Integrative Spatial Technologies for Mapping Axonal Vulnerability in Alzheimer’s Disease

Abstract

Alzheimer’s Disease (AD) is the most common neurodegenerative disorder and is histopathologically defined by the accumulation of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tau tangles. Pathology progression in AD follows a highly stereotyped, hierarchical pattern, implying a circuit-specific neuronal vulnerability to the underlying pathophysiological processes. Understanding the molecular and subcellular mechanisms driving this selective vulnerability has the potential to enable targeted, circuit-specific therapeutic approaches for early intervention in the detrimental spread of disease. This thesis systematically reviews the current mechanistic understanding of selective vulnerability and early disease development in AD and explores how emerging integrative spatial technologies can address remaining open questions. First, molecular and subcellular processes underlying axonal Aβ and tau accumulation are examined, with a focus on cytoskeletal dynamics and axonal transport deficits. Second, intrinsic structural and metabolic risk factors shared by vulnerable axons are outlined, offering a potential explanation for the early regional onset of pathology. Since AD pathology appears to spread from these initial sites along synaptic connections, mechanisms of transsynaptic propagation of vulnerability are discussed next. Finally, the thesis compares integrative spatial technologies used to map disease progression and proposes neuronal barcoding as a promising strategy to overcome existing limitations.