Diagnostic association of ante-mortem biomarkers with cerebral amyloid angiopathy in a cohort with high Alzheimer's disease comorbidity

Background Cerebral amyloid angiopathy (CAA) frequently co-occurs with Alzheimer's disease (AD), complicating the interpretation of biomarkers. Current diagnostic approaches rely largely on neuroimaging but remain constrained by limited accuracy. Objective This study aimed to evaluate the diagnostic discrimination and pathological association of neuropathological scoring systems and fluid biomarkers for CAA using pathologically confirmed samples. Methods We examined 100 participants from the Alzheimer's Disease Neuroimaging Initiative with complete neuropathological assessments. Associations and diagnostic performance of amyloid-β (Aβ)-related measures were evaluated using multivariable regression and receiver operating characteristic analyses. Results Both Thal phase and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) score were associated with CAA status. Cerebrospinal fluid (CSF) Aβ 42 , Aβ 40 , and Aβ 38 concentrations were significantly reduced in CAA, with CSF Aβ 42 showing the greatest decrease and highest diagnostic accuracy [area under the curve (AUC) 0.962; sensitivity 88.6%; specificity 100%). Plasma Aβ 42/40 ratio was also markedly lower in CAA and demonstrated robust diagnostic discrimination (AUC 0.913; sensitivity 84.6%; specificity 100%). In contrast, inflammatory and neuronal injury markers did not differ significantly between groups. Conclusions Neuropathological scores and fluid biomarkers are associated with the presence and severity of CAA, but this association is confounded by co-existing advanced AD pathology. Despite high discriminative accuracy, the small control sample warrants cautious interpretation of specificity estimates.