Brain resilience

This project's goal is to enhance brain resilience by promoting vascular brain health during aging. The research team's overarching hypothesis is that many people experience cognitive decline and dementia due to pathological aging. In pathological aging, mild brain injuries that would be repairable in the young, and even in older people with resilience, lead to damaged blood vessels in the brain.

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.

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.

Recent data suggest that increased circulation of cerebrospinal fluid (CSF) to clear the brain and spinal cord of waste is associated with improved outcomes in aging and recovery from brain injury, suggesting that inducing CSF clearing could enhance brain resilience. However, a therapeutic modality for directly inducing CSF clearing has not been available. Recently, this research team has shown that a low-intensity, noninvasive therapeutic ultrasound protocol increases CSF clearing in rodents.

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.

The intricate workings of signaling pathways are well-established with regard to neurodevelopment. Yet, the implications of these pathways for sustaining brain health and resilience during the aging process are not clear. The Hedgehog (Hh) pathway is a system of particular interest due to its dual role in both early development and its lesser-known functions in adult tissue regulation and repair. Their previous research has demonstrated roles of the Hh pathway beyond embryonic development, indicating its active involvement in the regeneration of adult tissues.

Sleep is critical for brain function in many animals, and chronic disruptions in sleep patterns are strongly linked to the emergence of neurodegenerative diseases like Alzheimer’s and Parkinson’s. When animals sleep, neural activity and brain metabolism change dramatically; however, we do not know what the molecular functions of sleep are in the brain, nor do we know how these processes are linked to brain health.

Maintaining the health and function of the aging brain is crucial to improving the quality of older people’s lives and reducing societal burden. Aging is often accompanied by a decline in memory for life events (episodic memory), especially in those at risk for Alzheimer’s disease (AD). Yet some at-risk individuals manage to maintain memory function, which raises important questions about the brain mechanisms that underly memory resilience.