Neuroinflammation as a failure of allostatic integrity: a hierarchical-circular model of biological memory for pathogenesis in neurodegenerative and neuropsychiatric diseases

Introduction: Chronic 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. Hypothesis: We 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 hypothesis: Synthesizing 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 predictions: The 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. Conclusion: The 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.