The moderating effect of <i>APOE</i> E4 on the association of plasma biomarkers with markers of cognition and brain health in Alzheimer’s disease
Bibliographic record
Abstract
Abstract Background Due to low success rates in clinical trials for Alzheimer’s disease (AD), there is a need to apply precision medicine approaches, such as stratifying based on APOE genotype, in order to assess its effects on outcome measures. Herein, we aim to better understand how plasma biomarkers of AD and neurodegenerative pathology are associated with cognition and neurodegeneration in APOE E4 carriers compared to non‐carriers. Method Patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) diagnosed with AD were included (n = 126, age = 71.0±8.2, 55%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using Simoa assays. Composite cognitive domain scores (attention & working memory, executive function, language, memory, and visuospatial function) were computed from a comprehensive neuropsychological assessment. Volumes of regional grey matter, ventricular cerebrospinal fluid, white matter hyperintensities, perivascular spaces, lacunes and strokes were extracted from 3T structural MRI sequences using the SABRE pipeline. Linear regression models with an interaction term, controlling for age, sex and education were used to test the moderating effect of the APOE E4 allele on the association of plasma biomarkers with cognitive and MRI variables. When interaction effects were significant, post‐hoc models stratified by APOE E4 carrier status and controlling for age, sex and education were assessed. Result The APOE E4 allele moderated the association of GFAP, NfL and p‐tau181 with memory. Further stratification revealed that higher levels of GFAP, NfL and p‐tau181 were all associated with worse memory only in APOE E4 carriers. APOE E4 was also found to moderate the association of GFAP and p‐tau181 with many imaging markers. Further stratification revealed that higher levels of GFAP were associated with increased white matter hyperintensities, ventricular expansion and grey matter atrophy (temporal lobe, occipital lobe, hippocampus, basal ganglia and thalamus) only in APOE E4 carriers. Higher levels of p‐tau181 were also associated with increased temporal, parietal, and hippocampal atrophy only in APOE E4 carriers. Conclusion Plasma biomarkers, especially GFAP and p‐tau181, appear to be significantly more predictive of memory deficits and brain neurodegeneration in APOE E4 carriers compared to non‐carriers in AD.
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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 | 0.002 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| 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".