<i>CYP2C19</i> variant mitigates Alzheimer disease pathophysiology in vivo and postmortem
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Bibliographic record
Abstract
<h3>Objective</h3> To verify whether <i>CYP</i> polymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 independent cohorts. <h3>Methods</h3> A candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [<sup>18</sup>F]florbetapir PET standardized uptake value ratio (SUVR) in 338 Alzheimer9s Disease Neuroimaging Initiative participants. Significant results were then tested using plasma Aβ and CSF Aβ and Aβ/phosphorylated tau (Aβ/p-tau) ratio in the same cohort. The significant association was also generalized to postmortem Aβ load measurement in the Rush Religious Orders Study/Memory and Aging Project cohorts. In addition, global cognition was used as a phenotype in the analysis in both cohorts. <h3>Results</h3> Analysis of Aβ PET identified a variant in the <i>CYP2C19</i> gene (rs4388808; <i>p</i> = 0.0006), in which carriers of the minor allele (MA) had a lower global SUVR. A voxel-wise analysis revealed that the variant is associated with a lower Aβ load in the frontal, inferior temporal, and posterior cingulate cortices. MA carriers also had higher CSF Aβ (<i>p</i> = 0.003) and Aβ/p-tau ratio (<i>p</i> = 0.02) but had no association with Aβ plasma levels. In postmortem brains, MA carriers had a lower Aβ load (<i>p</i> = 0.03). Global cognition was higher in MA carriers, which was found to be mediated by Aβ. <h3>Conclusions</h3> Together, these findings point to an association between <i>CYP2C19</i> polymorphism and Aβ pathology, suggesting a protective effect of the MA of rs4388808. Despite the several possibilities in which <i>CYP2C19</i> affects brain Aβ, the biological mechanism by which this genetic variation may act as a protective factor merits further investigation.
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| 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 it