An explorative analysis of plasma biomarkers associated with cerebral amyloid angiopathy

Background: Cerebral amyloid angiopathy (CAA) remains diagnostically challenging, particularly in asymptomatic individuals. While CAA often co-exists with Alzheimer's disease (AD), it may even have a direct impact on AD pathophysiology and the cognitive decline within the clinical course of AD. While fluid biomarkers are well-established for AD pathology, reliable markers to improve the characterization of CAA are lacking. Methods: We analyzed two subsets of participants from the Alzheimer's Disease Neuroimaging Initiative: one with available T2*-weighted gradient echo magnetic resonance imaging (MRI) (n=21) and another with postmortem neuropathological data (n=24), all with available plasma biomarkers from a 145-analyte multiplex immunoassay panel. We defined CAA as two or more lobar microbleeds in MRI or moderate to severe neocortical amyloid angiopathy in neuropathological examination. Plasma analytes were assessed twice per subject, one year apart, with the earlier sample obtained up to 6.6 years prior to either the first MRI or neuropathological examination. Non-parametric correlation and receiver operating characteristic curves were mainly reported. Results: In both cohorts, various markers related to inflammation, lipid metabolism, and cell adhesion were associated with CAA proxy measures. Specifically, both increased (Osteopontin, VCAM-1) and decreased (vitronectin or endothelial growth factor) biomarker levels were associated with MBs, while increased apolipoproteins (ApoAII, ApoCI and ApoCIII, ApoE and clusterin) and decreased AXL were associated with CAA severity in neuropathology. Ratios between inversely associated markers enhanced correlation strength and discriminated CAA status. Conclusions: Several candidate plasma biomarkers of CAA were identified in individuals with either MRI or neuropathological indicators of CAA.