Project Summary/Abstract Alzheimer’s Disease (AD) is a progressive neurodegenerative disease, manifesting in brain pathology, neuropsychiatric symptoms, and cognitive decline. In general, confirmatory diagnosis of AD involves both pathological hallmarks (such as plaques and tangles) as well as clinically observed cognitive decline. Whereas most cases of patients with AD pathology show cognitive and clinical phenotypes, a subset of individuals have pathology suggestive of AD without the corresponding cognitive impairment. One possible explanation is that these “resistant” individuals have compensatory mechanisms protecting their cognitive status from the presence of pathology. Recent work from single-nucleus RNA-sequencing on post- mortem human frontal cortex tissue suggests molecularly distinct subsets of astrocytes (a non-neuronal cell type in the brain) are differentially present in “resistant” versus “susceptible” (cognitively declined with pathology) individuals. However, this observation so far has been limited to a single brain region in a small sample of primarily Caucasian individuals. This proposal aims to corroborate and extend this finding by investigating astrocyte subpopulations, their molecular profiles, and their associations with other cell types in multiple regions of the brain in an ethnically diverse. Through a combination of single- nucleus RNA-sequencing, spatial transcriptomics, immunohistochemistry, and systems biology, we propose to create a map of the differential distribution of astrocyte subpopulations in “resistant” and “susceptible” individuals, their spatial relation to pathology and other cell types, and candidate genes and pathways that involved in astrocyte-mediated resistance to tau pathology. Ultimately, characterizing the association between specific astrocyte subpopulations, their interactions, and pathways involved in resistant individuals may identify therapeutic avenues to mitigate cognitive decline in the presence of AD pathology.

Project Narrative Whereas Alzheimer's Disease (AD), a progressive neurodegenerative disease, generally manifests in cognitive decline and brain pathology in the form of plaques and tangles, a subset of aged individuals show AD-like pathology without the corresponding cognitive decline. Initial post-mortem analysis of brain tissue from these “resistant” individuals has highlighted changes in the composition of a specific class of non-neuronal cells called astrocytes, suggesting that distributions of these cells may confer protection against AD pathology. This proposal aims to shed light on astrocytes and coordinated changes in their composition with other cells at the molecular level, thus furthering our understanding of the disease, and potentially identifying sets of therapeutic avenues to counter cell type- dysregulation in AD.