Exercise timing as a potential temporal regulator of neurolymphatic physiology in neurodegenerative proteinopathies:...

Although physical activity is consistently associated with lower risks of cognitive decline, dementia, and Parkinson's disease, most exercise research in neurodegeneration still defines exposure by dose-based variables such as duration, intensity, frequency, step count, and cardiorespiratory fitness. This framework is useful for public-health guidance but biologically incomplete for progressive proteinopathies, in which the temporal accumulation and dissemination of misfolded proteins are central to disease evolution. In this review, we propose a temporal intervention framework in which exercise timing is treated as a mechanistic variable that may influence neurodegenerative biology through glymphatic-meningeal lymphatic clearance, vascular pulsatility, circadian alignment, and sleep architecture. We focus on Alzheimer's disease and Parkinson's disease because tau and α-synuclein propagation are disease-relevant processes that may be most amenable to intervention during preclinical or prodromal stages. Morning exercise may act primarily through circadian entrainment, afternoon exercise through vascular-metabolic stimulation, appropriately timed evening or low-intensity activity through sleep-related pathways, and sedentary fragmentation through effects on daytime cerebrovascular dynamics and rest-activity rhythm stability. Although the glymphatic-meningeal lymphatic axis provides a plausible link between timed exercise and extracellular protein handling, current human evidence remains indirect and relies heavily on imaging surrogate markers. Future matched-dose trials should integrate accelerometry, sleep physiology, circadian measures, vascular assessments, neurolymphatic imaging, and disease-specific protein biomarkers, including tau PET, plasma p-tau217, and α-synuclein seed amplification assays. Timed exercise should therefore be viewed as a testable biological perturbation that may clarify whether movement timing influences protein propagation in early neurodegenerative disease, not as a proven disease-modifying treatment.