Innovative Approaches to Combat Aging and Neurodegenerative Diseases

Li-Huei Tsai discusses groundbreaking research on aging and neurodegenerative diseases, particularly Alzheimer's, highlighting innovative methods such as non-invasive brain stimulation, stem cell technology, and personalized medicine to improve brain health and combat dementia.

It is a pleasure to share insights from my research at the Institute for Learning and Memory, where we focus on age-related neurodegenerative diseases, particularly Alzheimer's and dementia. As our nation ages, the demographic shift is significant: by 2034, seniors over 65 will outnumber children under 18, and by 2060, 25% of the population will be seniors. This shift brings a sharp increase in age-related chronic diseases, especially dementia, which currently affects 55 million people worldwide and is expected to triple by 2050.

The Challenge of Dementia

Dementia presents unique challenges compared to other chronic illnesses. While death rates from diseases like cardiovascular issues and cancer have decreased, deaths from dementia have risen annually. Currently, there are no treatments available that can prevent or slow the progression of dementia, making our research critical.

Research Approaches to Alzheimer's Disease

To tackle dementia, we employ three experimental approaches:

1. Large-Scale Brain Circuit Analysis

We investigate large-scale brain circuits and system activities to understand how interventions can stimulate healthy brain activity. By manipulating natural brain waves, we aim to enhance cellular and tissue health in Alzheimer's-affected brains. Collaborating with computer scientists, we conduct machine learning analyses to identify how various brain cell types execute their genetic instructions, providing insights into molecular and cellular dysfunctions.

2. Stem Cell Biology and Genome Editing

We combine stem cell biology, genome editing, and tissue engineering to explore genetic and environmental risk factors for Alzheimer's. Our goal is to understand why some individuals are more resilient to age-related neurodegeneration. For instance, we have created brain vasculature in a Petri dish using patient-derived stem cells, which allows us to study disease mechanisms in a controlled environment.

3. Non-Invasive Brain Stimulation

We have developed a non-invasive method to stimulate the brain using light and sound. Our research shows that gamma brain waves, which are crucial for higher-order functions, are compromised in Alzheimer's disease. By boosting gamma power in Alzheimer's model mice through light and sound stimulation, we observed a reduction in beta amyloid levels, a key pathological feature of Alzheimer's.

Results from Animal Studies

Our studies on Alzheimer's model mice revealed profound neuroprotective effects from gamma stimulation:

• Brain Volume Preservation: Stimulation preserved brain size and reduced ventricular enlargement.
• Pathology Reduction: There was a significant decrease in amyloid plaques and tau tangles associated with Alzheimer's.
• Functional Improvement: Enhanced circuit connectivity and improved learning and memory functions were noted.

Mechanisms of Action

Increased gamma power not only alters gene expression but also enhances the biochemical properties of neurons and supporting glial cells. This leads to improved synaptic transmission and network connectivity. Additionally, we observed increased blood flow and vessel size in the brain, facilitating better nutrient delivery and waste clearance.

The Glymphatic System

A recent discovery in our lab involves the glymphatic system, a waste clearance system in the brain. We found that increased gamma power significantly enhances the glymphatic clearance of brain waste, including beta amyloid. This discovery is pivotal in understanding how to maintain brain health and prevent neurodegeneration.

Human Trials and Future Directions

We have initiated a phase II trial using our light and sound stimulation device on mild Alzheimer's patients. Early results indicate that this approach is safe and leads to improved network connectivity and preserved hippocampal volume, crucial for memory. Encouragingly, an MIT spinoff, Cognito Therapeutics, has received FDA breakthrough device designation based on these promising results and is moving into phase III trials.

Prevention Trials

We are also starting prevention trials for individuals with a family history of Alzheimer's, aiming to delay the onset of memory impairment. Additionally, we are exploring similar approaches for Parkinson's disease and Down syndrome.

Building Trackable Models of the Human Brain

Our research also focuses on creating trackable models of the human brain to unravel the complexities of neurodegenerative diseases. By combining human genetics, single-cell transcriptomics, and stem cell biology, we can stratify patient populations and study the effects of genetic risk factors on brain cell types.

The Role of APOE Gene

A significant focus is on the APOE gene, particularly the APOE4 variant, which increases Alzheimer's risk. We have developed isogenic pairs of stem cells to compare the effects of APOE4 and APOE3 on various brain cell types, revealing how APOE4 contributes to Alzheimer's pathology.

Personalized Medicine

Our ultimate goal is to create personalized medicine approaches using our mini-brain models. By reprogramming skin cells into stem cells, we can create individualized brain models to test drug responses, optimizing treatment protocols for each patient. This personalized approach allows us to track responses over time and refine therapeutic strategies.

Conclusion

We are establishing a de-risking center dedicated to advancing therapies for neurodegenerative diseases. Our research aims to bridge the gap between laboratory findings and clinical applications, ultimately improving the lives of those affected by these conditions. Thank you for your attention as we strive to make the world a better place for everyone.