Complement proteins C1q, C3, and Factor H are associated with early tau pathology and synaptic integrity in persons with pre‐symptomatic Alzheimer’s disease
Bibliographic record
Abstract
Abstract Background The immune complement system is key to the elimination of redundant neural connections in the brain through a process called synaptic pruning. In neurodegenerative diseases such as Alzheimer's disease (AD), this system may result in excessive synapse loss, leading to brain atrophy and cognitive impairment. While increased cerebrospinal fluid (CSF) levels of complement proteins have been observed in patients with AD dementia, no studies have yet investigated the role of complement in the pre‐symptomatic phase of AD, nor throughout its progression. Method We used Luminex technology to assess complement protein levels in 566 CSF samples obtained over five years from 160 high‐risk asymptomatic subjects with familial history of AD [the PREVENT‐AD cohort; Breitner et al, 2016: JPAD 3,(4) 236]. Baseline complement levels were contrasted with CSF biomarkers of AD pathology (Aβ42, p(181) and total tau, NFL) and markers of synaptic dysfunction (GAP‐43, SYT1, SNAP‐25, ADAM22, ADAM23). Analyses were stratified by sex and ApoE4 carrier status. Currently pending are additional longitudinal analyses probing complement levels versus PET‐quantified cerebral amyloid and tau deposition, MRI volume of AD‐implicated structures, and cognitive ability (RBANS). Result Preliminary analyses revealed significant positive associations between complement proteins and p‐(181)tau (C1q: R2 = .238, p < .0001; C3: R2 = .041, p = .0099; C3b: R2 = .027, p = .0384; Factor H: R2 = .128, p < .0001) and total tau levels (C1q: R2 = .247, p < .0001; C3: R2 = .023, p = .0543; Factor H: R2 = .128, p < .0001). Complement relationships with synaptic protein levels were more significant overall in females, which showed the following associations [GAP‐43 (C1q: R2 = .389, p < .0001; Factor H: R2 = .315, p = .0002); SNAP‐25 (C1q: R2 = .367, p < .0001; C3: R2 = .106, p = .0459; Factor H: R2 = .278, p = .0072); SYT1 (C1q: R2 = .316, p = .0002; Factor H: R2 = .246, p = .0015)]. Conclusion There is a clear association between complement levels, tau pathology, and synaptic markers in the asymptomatic phase of AD, especially in women. Longitudinal and multimodal investigation is ongoing to further characterize these relationships.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".