Temporomandibular Disorder within the Sleep–Proteostasis Axis: A Translational Hypothesis Integrating Postural Biomechanics and Amyloid Regulation

Abstract Temporomandibular disorders (TMD) have been epidemiologically associated with accelerated cognitive decline, yet the biological substrates potentially underlying this association remain undefined. The glymphatic system, a sleep-dependent pathway implicated in cerebral β-amyloid (Aβ) clearance, is modulated by sleep architecture and body position. It has been proposed that compressive sleep postures adopted to mitigate mandibular discomfort in TMD may alter cervical biomechanics and venous outflow dynamics, thereby conceivably influencing cerebrospinal fluid circulation relevant to glymphatic transport. Convergent experimental and clinical evidence provides biological plausibility for this hypothesis without constituting direct validation. Animal imaging studies demonstrate posture-dependent modulation of glymphatic flux, whereas human neuroimaging data indicate that acute sleep disruption alters regional Aβ kinetics. Chronic pain states, including TMD, are characterized by sleep fragmentation and hypothalamic–pituitary–adrenal axis dysregulation, both independently associated with amyloid-related pathways in non-TMD populations. In parallel, alterations in endocannabinoid signaling described in TMD have been experimentally linked to mechanisms of neuroinflammation and proteostatic balance in preclinical models. No study to date has demonstrated glymphatic impairment, altered Aβ metabolism, or longitudinal cognitive sequelae in individuals with TMD. Likewise, postural interventions have not been shown to modulate molecular indices of amyloid dynamics. Accordingly, the present work advances a hypothesis-generating translational framework that integrates sleep physiology, chronic pain, and proteostasis, and delineates priorities for biomarker-stratified prospective investigation. This model is intended to structure future mechanistic inquiry rather than to imply established causal relationships.