Central Sensitization and Cognitive Vulnerability: A Neurobiological Framework for CNS Resilience and Brain Aging

Preservation of central nervous system (CNS) resilience during midlife is increasingly recognized as an important determinant of healthy cognitive aging, as biological processes contributing to Alzheimer's disease and related dementias (ADRD) may begin decades before clinically apparent impairment. Identifying measurable physiological states associated with diminished CNS resilience during this period is therefore an important objective of brain-aging research. Central sensitization is a neurophysiological process characterized by enhanced CNS responsiveness, impaired inhibitory modulation, and altered nociceptive processing that may occur within broader biological contexts involving neuroimmune activation, autonomic dysregulation, metabolic stress, and network dysfunction.

This narrative review examines whether persistent sensitization-related physiology may represent one measurable component of diminished CNS resilience. We synthesize epidemiologic evidence linking chronic pain with adverse cognitive outcomes and review areas of biological convergence involving neuroimmune signaling, mitochondrial dysfunction, autonomic regulation, synaptic plasticity, and functional brain network organization. Fibromyalgia is considered as one extensively studied but biologically heterogeneous clinical disorder in which sensitization-related mechanisms are frequently observed, rather than as a surrogate for central sensitization itself. Emerging approaches for characterizing sensitization-related physiology, including quantitative sensory testing, neuroimaging, metabolomics, blood-based vibrational spectroscopy, and multimodal biomarker strategies, are also discussed.

Current evidence demonstrates biological overlap between sensitization-related physiology and processes implicated in brain aging but does not establish that central sensitization independently accelerates cognitive aging or causes neurodegenerative disease.

We propose a hypothesis-generating framework in which persistent sensitization-related physiology represents one candidate component of systems-level CNS resilience. Prospective longitudinal studies integrating objective physiological measures with cognitive and biological phenotyping will be required to determine whether this framework contributes meaningfully to understanding cognitive trajectories or precision brain health.