Leveraging the glymphatic and meningeal lymphatic systems as therapeutic strategies in Alzheimer’s disease: an updated overview of nonpharmacological therapies

Abstract

Understanding and treating Alzheimer’s disease (AD) has been a remarkable challenge for both scientists and physicians. Although the amyloid-beta and tau protein hypothesis have largely explained the key pathological features of the disease, the mechanisms by which such proteins accumulate and lead to disease progression are still unknown. Such lack of understanding disrupts the development of disease-modifying interventions, leaving a therapeutic gap that remains unsolved. Nonetheless, the recent discoveries of the glymphatic pathway and the meningeal lymphatic system as key components driving central solute clearance revealed another mechanism underlying AD pathogenesis. In this regard, this narrative review integrates the glymphatic and meningeal lymphatic systems as essential components involved in AD pathogenesis. Moreover, it discusses the emerging evidence suggesting that nutritional supplementation, non-invasive brain stimulation, and traditional Chinese medicine can improve the pathophysiology of the disease by increasing glymphatic and/or meningeal lymphatic function. Given that physical exercise is a well-regarded preventive and pro-cognitive intervention for dementia, we summarize the evidence suggesting the glymphatic system as a mediating mechanism of the physical exercise therapeutic effects in AD. Targeting these central solute clearance systems holds the promise of more effective treatment strategies.

Transcranial Photobiomodulation and Chronic Traumatic Brain Injury

“…Overall, the literature has suggested that tPBM has the potential to be beneficial for individuals with chronic TBI, both behaviorally and physiologically. In addition to decreases in CBF, there are other impairments, such as blood-brain barrier disruption and the glymphatic system [67], associated with behavioral deterioration that may also benefit from tPBM treatment [68,69]. More randomized controlled trials are needed to understand the mechanisms of tPBM in chronic TBI and how increasing blood flow and brain activity are related to behavioral changes post-tPBM by including neuroimaging measures.…”

Phototherapy of Alzheimer’s Disease: Photostimulation of Brain Lymphatics during Sleep: A Systematic Review

“…Noninvasive brain stimulation (NIBS) is another strategy for AD treatment [ 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 ]. Transcranial magnetic stimulation (TMS) is the most widely used technique for NIBS.…”

The Anatomy and Physiology of the Glymphatic System and Its Role in Craniectomies and Syndrome of the Trephined

“…The meningeal lymphatic system therefore contributes to efflux of waste from the glymphatic system to the lymph nodes. 51 Deep and cervical lymph nodes have been identified as major drainage sites for tracers injected intrathecally in humans and cisternally in rodents. 49,52 In rabbits, 50% of a radioiodinated tracer injected into the brain parenchyma drained along perivascular spaces and cleared to the deep cervical lymphatics.…”