Impaired CSF Clearance Contributes to the Retention of Alzheimer's Biomarkers Independent of Blood‐Brain Barrier Dysfunction
Bibliographic record
Abstract
Abstract Background Ratio between plasma and cerebrospinal fluid (CSF) biomarkers might inform about the peptide clearance from the central nervous system (CNS) to the peripheral body compartments. However, whether this clearance is linked to blood‐brain barrier (BBB) alterations in Alzheimer's disease (AD) remains unclear. In this study, we examined the ratio between plasma and CSF neurofilament light chain (NfL) and p ‐tau181 and its relationship with BBB permeability in individuals across the AD spectrum. Method We analyzed data of 102 participants (median age 66 years, 54% female) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Plasma and CSF levels of NfL and p ‐tau181 were measured using Lumipulse G1200 (Fujirebio). The CSF/serum albumin quotient, a marker of BBB integrity, was calculated, where higher values indicate increased permeability. Mann‐Whitney U test compared the biomarker ratios among ATN groups. Spearman's correlation examined the association between the plasma/CSF biomarker ratios and amyloid PET ( 18 F‐NAV4694) global standardized uptake value ratio (SUVR), and between plasma/CSF biomarker ratios and the albumin quotient. Result Plasma p ‐tau181/CSF p ‐tau181 ratio and plasma NfL/CSF NfL ratio were decreased in A+T+ individuals (Figure 1), suggesting impaired CSF clearance in AD. No significant differences in albumin quotient values were observed among ATN groups. Moreoever, increased amyloid burden on PET correlated with reduced plasma/CSF p ‐tau181 and NfL ratios (Figure 2), further supporting a link between amyloid pathology and impaired clearance mechanisms. Finally, no significant correlation was found between plasma/CSF p ‐tau181 and NfL ratios and albumin quotient (Figure 3), suggesting that CSF clearance deficit is independent of BBB integrity. Conclusion Our results support the concept that impaired CSF clearance contributes to the accumulation of AD biomarkers in the CNS. Moreover, the impaired CSF clearance does not seem to be associated with BBB dysfunction. These results highlight CSF clearance as a potential therapeutic target for AD, emphasizing the need to explore mechanisms that enhance peptide drainage from the CNS.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".