{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:05:37Z","timestamp":1790057137421,"version":"4.0.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The Hierarchical-Circular Model of Biological Memory (HCM) proposes that dementia results from disrupted circular information flow across five levels: genetic, epigenetic, allostatic, PNEI network, and interoceptive. Allostatic integrity\u2014the adaptive capacity for circular flow\u2014determines whether pathology translates into dementia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To evaluate whether a recently published blood DNA methylation signature for incident dementia is consistent with the predictions of the HCM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We systematically mapped Zhang et al.\u2019s findings (44 CpGs, 44 DMRs, pathway enrichments, methylation risk score) to HCM levels and predictions. We interpreted these findings as providing indirect and conceptual support for the model rather than direct empirical validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The 44 CpGs\/DMRs linked to dementia were enriched in immune and metabolic pathways. Their methylation risk score predicted cognitive decline independently of age, sex, APOE\u03b54, education, and MMSE. These findings are consistent with the HCM\u2019s Level 2 (epigenetic memory), Levels 3\u20134 (allostatic load\/PNEI), and Predictions 1 (composite biomarkers outperform single) and 4 (allostatic integrity moderates reserve).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Epigenetic changes precede dementia, supporting Level 2 as an early event. Immune\/metabolic pathways link to allostatic load. Independence from APOE\u03b54\/education is consistent with allostatic integrity being distinct from genetic risk and reserve.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Zhang et al.\u2019s study provides large-scale evidence that blood DNA methylation may serve as a peripheral biomarker of lost allostatic integrity, consistent with the HCM and supporting a shift from linear to circular, multilevel frameworks for dementia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1919708","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:41:15Z","timestamp":1790055675000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic memory and allostatic integrity: a theoretical integration of the hierarchical-circular model using a longitudinal methylation signature of dementia"],"prefix":"10.3389","volume":"18","author":[{"given":"Samuel","family":"Ruesga Mundo","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Regional General Hospital No. 180,Instituto Mexicano del Seguro Social (IMSS)","place":["Tlajomulco de Z\u00fa\u00f1iga, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1186\/s13073-025-01548-z","article-title":"Polygenic risk for Alzheimer\u2019s disease in healthy aging: age-related and APOE-driven effects on brain structures and cognition","volume":"17","author":"Chen","year":"2025","journal-title":"Genome Med."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.cobeha.2017.08.014","article-title":"The influence of physiological signals on cognition","volume":"19","author":"Critchley","year":"2017","journal-title":"Curr. 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