IL6 Transsignaling in Alzheimer's Disease
Bibliographic record
Abstract
Alzheimer’s Disease (AD) is a neurodegenerative disease process manifesting clinically with cognitive impairment and dementia (63). While AD pathology is complicated neuroinflammation has been shown as a consistent feature (35). IL6 is a multifaceted cytokine involved in a plethora of cellular mechanisms including both anti-inflammatory and inflammatory processes (1,2). IL6 can signal classically through the membrane bound receptor or by transsignaling forming a complex with the soluble IL6 receptor (sIL6R) and activating membrane bound glycoprotein 130 (gp130) (13-16). Transsignaling has been hypothesized to be the primary mechanism of IL6 mediated neurodegeneration (19). The IL6R rs2228145 coding polymorphism (Asp358Ala) has been demonstrated to increase the levels of sIL6R in both plasma and CSF (56). To determine whether IL6 transsignaling could have a potential role in AD, we genotyped the Ala358 allele and assayed IL6 and sIL6R concentrations in paired samples of plasma and CSF obtained from 120 participants with normal cognition, mild cognitive impairment, or probable AD enrolled in the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core. Inheritance of the Ala358 variant and measures of plasma IL6 and sIL6R were correlated with cognitive status as well as clinical data, including the: Montreal Cognitive Assessment (MoCA), modified Preclinical Alzheimer’s Cognitive Composite (mPACC), cognitive domain scores obtained from the Uniform Data Set (UDSv3), CSF concentrations of pTau 181, β-amyloid (Aβ) Aβ40 and Aβ42 concentrations to determine transsignaling effect on AD Severity. We found that inheritance of one or two copies of the IL6R Ala358 allele and elevated sIL6R levels in plasma and CSF were correlated with poorer scores on mPACC, MoCA and memory domain scores, increases in CSF pTau and decreases in CSF Aβ42/40 ratio in both unadjusted and covariate adjusted statistical models. These data suggest that IL6 transsignaling and the possession of the IL6R Ala358 allele may be modifiers of AD. Follow-up, prospective studies are necessary, as this subgroup of patients may be identified as ideally responsive to IL6 receptor–blocking therapies.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".