Five advances in Alzheimer’s research over the last year

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

Alzheimer’s occurs when there is an excessive accumulation of protein in the brain, a hallmark of this disease. These proteins, namely, amyloid – which forms plaque around brain cells – and tau – deposits forming tangles in brain cells – which affect the brain, causing a decrease in chemical messengers known as neurotransmitters, which are key to proper brain function.

A common misconception about Alzheimer’s is that only people in their 70s are diagnosed with this disease. While it’s true that most people experience symptoms later in their lives, early Alzheimer’s disease – though rare – affects those under 65 years of age.

As various drug targets have been discovered over time, therapeutic options have also advanced.

For the treatment of Alzheimer’s, lecanemab, a monoclonal antibody targeting amyloid plaques, was developed by Japanese pharmaceutical Eisai in collaboration with American biopharma Biogen. It was granted expedited approval by the European Medicines Agency (EMA) earlier this year. The drug has also been cleared 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 increase levels of the neurotransmitter acetylcholine, important for nerve cell communication – memantine – works by regulating glutamate levels in the brain – as well as cognitive stimulation therapy and rehabilitation techniques. And recently, artificial intelligence has emerged in the process of finding a drug to treat Alzheimer’s.

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

Coya Therapeutics shows Treg cells can cope with disease progression

While many therapeutic studies have targeted proteins associated with Alzheimer’s, inflammation resulting from nerve damage is another factor under study in connection with neurodegeneration. Leveraging this knowledge, US-based clinical stage company Coya Therapeutics is developing drugs to treat mild to moderate Alzheimer’s disease.

The drug candidate COYA 301 is a low-dose interleukin two (IL2) therapy designed to enhance the function of Treg cells in the body. Increasing Treg cells can inhibit the inflammatory cascade and thereby improve the condition, explains Howard Berman, chief executive of Coya Therapeutics.

“Synapses – the areas in between, where neurons fire, which allow you to think properly – are compromised because inflammatory mediators, cytokines, microglia, and prevent these nerve signals from firing,” says Berman who believes COYA 301 has a powerful effect. therapeutic potential.

In a study of eight patients published in June, COYA 301 showed decreased expression of proinflammatory cytokines. The drug is given as a five-day course over four months. Cognitive function was observed to improve, as measured by the MMSE score – an assessment for dementia.

In addition, one of the patients underwent positron emission tomography (PET) scans before and after treatment. Post therapy, there was a marked reduction in inflammation throughout the brain, including the hippocampal area.

“Alzheimer’s is a family disease. It is a disease that doesn’t just affect the individual; the person doesn’t really have the means to understand what they are going through with dementia, but the family is deeply affected. And that is a tragedy because the family sees what is stripped of personality. So, we believe this is a therapy that can inform patient care, and alleviate a lot of the burden that we all see in these patients,” said Berman, who added that the incidence of Alzheimer’s is increasing because of an aging population.

Focusing on Treg cell therapy, the company is also advancing in clinical trials for the neurological condition amyotrophic lateral sclerosis (ALS), which is expected to be commercialized in 2025 following FDA approval.

New research uncovers promising drug targets for Alzheimer’s disease

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

They observed the interaction between apolipoprotein E (ApoE) and heparan sulfate (HS). ApoE is a protein that binds to fat to transport cholesterol throughout the body, while heparan sulfate is a sugar molecule that exists on the surface of cells and plays a key role in cellular communication. Variants of ApoE, ApoE3 and ApoE4 – inheriting the last gene increases the risk of Alzheimer’s by three times, and two copies by eight to 12 times – were observed to bind to the sulfate bond in heparin sulfate. In addition, the stronger the bond, the higher the chance of developing Alzheimer’s. This binding pattern was noted to be somewhat similar to that of the Tau protein, which is misfolded in the brains of people with Alzheimer’s.

Since heparan sulfate 3-O transferase is an enzyme that catalyzes the sulfation process in sugar molecules, this leads to potential drug targets for delaying disease progression.

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

The research team aimed to create a 3D structural model of the ApoE-HS and monitor its further interactions in cell culture and animal models.

Can sleeping pills stop the development of Alzheimer’s?

On average, adults need seven to nine hours of sleep each day. But about 10% of the world’s population struggles with insomnia, which means they don’t get enough sleep on a regular basis. While changing sleep habits is recommended to treat sleep disturbances, in extreme and rare cases, sleeping pills are prescribed. Suvorexant is one of the drugs that has been approved by the FDA for the treatment of insomnia. Now, research shows that it could slow or even hinder the development of Alzheimer’s.

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

Although Alzheimer’s is a neurodegenerative disease known to cause memory loss, many people who have been diagnosed with the condition experience sleep disturbances early on. Because sleep deprivation accelerates detrimental changes in brain function, it’s a vicious cycle. But drugs like suvorexant can prevent this from happening research conducted by the University of Washington School of Medicine in St. Louis in the US.

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

Recognizing that extensive research is critical to better understanding the effects of drugs, Brendan Lucey, senior author of the study and director of the Washington University Center for Sleep Medicine, said: “We don’t yet know if long-term use is effective in staving off. off cognitive decline, and if so, at what dosage and for whom. Even so, these results are very encouraging. These drugs are readily available and proven safe, and now we have evidence that they affect levels of a protein that is critical to triggering Alzheimer’s disease.”

New research suggests molecules that block enzymes that cause neurodegeneration can reverse Alzheimer’s disease

Hyperactivity of the CDK5 enzyme in Alzheimer’s patients is not a recently discovered knowledge. It has long been understood that when the enzyme interacts with the modified P25 protein – causing structural changes in CDK5 – it allows CDK5 to more easily influence the tau protein to form neurofibrillary kinks, a key characteristic in Alzheimer’s. Recently, researchers at the Massachusetts Institute of Technology (MIT) in the US, discovered that the peptide could target P25, and potentially treat Alzheimer’s disease.

The peptide, which is designed to contain a sequence identical to the segment in CDK5 – essential for CDK5 and P25 binding – inhibits the formation of the CDK5-P25 complex, and was observed in mouse models to have reduced DNA damage, neuroinflammation. , and loss of neurons.

“We saw remarkable effects in terms of reducing neurodegeneration and neuroinflammatory responses, and even salvaging behavioral deficits,” said Li-Huei Tsai, senior author of the Study and director of MIT’s Picower Institute of Learning and Memory.

Not only did the peptides not affect the function of CDK1, an enzyme structurally similar to CDK5, but also unlike the previously tested drugs, the peptides did not interfere with another cyclin-dependent kinase – an enzyme that regulates the cell cycle.

Since P25 has been linked to various neurodegenerative diseases, it could be a therapeutic breakthrough for conditions such as Parkinson’s disease as well as frontotemporal dementia.

The drug candidate TauRx is promising

In an effort to counteract the aggregation effect of tau protein in the brain, life sciences company TauRx Therapeutics, headquartered in Singapore, has developed a tau protein inhibitor orally, to reduce 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), administered to patients with mild to moderate forms of the disease, showed a significant reduction in disease progression in these patients, as measured by changes in cognitive decline and brain atrophy.

“This is the first time any treatment has resulted in evidence of sustained improvement over an individual pre-treatment baseline lasting 18 months in the clinically detectable early stages of AD, and stabilization of disease progression in more severe stages,” said Claude Wischik, executive chair and one of the founders of TauRx.

“The disease pathology Tau is now recognized as an important target for treatment, and it is encouraging that cognitive enhancement is seen in the early stages of the disease with drugs targeting Tau. This field focuses primarily on amyloid as a target for early intervention. Our data are consistent with evidence that Tau pathology begins at least 20 years before clinical symptoms appear and is a viable first-line treatment target.”

However, although the candidate’s safety profile remains consistent with previously published trial data, the current study was unable to compare the drug’s efficacy with that of a placebo. This is because when treated with HMTM, there is a change in the color of the urine, which makes it a challenge to give the right placebo. Although TauRx used methylthioninium chloride (MTC) — a dye used to treat blood disorders — in its control arm, those given MTC “were unexpectedly found to have blood levels of the active drug above the threshold needed to produce a clinical effect.” Nonetheless, the company plans to proceed with applying for FDA authorization.