key characteristic in Alzheimer’s. Recently, researchers at Massachusetts Institute of Technology (MIT) in the U.S., discovered that a peptide can target P25, and potentially treat Alzheimer’s disease.

    The peptide, which was designed to contain a sequence identical to a segment in CDK5 – critical to the binding of CDK5 and P25 – inhibited the CDK5-P25 complex from forming, and was observed in a mouse model to have reduced DNA damage, neural inflammation, and neuron loss.

    “We saw wonderful effects in terms of reducing neurodegeneration and neuroinflammatory responses, and even rescuing behavior deficits,” said Li-Huei Tsai, senior author of the study and director of MIT’s Picower Institute for Learning and Memory.

    Not only did the peptide abstain from affecting the functioning of CDK1, an enzyme structurally similar to CDK5, but also unlike previously tested drugs, it did not interfere with other cyclin-dependent kinases – enzymes that regulate the cell cycle.

    As P25 has been linked to multiple neurodegenerative diseases, this could be a therapeutic breakthrough for conditions like Parkinson’s disease and frontotemporal dementia as well. 

    TauRx’s drug candidate offers promise

    In an effort to neutralize the effect of aggregation of tau protein in the brain, life science company TauRx Therapeutics, headquartered in Singapore, has developed an oral inhibitor of the protein, to mitigate Alzheimer’s disease. A phase 3 clinical trial was announced to have observed promising results, in October last year.

    In the LUCIDITY study, the drug candidate hydromethylthionine mesylate (HMTM), which was given to patients with mild to moderate forms of the disease, demonstrated a significant reduction in disease progression in patients, which was measured by changes in cognitive decline and brain atrophy.

    “This is the first time any treatment has produced evidence of sustained improvement over the individual’s own pre-treatment baseline lasting 18 months at an early clinically detectable stage of AD, and stabilization of disease progression at more severe stages,” said Claude Wischik, executive chairman and co-founder of TauRx.

    “Tau pathology of the disease is now recognized as an important target for treatment, and it is encouraging that cognitive improvement is seen at such an early stage of the disease with a drug targeting Tau. The field has focused mainly on amyloid as a target for early intervention. Our data are consistent with the evidence that Tau pathology begins at least 20 years before clinical symptoms appear and is a viable first-line target for treatment.”

    However, although the candidate’s safety profile remains consistent with previously published trial data, the recent study was unable to compare the drug’s efficacy against a placebo. This was because when treated with HMTM, urinary discoloration occurs, posing a challenge to administer an appropriate placebo. Despite TauRx using methylthioninium chloride (MTC) – a dye used to treat a blood disorder – in its control group, those dosed with MTC were “unexpectedly found to have blood levels of active drug above the threshold needed to produce a clinical effect.” While this is the case, the company plans to go ahead with filing for FDA authorization.

    Could nicotinamide riboside solve neurodegeneration?

    As we’ve seen the therapeutic potential of nicotinamide riboside in treating Parkinson’s, a study led by Dr. Adil Mardinoglu, Professor of Systems Biology in the Science for Life Laboratory at the Royal Institute of Technology (KTH), Stockholm, Sweden ​​and Centre for Host-Microbiome Interaction at the King’s College London, U.K., observed its impact on Alzheimer’s disease.

    The study investigated a combined metabolic activator (CMA) Niagen, which is the patented form of nicotinamide riboside, in addition to L-carnitine tartrate, serine, and N-acetyl-L-cysteine (NAC) in 60 mild-to-moderate patients with Alzheimer’s disease (AD). It was found that cognitive function was improved by 29% when compared to only 14% in patients who were given the placebo, after 84 days of treatment.

    “Recent research suggests that maintaining optimal mitochondrial health is not only vital for supporting neuronal activity by supplying sufficient energy but also for protecting neurons against oxidative stress, which refers to an imbalance between the production of reactive oxygen species (free radicals) and the body’s antioxidant defenses. Therefore, therapeutic strategies targeting mitochondria may prove useful against neurodegenerative disorders. One such strategy, which has so far produced promising preclinical and clinical results, is NAD-replenishment, using precursors such as nicotinamide riboside (NR),” said Charalampos Tzoulis, Professor of Neurology and Neurogenetics at the University of Bergen and Haukeland University Hospital in Norway.

    Tzoulis has conducted similar research with regard to Parkinson’s, showcasing NR supplementation significantly increased brain NAD+ levels and patients experienced a mild but significant clinical improvement, which correlated with the change in the brain’s metabolic pattern.

    NAD is central to cellular functions including energy production in the mitochondria – popularly known as the powerhouse of the cell – and restoring its levels through intake of oral NR could combat brain aging and neurodegeneration.

    The use of CMA builds on previous successful clinical and preclinical studies led by Mardinoglu, which demonstrated that CMA supplementation had enhanced brain and liver metabolism. Moreover, results revealed that hyperemia (blood flow), degeneration (loss of nerve structure or function) and necrosis (death of neurons) in brain neurons were improved by CMA administration in both Alzheimer’s disease and Parkinson’s disease (PD) animal models.

    As further studies investigate the efficacy of nicotinamide riboside in treating Alzheimer’s, Tzoulis believes that as the decline in mitochondrial function can have detrimental effects on the brain, it could prove to be a significant drug target for neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease.

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