Cannabinoids Show Promise As New Treatment For Alzheimer's Disease
By Eric Hsu, Ph.D., senior VP, preclinical research and development, InMed Pharmaceuticals
Major advances have been made over the last decade in the understanding of Alzheimer’s disease pathology and have resulted in the introduction of a few disease-modifying treatments. While these new treatment options offer some hope to those affected by Alzheimer’s disease — an estimated 6.7 million people in the U.S. aged 65 and older — the side effects and limited efficacy remain challenges for those affected by this destructive disease. What’s more, the cost of dementias, including Alzheimer’s disease, to the U.S. economy is an estimated $321 billion per year, in addition to an estimated $271 billion in unpaid caregiving, and is said to be one of the costliest conditions to society.1,2 While breakthrough treatments offer some hope to patients and their caregivers, the high costs, drug administration challenges, variations in efficacy, and undesired side effects remain barriers to long-term sustainability. Therefore, new pathways need to be explored to address the multiple facets of this progressive disease.
Alzheimer’s Disease Is Characterized By Multiple Pathologies
Alzheimer’s is a complex neurodegenerative disease with multiple pathologies that contribute to its progression. Hallmarks of the disease point to the buildup of amyloid-beta plaques and neurofibrillary tangles or tau tangles. Amyloid-beta is a naturally occurring protein in the brain; however, in a brain plagued by Alzheimer’s disease, abnormal levels of amyloid-beta clump together to form plaques that damage neuronal cell integrity and function.
While amyloid-beta has traditionally been the focus of Alzheimer’s research and drug development, recent attention has shifted to tau, a protein that is correlated with Alzheimer’s disease progression. Tau plays a crucial role in stabilizing microtubules within neurons, supporting their structure and function. Increased activity of enzymes called tau kinase causes the tau protein to misfold and clump, creating neurofibrillary tangles. These neurofibrillary tangles disrupt the normal functioning of neurons, and the abundance of these tangles in the brain has been linked to the stage and severity of the disease.
In addition to these two aspects of Alzheimer’s disease, neuroinflammation and synaptic dysfunction are also recognized as key contributors to Alzheimer's progression.3 Microglia, the brain's immune cells, are involved in the removal of amyloid-beta and have been a focus of research in neuroinflammation.4 Therapies that target the modulation of microglial activity aim to reduce inflammation and protect neurons.
Anti-Amyloid-Betas Are The First Disease-Modifying Treatments For Alzheimer’s Disease
Many exciting advances have been made in the research and development of treatments for Alzheimer’s disease — including the recently approved anti-amyloid beta treatments. These disease-modifying treatments are designed to remove or reduce the buildup of amyloid-beta plaques to slow cognitive decline. While the studies have shown a mixed response to this treatment approach by patients, the introduction of anti-amyloid beta therapy has offered hope to the millions affected by this devastating disease.
Currently, the regulatory-approved anti-amyloid-beta treatments are biologics, which are large molecules and present accessibility challenges such as high costs, special storage requirements, and intravenous infusion delivery every two to four weeks. The resulting inconvenience can impact patient compliance. As large molecules, biologics may also require larger doses or have a delayed response as their size limits their ability to cross the blood-brain barrier and penetrate tissues. In addition to the drug delivery challenges of these new antibody therapies, efficacy has been limited and there are safety concerns over brain swelling. These therapies are only suitable for a specific group of Alzheimer’s patients.5
A Multifactorial Approach Is Needed For The Treatment Of Alzheimer’s Disease
As research deepens our understanding of Alzheimer’s disease, it becomes increasingly evident that a multifactorial approach is essential to address its intricate and diverse nature.
While major strides have been made recently in the development of new treatments for Alzheimer’s disease, few treatments are taking a multi-targeted approach in addressing the other aspects of the disease, such as neuroinflammation, neuroprotection, or the restoration of the affected neurons — factors that may help to restore brain function loss or reverse the damage caused by Alzheimer’s.
Microglial cells play a pivotal role in neuroinflammation and Alzheimer’s disease progression. Microglia cells contribute to the phagocytosis of amyloid-betas, resulting in the removal and clearance of amyloid plaques. This process also can lead to the overactivation of microglia, the release of inflammation-causing agents, and the development of chronic neuroinflammation. Once this inflammation process is initiated, it also can impact microglias’ ability to clear amyloid plaques, which leads to additional accumulation of the plaque and further neurodegeneration. Therefore, understanding the neuroinflammatory process associated with disease progression and effectively controlling this process are critical in Alzheimer’s disease treatment.
Neuritogenesis In Alzheimer’s Disease — Restoring Lost Neuronal Functions
While brains are developing in young children, neurons are resilient and reproducing and extending at a steady rate. This process, known as neurogenesis and neuritogenesis, slows in adults and, to a greater degree, in patients with Alzheimer’s disease.6
Neurogenesis is the generation of new neurons, while neuritogenesis is the growth and extension of the neurites of a neuron. The extension of these neurites enables communication signals between neurons and represents enhanced brain processing; however, neurite growth is reduced or altered in old age, particularly in patients with dementia. Restoring the neuritogenesis process presents an opportunity to reverse the loss of neuronal function caused by Alzheimer’s disease.
The Endocannabinoid System And Its Impact On Neuronal Functioning
Mounting research into the pharmacological effects of cannabinoids and their innate interaction with the endocannabinoid system has made certain cannabinoids interesting therapeutic targets for several conditions, such as Alzheimer’s disease. Almost every aspect of the body’s functioning involves the endocannabinoid system, which consists of receptors and endocannabinoids found throughout the human body, including in the brain, playing a major role in many aspects of neural functioning.
CB1 and CB2 receptors are among the many receptors that make up the endocannabinoid system. CB1 receptors, primarily situated in the central nervous system, play roles in memory, cognition, and motor function, while CB2 receptors are known to modulate neuroinflammation and immune responses.
Research indicates that activating CB1 and CB2 receptors may induce neuroprotective effects and may help to protect brain cells from damage and death. Enhancing the activity of these receptors may help to slow down the progression of Alzheimer’s disease, in which neuronal cell death is a hallmark. Moreover, the activation of these receptors, along with other cellular receptors, also has been shown to have an impact on neuroinflammation. As neuroinflammation is believed to contribute to the progression of Alzheimer’s, targeting these receptors could help alleviate this inflammatory response.
Cannabinoids As Potential Pharmacological Candidates For Neurological Diseases
Cannabinoids are small molecules known to be highly lipophilic and can safely cross the blood-brain barrier, enabling the potential therapeutic modulation of brain signaling and making them promising pharmaceutical targets for neurological diseases such as Alzheimer’s.
Small molecule drugs have several advantages that contribute to their widespread use. Those advantages include oral administration (making it convenient for patients to comply), good bioavailability (allowing these compounds to be efficiently absorbed), ability to cross the blood-brain barrier (enabling therapeutic modulation in brain signaling), and stability in storage and transport (ease of drug handling and dose adjustment and low-cost manufacturing).
InMed Pharmaceuticals’ Studies Demonstrate Encouraging Multi-Targeted Effects In Alzheimer’s Preclinical Study Models
Recent research on a rare cannabinoid and analog compounds is showing promising results that may tackle more than one aspect of Alzheimer’s disease. InMed Pharmaceuticals’ preclinical research is showing how certain cannabinoid-like molecules are not only providing neuroprotective effects and reducing neuroinflammation but also enhancing neuronal function via neurite outgrowth. These compounds appear to be proactive in keeping neurons from further damage due to disease progression.
Specifically, InMed’s in vitro and in vivo studies demonstrated encouraging effects in well-recognized Alzheimer’s disease preclinical study models. In a neuroprotection study, a rare cannabinoid analog demonstrated cell survival and proliferation and decreased neuroinflammation, while another study demonstrated an extension of the length of neurites, signifying enhanced neuronal protection and function. In the study, behavioral and molecular analysis demonstrated the selected cannabinoid analogs reduced brain inflammation and improved key brain functions and aspects of the disease.
Next Generation Of Alzheimer’s Disease Treatments To Target Multiple Pathologies
The landscape of Alzheimer's research and treatment is evolving rapidly, offering hope to the millions affected by this devastating disease. Until only a few years ago, the only treatment options were to help manage symptoms related to the disease. While new drugs and therapeutic approaches show promise, high costs, accessibility, and efficacy remain challenges for this complex disease.
Cannabinoids and their innate interaction with the endocannabinoid system, specifically with neuronal functioning, present an attractive therapeutic pathway. Encouraging preclinical studies by InMed further support the therapeutic potential of certain cannabinoid analogs as a pharmacological pathway with a multifactorial approach to treating Alzheimer’s disease.
References:
- https://www.jec.senate.gov/public/index.cfm/democrats/issue-briefs?ID=02F4CADC-954F-4E3B-8409-A4213E3C0759
- https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf
- Lancet Neurol. 2015 Apr; 14(4): 388–405. doi: 10.1016/S1474-4422(15)70016-5
- Front. Cell. Neurosci., 22 April 2014 Sec. Non-Neuronal Cells
- https://doi.org/10.1186/s13024-023-00637-0
- https://doi.org/10.1007/s12035-022-03145-2
About The Author:
Eric Hsu, Ph.D. is senior vice president of preclinical research and development at InMed Pharmaceuticals. He has 20+ years of scientific leadership experience in the field of gene therapy. Before joining InMed, he held various positions within enGene Inc., including VP of research and VP of scientific affairs and operations.
Dr. Hsu's experience includes benchtop research, formulation development, and manufacturing process development, as well as patent prosecution, vendor contract negotiations and execution, and research partnerships. He is also responsible for expanding product pipelines and managing R&D budgets and timelines. Dr. Hsu is an expert in gene transfer and gene expression using vector systems.
Dr. Hsu received his doctorate from the Department of Medical Biophysics at the University of Toronto and his bachelor’s degree from McGill University.