Fluid biomarkers in cerebral amyloid angiopathy: current limitations and future directions

Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage and cognitive decline in older adults. Current diagnosis relies mainly on neuroimaging, which lacks pathophysiological specificity.

This narrative review summarizes evidence on cerebrospinal fluid (CSF) and plasma biomarkers in sporadic CAA. In CSF, CAA is typically associated with reduced Aβ42 and Aβ42/Aβ40 ratio, although similar alterations are observed in Alzheimer's disease (AD), limiting diagnostic specificity. Lower Aβ40 levels may reflect vascular amyloid deposition and appear more characteristic of CAA, but alone provide insufficient discrimination. Plasma biomarker studies have yielded inconsistent findings due to methodological and population heterogeneity. Nevertheless, amyloid isoforms, phosphorylated tau species, and neurofilament light chain (NfL) show potential, with NfL correlating with imaging markers and disease burden. The increasing need to distinguish CAA from AD and other cerebral small vessel diseases has driven growing interest in fluid biomarkers.

Despite promising findings, no fluid biomarker currently demonstrates sufficient specificity or validation for routine clinical use in CAA. Significant overlap with AD pathology remains a major limitation. Large longitudinal real-world studies are needed to determine the diagnostic, prognostic, and incremental clinical value of fluid biomarkers in CAA.