Association of Aβ monomers with cerebral amyloid angiopathy in brains without parenchymal Aβ deposition.

β-Amyloid (Aβ) deposition is a hallmark of both Alzheimer's disease and cerebral amyloid angiopathy. Whilst insoluble Aβ aggregates have been extensively studied, the role of soluble Aβ monomers in vascular amyloid pathology-and their association with cognitive decline-remains unclear in plaque-free brains. This study examined whether soluble cortical Aβ species are associated with cognitive outcomes and amyloid-related pathologies, including cerebral amyloid angiopathy, in the absence of parenchymal Aβ deposition. We examined post-mortem cortical tissue from nearly 200 individuals without parenchymal Aβ deposition, drawn from two longitudinal community-based cohorts. Soluble Aβ37, Aβ40 and Aβ42 were quantified by immunoassays, and total Aβ levels were measured using selected reaction monitoring proteomics. Associations with semiquantitative cerebral amyloid angiopathy burden and longitudinal cognitive trajectories were assessed using regression models adjusting for age, sex and education. Higher levels of soluble Aβ-particularly longer species such as Aβ42, reflected by elevated Aβ42/40 and reduced Aβ37/42 ratios-were significantly associated with greater cerebral amyloid angiopathy severity. Whilst immunoassay based total Aβ and Aβ ratio measures showed limited associations with cognitive outcomes, total Aβ levels quantified by selected reaction monitoring remained significantly associated with global cognitive decline. These findings support a pathogenic role for certain soluble Aβ monomers in vascular amyloid deposition. In contrast, cognitive impairment may be driven by other amyloid species such as oligomeric or extended Aβ forms. Aβ ratios may serve as specific markers for cerebral amyloid angiopathy and provide insights into early therapeutic strategies targeting vascular amyloid pathology.