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.