Proteomic signatures of the <i>APOE ε4</i> and <i>APOE ε2</i> genetic variants and Alzheimer’s disease
Bibliographic record
Abstract
Abstract The ε4 and ε2 alleles of the Apolipoprotein E ( APOE ) gene confer opposite genetic risks for Alzheimer’s disease (AD), but their underlying molecular mechanisms remain poorly characterized in humans. To resolve this, we systematically profiled APOE -associated proteomic alterations across five cohorts—including the Global Neurodegeneration Proteomics Consortium (GNPC), BioFINDER-2, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Parkinson’s Progression Markers Initiative (PPMI), and UK Biobank (UKB)—using SomaLogic and OLINK platforms in plasma and cerebrospinal fluid (CSF) from over 10,000 individuals. Using GNPC (plasma SomaLogic, N=4,045), we mapped a comprehensive APOE -protein network and applied mediation modeling to classify genotype-related signals as upstream mediators, downstream consequences, or APOE -specific changes. We then leveraged CSF beta-amyloid (Aβ) biomarker data from BioFINDER-2 (plasma SomaLogic, N=1,421) to improve temporal resolution and isolate early, Aβ-independent proteomic programs. In the Aβ-individuals, APOE4 was linked to cell cycle and chromatin remodeling, while APOE2 was associated with mitochondrial regulation and DNA repair. Mediation analyses nominated proteins such as S100A13, TBCA, SPC25 for APOE4 , and APOB, SNAP23 for APOE2 as candidate upstream effectors, supported by CSF validation (ADNI, SomaLogic, N=666), brain transcriptomic co-expression, and AD GWAS colocalization. Longitudinal CSF data from PPMI confirmed the temporal stability of several APOE -associated proteins. Cross-platform comparisons (UKB plasma OLINK, N=4,820, and BF2 CSF OLINK, N=1,475) revealed matrix- and assay-specific heterogeneity, underscoring challenges in reproducibility. Together, our results delineate allele-specific, temporally structured proteomic signatures that precede AD pathology, offering insight into APOE -driven molecular pathways and potential therapeutic targets for early intervention.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".