P1‐076: Involvement of paraoxonase 1 (PON‐1) genetic variants in Alzheimer pathophysiology
Bibliographic record
Abstract
Evidence suggests that genes involved in brain cholesterol homeostasis are of particular relevance toward Alzheimer's disease (AD) etiology. Among these genes, paraoxonase 1 (PON1) has gained newfound interest from a public health perspective as recent studies suggest that PON1 L55M and Q192R genetic variants might affect individual susceptibility to environmental events, such as the exposure to cholinesterase inhibitors. This genetic study used a large cohort of clinical and autopsy-confirmed AD cases and age-matched, cognitively intact controls from the Douglas Hospital Brain Bank, Quebec, Canada (n = 1066) to examine the impact of PON-1 genetic variants on i) cholinergic integrity, ii) amyloid deposition and tangle density. Furthermore, we examine the effect that PON-1 risk variants may exert on drug responsiveness and efficacy in AD and MCI subjects treated cholinesterase inhibitors. Evidence presented here suggests multiple sex-specific effects of PON1 polymorphisms on AD etiopathology. The L55M Met allele exerts an AD risk enhancing effect only in men (p < 0.001), whereas both men and women carrying the M55M/Q192Q genotype exhibit an increased survival (2,5 years, p < 0.05) and a later age of onset of AD (1,5 years, p < 0.05). These genetic variants are also individually and significantly associated, sometimes in opposite directions for both sexes, with beta-amyloid levels (p < 0.001), senile plaque accumulation (p < 0.001) and choline acetyltransferase activity (p < 0.05) in respectively 2 out of 2, 5 out of 6, and 3 out of 6 brain areas. In regard to cholinergic drug reponse, we found little evidence supporting a role for PON-1 variants (as oppose to apoE4 and BuchE K variants) in modulating the clinical response to acetylcholine esterase inhibitors. Our results suggest an involvement of PON-1 genetic variants in the etiopathology of AD but a limited impact on cholinomimetic drug responses. Sponsered by the Canadian Institute for Health Research.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".