{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:45:09Z","timestamp":1790703909591,"version":"4.1.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"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. Dement."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease and related dementias remain largely resistant to disease-modifying therapies, despite decades of research focused on linear neuropathological pathways such as beta-amyloid and tau. Persistent paradoxes\u2014including the dissociation between pathology burden and clinical expression, the impact of early-life stress, and the role of systemic factors\u2014indicate the need for integrative theoretical frameworks. This article proposes a multilevel hypothesis conceptualizing dementias as disorders of biological memory and allostatic integrity rather than isolated brain pathologies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Hypothesis<\/jats:title>\n                    <jats:p>The Hierarchical-Circular Model of Biological Memory posits that dementia emerges from progressive disruptions in a circular, multilevel system that encodes and stabilizes biological information across the lifespan. The model is organized around the unifying principle \u201cSignal \u2192 Plasticity \u2192 Stable State\u201d and integrates five interconnected levels: (1) morphogenetic programming and genetic architecture, (2) epigenetic molecular memory, (3) allostatic load and systemic physiological adaptation, (4) the Psychological\u2013Neurological\u2013Endocrine\u2013Immunological (PNEI) network, and (5) interoceptive\u2013neuronal integration. At any level, perturbation can propagate bidirectionally through the system, establishing maladaptive stable states that manifest clinically as dementia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Development of the hypothesis<\/jats:title>\n                    <jats:p>Through a structured synthesis of longitudinal, mechanistic, and multisystem studies (2010\u20132025), the model specifies how gene\u2013environment interactions, epigenetic modifications, cumulative allostatic load, neuroimmune dynamics, and altered interoceptive timescales jointly shape vulnerability and resilience. The concept of allostatic integrity is introduced as a dynamic systems-level property\u2014distinct from allostatic load\u2014that explains why similar neuropathological burdens may result in divergent clinical trajectories. Distinct dementia phenotypes are proposed to reflect different patterns of circular reinforcement across the five levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Testable predictions<\/jats:title>\n                    <jats:p>This framework generates concrete, falsifiable predictions: (1) composite indices of allostatic integrity will outperform single biomarkers in predicting conversion from mild cognitive impairment to dementia; (2) multidomain interventions targeting more than one system level will have multiplicative, rather than additive, effects on slowing cognitive decline; (3) patients with similar amyloid\/tau profiles but contrasting allostatic integrity will show markedly different trajectories of clinical progression; and (4) allostatic integrity moderates the protective effect of cognitive reserve, a pattern not predicted by reserve frameworks alone.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The Hierarchical-Circular Model of Biological Memory offers a unifying hypothesis for Alzheimer\u2019s disease and related dementias that bridges genetic, epigenetic, physiological, neuroimmune, and interoceptive processes across the lifespan. By reframing dementias as failures of biological memory and allostatic integrity, the model provides a conceptual roadmap for mechanistic research, multidomain prevention, and personalized treatment strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/frdem.2026.1841647","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:51:23Z","timestamp":1782276683000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Hierarchical-circular model of biological memory: a multilevel hypothesis for pathogenesis and allostatic integrity in Alzheimer\u2019s disease and related dementias"],"prefix":"10.3389","volume":"5","author":[{"given":"Samuel","family":"Ruesga Mundo","sequence":"first","affiliation":[{"name":"High Specialty Medical Unit, Western National Medical Center, Mexican Institute of Social Security (IMSS)","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/nrn3950","article-title":"Interoceptive predictions in the brain","volume":"16","author":"Barrett","year":"2015","journal-title":"Nat. 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