Longitudinal imaging in a preclinical model of Alzheimer's Disease to identify early biomarkers of cognitive decline

About This Grant

Project Summary/Abstract There is a fundamental gap in understanding how ovarian hormones interact with preclinical Alzheimer’s disease (AD) pathology to influence the neural processes underlying cognitive decline. This limits progress in developing effective interventional strategies for middle-age around perimenopause, which is recognized as a time of heightened risk for dementia in women. This project addresses this gap by identifying early biomarkers of cortical dysfunction and cognitive decline in a transgenic rat model of Alzheimer’s disease and by determining how the loss of ovarian hormones timed to early AD pathology affects the progression of neural and behavioral deficits. The central hypothesis is that hormone loss and AD pathology alter the physiology of inhibitory interneurons such that their convergence accelerates pathological network disruption, accelerating cognitive decline. In the two Aims of this project, longitudinal in vivo calcium imaging of prefrontal cortical neuronal ensembles during a translationally relevant touchscreen operant test of working memory and 2-photon imaging of Aβ deposits will be used to track the changes in genetically defined excitatory and inhibitory neurons. The integration of machine learning and multilevel mixed effects models will decipher complex neural and behavioral activity patterns in an unbiased manner to reveal neural features that predict future cognitive deficits. Aim 1 will identify neuronal patterns associated with age, hormone status, amyloid burden, and behavior, as well as early indicators predictive of future cognitive decline in males and naturally cycling females during working memory testing at 3 pathology timepoints from 6 to 12 months. Aim 2 will determine how ovarian hormone loss—timed to the onset of initial amyloid deposition—affects prefrontal encoding of working memory and progression of amyloid/tau pathology and whether estradiol treatment restores adaptive network activity and buffers against AD-associated cognitive decline. The expected outcome is a new understanding of how reproductive aging and AD pathology converge to disrupt prefrontal circuits, providing critical insight into the timing and mechanisms of hormone- based interventions to prevent or delay AD in women.