Cerebrospinal Fluid Complement 4 Levels Were Associated with Alzheimer's Disease Pathology and Cognition in Non-Demented Elderly

Background: Numerous studies have shown that the complement system plays an important role in Alzheimer's disease (AD). However, whether complement 4 (C4) protein in cerebrospinal fluid (CSF) was associated with AD pathology, especially in the early stage of AD, is still unclear. Objective: We aimed to explore the association of CSF C4 with AD pathology and cognition in the preclinical AD. Methods: The study included a total of 287 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Based on the A/T scheme, they were divided into four groups to access the changes of CSF C4 in the preclinical AD. Linear regression models were used to test the associations between CSF C4 and AD core biomarkers, namely A beta(42), P-tau, and T-tau. Results: The level of CSF C4 decreased in the A+ T- group compared with the A-T- group (p = 0.04) and it increased in the A-T+ group compared to the A+ T- group (p = 0.01). In pooled samples, C4 was significantly associated with AD core biomarkers (all p < 0.05), but only in the A+ group after stratification according to the A/T scheme. Furthermore, CSF C4 levels at baseline were associated with longitudinal cognitive changes. Conclusions: Our results showed that CSF C4 levels changed dynamically in the preclinical AD, and that the responses of CSF C4 to brain A beta pathology, tau pathology and neurodegeneration were found only in the presence of amyloid plaques, both of which indicates the complex link between C4 and AD.