Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that slowly erodes memory and cognitive function, ultimately affecting a person’s independence. While current treatments only manage symptoms, researchers believe ketamine may help repair brain damage linked to AD. In this article, we explore the science behind ketamine as a potential treatment and examine the evidence and possible risks.
The Unmet Need in Alzheimer’s Disease
Alzheimer’s disease is the most common form of dementia, affecting over 55 million people worldwide. It primarily impairs memory, reasoning, and the ability to perform daily tasks. As the disease progresses, individuals require full-time care, placing significant emotional and financial burdens on families and caregivers.
The economic impact of Alzheimer’s is staggering. In the U.S. alone, the cost of caring for Alzheimer’s patients was estimated at $355 billion in 2021. With an aging population, this burden is expected to skyrocket in the coming decades. Although drugs like donepezil and memantine help manage symptoms, they do not stop or reverse cognitive decline. This unmet need has driven researchers to explore whether ketamine could offer a new solution.
Ketamine and Synaptic Plasticity
The brain’s ability to learn and store memories depends on synaptic plasticity—the ability of nerve cells to strengthen or weaken connections in response to activity. This process relies on two main mechanisms:
- Long-Term Potentiation (LTP): Strengthens synapses, improving memory and learning.
- Long-Term Depression (LTD): Weakens synapses, allowing the brain to filter out unnecessary information.
In Alzheimer’s disease, synaptic plasticity is severely impaired, leading to cognitive decline. However, research suggests ketamine enhances synaptic plasticity, potentially restoring its function.
Researchers have found that ketamine influences synaptic plasticity through multiple cellular processes, including:
- mTOR activation: Ketamine stimulates a series of molecules in what’s known as the mTOR pathway. These interactions promote nerve cells to grow and form new connections.
- BDNF (Brain-Derived Neurotrophic Factor): Ketamine increases BDNF, a protein essential for synaptic plasticity. BDNF also improves the health of nerve cells and can help them to grow, counteracting brain damage associated with Alzheimer’s.
- eEF2 phosphorylation: Ketamine modifies eEF2, which controls the production of different proteins involved in synaptic plasticity.
How Does Ketamine Affect Cognition?
Several studies suggest that low doses of ketamine can help improve cognitive function, which could be helpful in the treatment of Alzheimer’s. For instance, a study on rats found that a dose of 10 mg/kg of ketamine reversed cognitive deficits associated with depression. In humans, low doses of sublingual ketamine improved scores of visual memory and short-term memory in patients with treatment-resistant depression.
However, the effects of ketamine on cognition depend on dosage. While low doses appear beneficial, high doses can impair cognitive function, causing confusion and impaired motor skills.
Chronic, high-dose ketamine use is also linked to neurological damage. People with ketamine abuse disorders show low scores in cognitive tests and abnormalities in their brain structure in imaging experiments.
Ketamine Treatment for Alzheimer’s: Current Evidence
Ketamine Reduces Brain Changes Associated with Alzheimer’s Disease
Tau protein tangles commonly accumulate in the brains of people with Alzheimer’s. Tau is a molecule found in nerve cells that helps maintain their structure. In Alzheimer’s, these molecules undergo excessive phosphorylation, where phosphates attach in abnormal amounts. This causes them to bundle up inside nerve cells, disrupting normal nervous system function.
In a mouse study, ketamine reduced the aggregation of tau protein in the space between nerve cells. These findings suggest that ketamine could help restore nerve communication in Alzheimer’s. However, no studies on humans, to date, have confirmed these findings.
Another key feature of Alzheimer’s is reduced synaptic plasticity in the hippocampus, the brain’s memory center. Studies in mice show that ketamine increases plasticity in this brain region, potentially helping restore memory function. But again, these effects have not yet been proven in humans.
Ketamine Shares a Similar Mechanism with Memantine
Memantine is one of the few FDA-approved drugs for Alzheimer’s. It works by blocking NMDA receptors, which help regulate the brain chemical glutamate. In Alzheimer’s, glutamate becomes overactive, which can damage nerve cells. By reducing this excessive signaling, memantine may help slow cognitive decline.
Interestingly, ketamine also blocks NMDA receptors, but in a more potent and nuanced way. This similarity suggests that ketamine could provide some of the same cognitive benefits as memantine.
Is Ketamine Safe for Alzheimer’s Patients?
While low doses of ketamine may be beneficial, high doses have been associated with brain changes that resemble Alzheimer’s pathology:
- Increased phosphorylated tau: High doses of ketamine have been shown to induce tau phosphorylation, a key contributor to neurodegeneration.
- Amyloid-beta plaque formation: Amyloid-beta plaques are another neurological hallmark of Alzheimer’s. These are protein deposits that accumulate between nerve cells and prevent them from communicating properly. Studies show that ketamine may interfere with the brain’s ability to degrade amyloid plaques.
- Cognitive side effects: High doses of ketamine can cause delirium, confusion, and memory loss, mirroring Alzheimer’s symptoms.
Given these risks, researchers suggest that low-dose sublingual ketamine may be the safest approach. However, more long-term studies are needed to confirm its safety and efficacy in Alzheimer’s patients.
Key Takeaways
- Alzheimer’s disease is a growing public health crisis with limited treatment options that do not reverse cognitive decline.
- Ketamine enhances synaptic plasticity through mechanisms like mTOR activation and BDNF release, which may improve memory function.
- Studies suggest that ketamine improves cognition at low doses, but high doses can cause cognitive impairment and neurotoxicity.
- Ketamine reduces Alzheimer ’s-related brain changes, including tau accumulation and synaptic dysfunction.
- While promising, ketamine treatment for Alzheimer’s needs further research to determine its long-term safety and effectiveness.
Sources
https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2019.00186/full