Baseline cerebrospinal fluid complement balance is associated with longitudinal memory decline in relation to plasma p‑tau181 levels in mild cognitive impairment

INTRODUCTION: The role of complement in Alzheimer's disease (AD) remains unclear, particularly regarding tau pathology and memory decline. METHODS: In 123 mild cognitive impairment (MCI) participants from Alzheimer's Disease Neuroimaging Initiative (ADNI), linear mixed‑effects models and Johnson-Neyman analysis examined associations of baseline cerebrospinal fluid (CSF) C3/FH ratio with longitudinal memory decline moderated by time‑varying plasma phosphorylated tau181 (p‑tau181). RESULTS: The three‑way interaction was significant (p = 0.023). A region of statistical significance was identified: the conditional association of C3/FH with memory decline became significant when p‑tau181 exceeded 0.76 SD, with higher C3/FH associated with slower decline at elevated p‑tau181 levels. Cross-sectionally, no significant C3/FH-memory associations were observed in any diagnostic group (all p > 0.05). DISCUSSION: These findings indicate that complement balance is associated with memory decline in MCI in a manner dependent on plasma p‑tau181 levels, suggesting that complement may interact with AD‑related pathophysiology during the prodromal phase. The identified statistical region provides a hypothesis‑generating benchmark for future studies.