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Neuroinflammation as a failure of allostatic integrity: a hierarchical-circular model of biological memory for pathogenesis in neurodegenerative and neuropsychiatric diseases
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DOI：10.3389/fnsys.2026.1888548.png)
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Abstract
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IntroductionChronic neuroinflammation is a hallmark of neurodegenerative diseases (Alzheimer’s disease; Parkinson’s disease) and neuropsychiatric disorders (major depression; schizophrenia). However; current models fail to explain why some individuals develop persistent neuroinflammation while others maintain homeostasis; nor why similar inflammatory pathology produces such diverse clinical phenotypes.HypothesisWe propose that pathological neuroinflammation emerges from a failure of allostatic integrity—the capacity of the organism to maintain adaptive circular information flow across five interconnected levels: (1) genetic architecture and morphogenetic programming; (2) epigenetic molecular memory; (3) allostatic load and systemic physiological adaptation; (4) the psychoneuroimmuneendocrine (PINE) network; and (5) interoceptive-neuronal integration. When this circular flow is disrupted; maladaptive stable states become entrenched; perpetuating chronic inflammation.Development of the hypothesisSynthesizing evidence from longitudinal and mechanistic studies (with foundational older works cited where necessary); we discuss how: (a) early-life stress epigenetically programs inflammatory reactivity; (b) elevated allostatic load predicts chronic neuroinflammation; (c) PINE network dysregulation perpetuates pro-inflammatory signaling; and (d) interoceptive dysfunction may prevent the downregulation of inflammation. Allostatic integrity is introduced as a dynamic systems-level property hypothesized to moderate the relationship between inflammatory pathology and clinical expression.Testable predictionsThe framework generates falsifiable predictions: (1) composite indices of allostatic integrity will outperform single biomarkers in predicting transition to chronic neuroinflammation; (2) multidomain interventions targeting multiple levels will produce multiplicative (synergistic) effects; (3) patients with similar inflammatory profiles but contrasting allostatic integrity will show markedly different clinical trajectories; and (4) improvements in allostatic integrity will correlate with reduced neuroinflammation independent of direct anti-inflammatory therapies.ConclusionThe Hierarchical-Circular Model reframes chronic neuroinflammation not as a linear cascade but as a potential systemic failure of biological memory and allostatic integrity. Pending empirical validation; this framework may offer a conceptual basis for biomarker development; multidomain prevention; and personalized treatment strategies.
Keywords:
neurodegeneration
neuroinflammation
neuropsychiatry
allostasis
biological memory
PINE system
allostatic integrity
hierarchical-circular model
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