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

## TL;DR

The study finds that certain soluble Aβ monomers are linked to vascular amyloid buildup in brains without plaque, while cognitive decline may involve other Aβ forms.

## Contribution

The study identifies specific soluble Aβ monomers as markers for cerebral amyloid angiopathy in plaque-free brains.

## Key findings

- Higher levels of soluble Aβ42 and Aβ ratios are significantly associated with cerebral amyloid angiopathy severity.
- Total Aβ levels measured by selected reaction monitoring correlate with global cognitive decline.
- Cognitive impairment may be driven by aggregated or extended Aβ forms rather than monomers.

## Abstract

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.

Liu et al. report that soluble Aβ monomers, particularly longer species such as Aβ42, are strongly associated with cerebral amyloid angiopathy in plaque-free human brains, whereas cognitive decline relates more to aggregated or extended Aβ forms. These findings highlight soluble Aβ ratios as potential early markers of vascular amyloid pathology.

Graphical AbstractFor image description, please refer to the figure legend and surrounding text.