Table 1.
Mapping of Zhang et al. (2025) findings to the hierarchical-circular model of biological memory.
| Finding | HCM level | Evidence from Zhang et al. (2025) | Consistency |
|---|---|---|---|
| 44 CpGs and 44 DMRs associated with incident dementia | Level 2: Epigenetic molecular memory | Meta-analysis identified 44 CpGs (FDR < 5%) and 44 DMRs (Sidak p < 0.05) consistently associated with time to dementia in FHS9 and ADNI. | Indirect/conceptual – DNA methylation is the molecular substrate of epigenetic memory. |
| Pathway enrichment: immune responses | Level 4: PNEI network | Enriched KEGG and Reactome pathways included B-cell receptor signaling, chemokine signaling, leukocyte transendothelial migration, IL-1 signaling, and Toll-like receptor cascades. | Indirect/conceptual – The PNEI network encompasses neuroimmune dynamics; inflammation is a core component of allostatic load. |
| Pathway enrichment: metabolic dysfunction | Level 3: Allostatic load | Enriched pathways included glycolysis/gluconeogenesis, insulin signaling, and steroid biosynthesis. | Indirect/conceptual – Metabolic dysfunction is a key component of allostatic load and systemic physiological adaptation. |
| MRS predicts cognitive decline | Level 2 → Prediction 1 | MRS significantly associated with progression (estimate = 0.142, p = 0.041) after adjustment for age, sex, APOE4, education, baseline diagnosis, and MMSE. | Supports Prediction 1 – Composite epigenetic indices outperform single biomarkers. |
| Independence from APOE4 and education | Prediction 4 | MRS remained significant after adjustment for APOE4 status and years of education. | Supports Prediction 4 – Allostatic integrity (reflected by epigenetics) is consistent with being distinct from genetic risk and cognitive reserve. |
| Temporal precedence: methylation precedes dementia | Circular dynamics | Longitudinal design (FHS9: 4.98 ± 2.33 years; ADNI: 5.97 ± 3.00 years) with DNAm measured at baseline, before dementia onset. | Consistent – Epigenetic changes precede clinical dementia, supporting Level 2 → Level 5 propagation. |
Evidence is classified as indirect/conceptual support because pathway enrichment and observational associations do not directly measure physiological allostatic load or establish causality.