Multi-omic Characterization of Astrocyte Reactivity in Alzheimer's Disease

Abstract

Astrocyte activation has emerged as an important early phenotype in Alzheimer’s Disease (AD), potentially linking amyloid pathology with downstream tau hyperphosphorylation and cognitive decline. Astrocyte activation affects the function of the brain’s glymphatic system, a recently characterized network of perivascular channels that facilitates clearance of metabolic waste, including amyloid-β. Additionally, recent findings using plasma glial fibrillary acidic protein (GFAP) as a biomarker of astrocyte activation have highlighted its predictive value as a minimally invasive, in vivo measure for predicting cognitive trajectories in preclinical AD. The field has largely focused on the clearance of amyloid-β as a primary therapeutic target, while mechanisms downstream of amyloid-β deposition may serve as intermediaries for subsequent tau hyperphosphorylation, neurodegeneration, and cognitive decline. The overarching goal of the analyses presented here was to more fully characterize key molecular markers of astrocyte activation in the pathogenesis of AD, focusing on multiple layers of phenotypic validation. This research sought to explore the relationship between gene and protein expression of key glymphatic molecules and AD pathology as well as cognitive decline (Aim 1). Furthermore, to evaluate whether brain GFAP expression reflects peripheral findings, this research characterized the relationship of brain GFAP with AD pathology and cognitive decline, as well as its potential role in modifying the association between amyloid and downstream outcomes (Aim 2). Finally, to elucidate genetically regulated gene expression in a brain transcriptome-derived signature of astrocyte activation, this work developed a polygenic prediction of brain astrocyte activation and tested its ability to predict AD biomarker burden and cognitive decline (Aim 3). In summary, this work deeply explored multiple phenotypes of astrocyte activation in AD, subsequently building on our understanding of astrocytic changes in disease, how they inform trajectories downstream of amyloid-β deposition, and the utility of GFAP as a preclinical biomarker of AD risk and progression.