Apolipoproteins and complement factors mediate vascular and endothelial injury across the Alzheimer's disease continuum

Background The longitudinal interplay among complement activation, lipid dysregulation, and endothelial dysfunction across the Alzheimer's disease (AD) continuum remains unclear. Objective The goal of this study was to determine longitudinal changes in plasma Complement C3 and Factor H across the AD continuum and their mediating effects linking lipid dysregulation to endothelial dysfunction and cognition. Methods Using longitudinal data from the Alzheimer's Disease Neuroimaging Initiative, we analyzed plasma Complement C3 (C3), Factor H (CFH), apolipoproteins, and markers of vascular and endothelial injury in stable mild cognitive impairment (MCI), progressive MCI, and AD over 1 year. Results Baseline C3 levels were higher in AD and were associated with worse cognitive performance. Over 1 year, C3 levels and the C3/CFH ratio decreased in all groups, whereas increased in stable and progressive mild cognitive impairment but remained unchanged in AD. MMSE showed a significant negative correlation (r = -0.26, p < 0.05) with baseline C3, which was highest in the AD-AD group. There was a strong correlation between C3, CFH, fibrinogen, and ICAM in the MCI-AD and AD-AD cohorts. The AUC for predicting cognitive impairment using clinical data with C3 and CFH was 0.92 (95% CI: 0.87–0.95). Importantly, mediation analysis revealed C3 as a key hub mediating the positive impact of Apolipoprotein H on the expression of Fibrinogen (Beta = 0.21, p < 0.001) and intercellular adhesion molecule-1 (ICAM-1). Conclusions Complement-related plasma biomarkers exhibited distinct longitudinal patterns across the AD continuum, characterized by a common decline in C3 but stage-specific changes in complement regulation markers.