Researchers at Stanford’s Knight Initiative for Brain Resilience merge spatial transcriptomics and AI to uncover how local cellular interactions drive brain aging and resilience
This project focuses on the brain’s “glycocalyx”—a complex network of sugars on the cell surface, which plays a crucial role in many brain functions including how neurons connect and communicate and how memories are formed and stored. Despite the glycocalyx’s importance in the brain’s response to aging and neurodegenerative diseases like Alzheimer’s, the exact roles and changes of the glycocalyx throughout life are poorly understood.
Normal aging and neurodegenerative disease are typically characterized by accumulation of waste products inside the brain and in particular by aggregation of various types of proteins like Amyloid-beta outside of cells or the proteins Tau, alpha-synuclein, and TDP-43 inside cells. These observations are so characteristic that some of them have elevated to the defining features of diagnosing a particular condition such as Alzheimer's disease.
The ketogenic diet, fasting, and ketone supplements switch the body's fuel source from carbs to fats, a state known as ketosis. This switch can be good for your brain, helping to keep it healthy and resilient to damage. In ketosis, your liver makes a special fat-derived fuel called beta-hydroxybutyrate (BHB). BHB is like a cleaner fuel for your brain—it doesn't leave as many harmful leftovers as sugar does, and it can also tell your brain to turn on defense mechanisms.
Brain resilience—the ability to withstand adverse outcomes despite significant risk factors—is crucial in late-onset Alzheimer’s disease (AD), where the Apolipoprotein E4 (APOE4) gene is a major risk factor. Carrying APOE4 increases AD risk up to 15-fold compared to the ApoE3 allele. Recent single-cell sequencing advancements reveal altered APOE4 expression in various brain cell types, reshaping our understanding of its impact. Despite most APOE4 carriers developing AD, some exhibit resilience, showing normal cognitive function despite pathology.
It has been appreciated for decades that cognitive decline and dementia are frequently accompanied by changes that cause proteins within brain cells to clump abnormally into structures called neurofibrillary tangles. Resilient brains are better able to resist this process but the underlying mechanisms for why individuals’ brains are either more or less resilient are not fully understood. This research seeks to understand the intrinsic mechanisms inside cells that help to determine whether proteins inside our brain cells clump or remain well-behaved.
Memories are stored at synapses and circuits, which tragically are pruned and deconstructed in Alzheimer's disease (AD). Genetic mutations including APP generate high levels of soluble oligomeric beta amyloid (oAbeta42), leading to insoluble beta amyloid plaques—hallmarks of late-stage disease. Clinical trials have designed "plaque-busting" drugs assuming that plaques cause disease. However, disappointing outcomes demand new approaches. Inflammation is also an AD risk factor, including complement cascade molecules.
This team aims to use the power of artificial intelligence to make new findings about brain aging, with the goal of boosting brain repair and resilience. They are particularly interested in spatial changes in the brain during aging. Their goal is to understand how aging renders the brain susceptible to injuries that accentuate neurodegenerative diseases. This is an underexplored question because brain injuries are usually not studied from the standpoint of age, and this viewpoint should identify new ways to boost brain repair and resilience.
Why do our brains get worse at learning as we get older, and what can we do about it? Institute affiliate Carla Shatz discusses our brain's capacity for change on this podcast episode.
This week on From Our Neurons to Yours, we talk with memory expert Anthony Wagner about the nature of memory and how to improve it.