Tuesday, March 18, 2025
3/18/2025
Cognitive decline in the aging brain is driven by overlapping neurodegenerative and cerebrovascular pathologies. Over 80% of Alzheimer's disease (AD) patients co-present with cerebral amyloid angiopathy (CAA), the vascular deposition of amyloid-β (Aβ). Though CAA and parenchymal Aβ plaques intersect at the levels of Aβ generation and clearance—and share APOE4 as their strongest risk factor—they trigger distinct disease processes: CAA develops insidiously to erode vascular structure and function, induce microbleeds, foment neuroinflammation, and complicate anti-Aβ antibody therapies. Thus, understanding the mechanisms of CAA formation, insult, and clearance in the context of Aβ plaque pathology and APOE genotype is essential to effectively target intertwined neurodegenerative and cerebrovascular pathways in dementia. Yet, the molecular and cellular processes underlying CAA remain incompletely understood. Single-cell genomics has provided insights into various neurological diseases—but not yet CAA because of a lack of high-quality human tissue at scale and the inability to effectively capture brain vascular cell types. Further, animal models of AD have lacked the ability to precisely control CAA formation for its mechanistic study. To address these challenges, we have assembled a multidisciplinary team with expertise spanning vascular neuropathology, clinical imaging, single-cell genomics of the neurovascular unit, AD models, microglia, and APOE biology. We have organized 200 human postmortem brains along CAA progression from ROSMAP with rich demographic, genomic, pathologic, MRI imaging, and longitudinal cognitive data. We will profile these samples with our new brain vascular and immune cell-capturing VINE-seq and spatial genomics approaches. Further, we recently established in mouse models of AD a new paradigm where modulating microglial function is sufficient to control the timing and burden of CAA and microbleeds. We hypothesize that in the healthy aging brain, microglia consolidate soluble Aβ into dense core parenchymal plaques to prevent more damaging vascular Aβ—and this process is disrupted by APOE4 and vascular dysfunction. Thus, we expect enhancing or impairing microglial function will modulate the balance of CAA versus parenchymal Aβ plaque burden. With parallel mechanistic studies in mouse models of CAA and molecular analyses of CAA in human tissue, we will elucidate key microglial mechanisms regulating the formation of vascular CAA versus parenchymal Aβ plaques, define single-cell and spatial human brain immunovascular signatures of CAA, and reveal how brain vascular Aβ clearance mechanisms synergize with microglia to clear CAA. With hypothesis-driven functional studies and foundational human molecular datasets of CAA informing one another, our integrated studies will advance fundamental understanding of CAA to inform the development of sensitive blood biomarkers and new approaches to enhance the safety of anti-Aβ immunotherapies.
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