P1‐061: HMG‐CoA reductase as a risk factor and modulator of Alzheimer pathology
Bibliographic record
Abstract
Several epidemiological studies report that utilization of 3-hydroxymethyl-3-glutaryl-coenzyme A reductase (HMGR) inhibitors at mid-life can reduce the risk of developing sporadic Alzheimer's disease (AD) by as much as 70%, depending on the type of statin used. However, administration of these inhibitors in clinically diagnosed subjects with mild-to-moderate AD confers no benefits over time. We have reported previously evidence of a genetic association between the specific HMGR genetic variants and sporadic AD. In this study, we systematically investigated the contribution of HMGR genetic heterogeneity on AD pathophysiology by examining single-nucleotide polymorphisms in a large but highly homogenous population isolate composed of French Canadians who are descendants of the French founder population who immigrated in North America in the 1700s. A polymorphism in intron B was found to reduce the risk of AD by more than 50%, equaling the protection provided by the apolipoprotein E2 allele in the same population. HMGR mRNA prevalence and protein levels were found to be markedly reduced in the cortical but not in cerebellar area. The effect was found to be genotype driven as well. In contrast, a second polymorphism in intron M was found to significantly increase the risk of AD in a gender specific manner, targeting more specifically women (O.R.: 3.6; p < 0.001). The presence of the intron M risk allele significantly correlates with neurofibrillary tangle densities in six different brain regions in apoE4-negative AD subjects, but not with senile plaque prevalence: consistent with the reported pathological changes reported in brains of AD cases who also happen to be long term users of statins. In conclusion, HMGR common polymorphisms act as genetic modifiers of risk, age of onset and NFTs accumulation, whereas the protective intron B variant reduces risk and HMGR expression in a manner consistent with the reported mode of action of statins.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 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) | 0.002 | 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".