Recent advances reveal that an epilepsy drug may reverse Alzheimer’s symptoms, paving the way for innovative dementia treatments.
Global Impact of Dementia and Alzheimer’s Disease
The prevalence of dementia, a complex condition characterised by a decline in cognitive functions, is rising globally, affecting approximately 55 million people. Common symptoms of dementia include memory loss, impaired thinking skills, reduced judgement and reasoning capabilities, decreased focus and attention, language difficulties, and behavioural changes. Alzheimer’s disease, the most prevalent form of dementia, accounts for 60-70% of these cases. The situation is particularly pronounced in Asia due to rapidly ageing populations, especially in countries like Japan, China, and South Korea. It is estimated that by 2050, nearly 23 million people in Asia will be living with Alzheimer’s disease, reflecting broader global trends in ageing demographics and the rising incidence of this neurodegenerative disease. This highlights the urgent need for enhanced healthcare strategies and scientific advancements. In this article, we delve into the current treatment landscape, including current management approaches and recent scientific breakthroughs.
Current Treatment Landscape for Alzheimer’s Disease
Current treatments for Alzheimer’s disease primarily address symptoms. Cholinesterase inhibitors and memantine (Namenda) are commonly used to enhance neurotransmitter function and mitigate memory loss and cognitive decline. However, these therapies do not stop the progression of neuron degeneration, which remains a significant factor in Alzheimer’s development.
Innovative Therapeutic Strategies on the Horizon
Emerging strategies in Alzheimer’s treatment are increasingly focusing on the molecular underpinnings of the disease, with several promising avenues under investigation:
Targeting Amyloid Plaques
Monoclonal antibodies like lecanemab and donanemab are being studied for their ability to target and facilitate the clearance of amyloid plaques from the brain, potentially slowing cognitive decline. Lecanemab, specifically, has received FDA approval for treatment in early stages following promising clinical trial results. However, lecanemab carries potential risks, including rare instances of brain swelling and bleeding. This necessitates careful evaluation of the benefits against the risks, particularly for individuals already at elevated risk for Alzheimer’s disease.
Beta-Amyloid Production Inhibition
Beta- and gamma-secretase inhibitors aim at reducing beta-amyloid formation. However, these have had limited success in slowing cognitive decline and have caused significant side effects in mild to moderate Alzheimer’s cases, dampening enthusiasm for these treatments.
Neuronal Protection Strategies
Saracatinib, initially developed for cancer, is now being tested for Alzheimer’s disease. It has shown potential in preclinical studies by reactivating synapses and reversing memory loss, with human trials underway.
Tau Protein Inhibitors
With the goal of preventing the formation of tau tangles, another pathological hallmark of Alzheimer’s, tau aggregation inhibitors and vaccines are currently undergoing clinical trials.
Anti-inflammatory Approaches
Given the chronic low-level inflammation observed in Alzheimer’s, treatments like sargramostim are being explored to modulate the immune response and protect against inflammation-induced neuronal damage.
Metabolic and Cardiovascular Linkages
Research indicates a strong connection between brain health and cardiovascular health, prompting ongoing investigations into how metabolic and cardiovascular conditions impact Alzheimer’s disease. Studies are exploring whether medications currently used to treat heart disease and diabetes might also reduce the risk or slow the progression of dementia.
Hormonal and Lifestyle Factors
The interplay between lifestyle choices, hormonal changes, and Alzheimer’s risk is also a significant area of research, highlighting the potential of non-pharmacological interventions to delay disease onset, including exercise and diet. Researchers are also investigating the potential of treatments targeting insulin signalling pathways.
Breakthroughs in Molecular Targeting of Alzheimer’s
These strategies mentioned above not only represent the forefront of Alzheimer’s research but also offer hope for more effective treatments that target the disease’s root causes rather than merely managing symptoms. In recent research led by Li-Huei Tsai at MIT’s Picower Institute for Learning and Memory, the team explored the therapeutic potential of an epilepsy drug and a peptide for treating Alzheimer’s disease. Here is a breakdown of the studies:
Results
Amyloid beta plaques, which are linked to Alzheimer’s symptoms, are densely packed in certain areas. These brain areas are particularly prone to hyperactivity and degeneration which are associated with memory impairments in mice. Experimental treatments with the epileptic drug, levetiracetam, reverses memory impairments, and treatments with a peptide significantly reduced DNA damage, neural inflammation, and neuron loss in Alzheimer’s disease mice models.
Mechanism
The peptide drug inhibits an overactive enzyme known as CDK5. CDK5, a protein involved in neuronal functions, is usually activated by another protein called P35. In Alzheimer’s, P35 degrades into a smaller form, P25, causing CDK5 to incorrectly phosphorylate Tau proteins, thus forming damaging Tau tangles.
Innovation
Traditional drugs targeting P25 inadvertently disrupted other crucial enzymes, causing undesirable effects. The MIT team pioneered a selective approach using a peptide that mirrors a specific segment of CDK5, effectively blocking its harmful interaction with P25.
Impact
This targeted intervention holds the potential to alleviate or prevent the progression of Alzheimer’s disease by interrupting a key pathological process without affecting other cellular functions, offering a promising avenue for therapeutic development.
Conclusion
In conclusion, with dementia affecting approximately 55 million people worldwide, the urgency for advanced treatments is evident. Existing treatments, such as cholinesterase inhibitors and memantine, primarily offer symptomatic relief for Alzheimer’s disease. Yet, promising developments, including monoclonal antibodies and innovative treatments like saracatinib, are emerging. A breakthrough at MIT’s Picower Institute with a peptide that inhibits CDK5 could significantly alter Alzheimer’s pathology by reducing neuron loss and inflammation. The future of Alzheimer’s treatment likely involves a multifaceted approach, akin to strategies used in cancer or HIV treatment. Initiatives like the Critical Path for Alzheimer’s Disease (CPAD) consortium are pivotal. It enhances research through collaboration and data sharing to accelerate clinical applications. As of 2020, CPAD’s database (https://codr.c-path.org/) already contains 41 studies. These advancements signal a shift towards more effective therapies, potentially transforming the management of neurodegenerative diseases and offering new hope to millions worldwide.
References
- World Health Organization. (2023, March 15). Dementia. https://www.who.int/news-room/fact-sheets/detail/dementia
- The Lancet Neurology. (2015). Dementia warning for the Asia-Pacific region. The Lancet Neurology, 14(1), 1. https://doi.org/10.1016/S1474-4422(14)70312-6
- Mayo Clinic Staff. (2024, February 13). Alzheimer’s treatments: What’s on the horizon? Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers-treatments/art-20047780
- Huang, W.-C., Peng, Z., Murdock, M. H., Liu, L., Mathys, H., Davila-Velderrain, J., Jiang, X., Chen, M., Ng, A. P., Kim, T., Abdurrob, F., Gao, F., Bennett, D. A., Kellis, M., & Tsai, L.-H. (2023). Lateral mammillary body neurons in mouse brain are disproportionately vulnerable in Alzheimer’s disease. Science Translational Medicine, 15, eabq1019. https://doi.org/10.1126/scitranslmed.abq1019
Pao, P.-C., Seo, J., Lee, A., Kritskiy, O., Patnaik, D., Penney, J., Raju, R. M., Geigenmuller, U., Silva, M. C., Lucente, D. E., Gusella, J. F., Dickerson, B. C., Loon, A., Yu, M. X., Bula, M., Yu, M., Haggarty, S. J., & Tsai, L.-H. (2023). A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes. Proceedings of the National Academy of Sciences, 120(16), e2217864120. https://doi.org/10.1073/pnas.2217864120
