Early Entorhinal-Hippocampal Vulnerability and Recovery in Alzheimer's Disease

Alzheimer’s disease (AD) is the most prevalent form of dementia and is expected to impact 2.5-fold more Americans by 2050. Despite this, no effective preventative treatment exists. Although AD research has largely targeted pathological inclusions, recent clinical trials have failed to significantly improve patient quality of life, highlighting the need for earlier intervention through alternative avenues. Recent studies suggest that significant physiological dysfunction which precedes neurodegeneration, may also be a catalyst driving pathological progression. In regions like the Entorhinal Cortex (EC) and hippocampus – areas known to be vulnerable to the earliest phases of AD - circuit malfunctions arise prior to accumulation of plaques or tangles. These regions may serve as prime targets for therapeutic interventions before memory and cognitive decline begin. Particularly, early aberrant excitability in the EC is suggested to propagate AD- related pathology into the hippocampus and, ultimately, throughout the rest of the brain. However, it is unclear whether AD spreads via migrating pathology and how this process begins affecting memory. We observed that early aberrant EC excitability leads to reduced communication between EC and hippocampal circuits, potentially marking the first disruption to a memory-critical circuit. This project proposes to assess for the relevance of these findings in vivo by 1. Determining if Dentate Spikes – crucial physiological events in the DG - are disrupted across AD mouse models and 2. Investigating whether enhancing the EC-DG circuit alleviates subsequent memory loss. The proposed experiments will not only clarify how early AD propagates throughout the brain, but will also provide an early point for AD intervention and a translatable therapeutic method with potential for neurodegeneration prevention.