O2‐02‐06: Butyrylcholinesterase pharmacogenomics in mild cognitive impairment
Bibliographic record
Abstract
Mild cognitive impairment (MCI) is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease. Genetic variations commonly occuring in the general population impact on cognitive performance and MCI to Alzheimer conversion. Using samples from the 2005 MCI double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function. Data was re-assessed following apolipoprotein E4 (apoE4) and butyrylcholinesterase K (BuchE-K) stratification: two key modulators of cholinegic activity in the adult central nervous system. From a total of 769 MCI subjects enrolled in the study, 212 patients developped possible or probable Alzheimer's disease. The conversion rates were significantly modulated by the presence of the apoE4 and BuchE-K allele. Among carriers of the apoE4 or BuchE-K alleles, the cognitive benefit on Alzheimer Disease Assessement Scale-cognitive scale of donepesyl versus placebo was statistically significant after 36 months of treatment for the K-carrier subjects (p <0.009) and nearly significant for the E4 cases (p = 0.07). In the combined placebo/Vitamin E data set, ADAS-Cog decline after 36 months averages 3.7 points for the E4/K (p < 0.005), 3.4 points for the E4/K-negative (p < 0.005), 4.6 points for E4-negative/K (p < 0.02) subjects, but is not significantly different from baseline (-1.8 point: p = 0.08) for the E4-negative/K-negative subjects. Determination of apoE and BuchE genotypes before treatment with cholinesterase inhibitors might prove useful in predicting clinical response in MCI subjects over time. Furthermore, results clearly indicate that combining apoE/BuchE genetic profilings to neuropsychological assessments may help identify a sub-group of fast converting individuals that could be used as prime “at risk” candidates for upcoming prevention trials.
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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 | 0.000 |
| 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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".