The IL‐18 signaling cascade is implicated in aging, tau pathology and synaptic degeneration
Bibliographic record
Abstract
BACKGROUND: Emerging evidence suggests a bidirectional role of inflammation in Alzheimer's Disease (AD), possibly protecting against amyloid deposition early but exacerbating later tau-related injury. The NLRP3 inflammasome, a driver of "inflammaging" (chronic low-grade inflammation increasing with age), is implicated in AD pathogenesis and progression. We explored a pivotal marker of NLRP3 activation, IL-18, and its signaling cascade through the AD continuum. METHOD: We used longitudinal data from the PREVENT-AD cohort of at-risk/pre-symptomatic AD participants, as well as cross-sectional data from the ADNI cohort of symptomatic AD and cognitively unimpaired (CU) participants. General and mixed linear models analyzed associations among cerebrospinal fluid (CSF) levels of IL-18 cascade proteins (OLINK p-E-A, SomaScan), AD pathology markers (p(181)tau, t-tau, Aβ42) (ELISA, ECLIA), and markers of synaptic damage (OLINK p-E-A, mass spectrometry), and cognition (RBANS). Post-mortem brain tissue samples of autopsy-confirmed AD and CU individuals were used to analyze cortical IL-18 cascade proteins and their mRNA in relation to AD pathological deposition of tau and Aβ. RESULT: CSF IL-18 levels significantly increased with age, where CSF IL-18 levels (β=0.0114, p = 0.027) and IL-18 mRNA (β=0.028. p = 0.005) in post-mortem tissue were longitudinally associated with subject age. IL-18 signaling proteins were significantly associated with increasing tau pathology, both in the CSF (β=0.00411, p = 0.003) and in post-mortem brain tissue (β=0.278, p = 0.035). As well, a naturally occurring genetic variant in the IL-1 receptor gene cluster was related significantly to tau-related pathological CSF markers and deposits. Subsequent analyses in the PREVENT-AD cohort demonstrated a significant association of IL-18 signaling on cognition (β=2.3203, p = 0.049) and synaptic marker levels in the CSF (β=0.8737, p <0.001). CONCLUSION: The IL-18 signaling cascade is modulated by age and plays a crucial role in the pre-symptomatic stage of AD. Contrary to expectation, IL-18 signaling appears to modulate tau pathology throughout the entire AD continuum, having little or no impact on Aβ pathology. We recently described very strong associations between markers of synaptic degeneration, tau pathology, and cognition (https://doi.org/10.1038/s41380-024-02884-z). The presented results on IL-18 signaling may help explain the relationship between tau pathology, synaptic damage and ensuing cognitive decline.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 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) | 0.001 | 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".