Complement-mediated neuroinflammation has been implicated in Alzheimer disease (AD), but its role during the pre-symptomatic phase remains unclear. Using the PREVENT-AD cohort of cognitively unimpaired individuals at elevated familial risk, the investigators tested whether cerebrospinal fluid (CSF) complement proteins relate to early AD molecular pathology and markers of synaptic dysfunction. They then examined reproducibility of key findings across the clinical AD spectrum using the ADNI dataset.
In PREVENT-AD, baseline CSF concentrations of complement proteins—C1q, C3, C3b, and Factor H—were measured and analyzed in relation to CSF AD biomarkers (including P-tau181 and T-tau), multiple synaptic protein markers (for example ADAM22, ADAM23, GAP43, SNAP25, SYT1), cognitive performance, MRI volumetry, and amyloid and tau PET imaging. Key associations identified in PREVENT-AD were then tested for reproducibility in a larger ADNI sample of 708 participants spanning cognitively normal, mild cognitive impairment (MCI), and dementia stages.
In PREVENT-AD, C1q showed positive associations with CSF phosphorylated tau (P-tau181) and total tau (T-tau). C1q was also positively associated with multiple CSF synaptic markers including ADAM23, GAP43, SNAP25, and SYT1. Among the complement analytes measured, C1q was the most consistently linked to early tau-related molecular changes and to indices of synaptic integrity.
Factor H exhibited similarly strong positive associations with P-tau181 and T-tau in PREVENT-AD. Factor H was also positively associated with synaptic markers such as ADAM22, ADAM23, GAP43, and SYT1, indicating that complement regulatory components may track with tau-linked synaptic alterations in asymptomatic individuals at risk.
By contrast with C1q and Factor H, C3 demonstrated minimal associations with CSF tau and synaptic markers in the PREVENT-AD cohort. C3b showed weaker positive relationships with P-tau181, T-tau, and ADAM proteins, but these effects were less pronounced than those observed for C1q and Factor H.
Complement protein measures were not robustly associated with amyloid PET or tau PET measures in PREVENT-AD, suggesting a weaker or temporally distinct relationship between fluid complement changes and PET-detectable pathology in this asymptomatic at-risk population. Of the complement analytes, only C1q related to lower global cognitive performance in the PREVENT-AD sample.
In the ADNI sample spanning cognitively normal, MCI, and dementia stages, C1q again emerged as the most consistent analyte, showing positive associations with tau measures, neurofilament light, and synaptic markers across diagnostic groups. C3 exhibited predominantly negative associations in ADNI, whereas C3b and Factor H showed stage-dependent relationships, becoming more evident with clear neurodegeneration and synaptic injury in symptomatic individuals. These replication results indicate both consistency for certain complement associations (notably C1q) and complexity in how different complement factors relate to disease stage.
Together, these observations identify complement dysregulation, particularly involving C1q, as an early correlate of tau-linked synaptic pathology in individuals at elevated familial risk for AD. The pattern of findings—stronger CSF associations with tau and synaptic markers than with PET measures—supports a model in which complement activation may participate in early molecular events of the AD cascade, potentially preceding or occurring independently of PET-detectable amyloid or tau deposition. Replication in the ADNI cohort reinforces C1q's consistent association with neurodegeneration and synaptic injury across clinical stages, while other complement components (C3, C3b, Factor H) show variable, stage-dependent relationships.
The source text reports the principal associations and cohort comparisons but does not provide detailed numerical effect sizes, confidence intervals, exact statistical models, covariates, or sample size breakdowns for each analysis in the abstract. Specific methods for assay platforms, quality control, adjustment for multiple comparisons, and temporal or longitudinal analyses (if any) were not detailed in the provided text. Any limitations discussed by the authors in the full manuscript or supplementary material were not included in the abstract and therefore are not reported here.
In summary, CSF complement proteins—most notably C1q and Factor H—are associated with early CSF tau and synaptic protein changes in an asymptomatic population at increased familial risk for AD. Complement dysregulation may therefore be an early component of the AD molecular cascade, with C1q showing reproducible associations across independent cohorts and across diagnostic stages. Further details and quantitative results require consultation of the full manuscript and supplementary materials.