Targeting the glymphatic system: Aβ accumulation and phototherapy strategies across different stages of Alzheimer's disease.

The glymphatic system serves as the brain's clearance system. It deteriorates with age and is a significant contributor to the onset and progression of Alzheimer's disease (AD). Modulating cerebrospinal fluid (CSF)-based clearance and targeting key components of the glymphatic system, such as aquaporin-4, can enhance amyloid-beta (Aβ) clearance. Light therapy is emerging as a potential AD treatment approach, which involves the use of visible and near-infrared light at specific wavelengths (630/680/808/850/1070 nm), photosensitive proteins, and sensory stimulation at particular frequencies (e.g., 40 Hz). This phototherapy strategy can broadly influence the intracerebral fluid dynamics, including cerebral blood flow, CSF, and interstitial fluid (ISF), as well as structures related to the glymphatic system, such as vascular endothelial cells, glial cells, and neurons. Additionally, it may directly or indirectly inhibit Aβ accumulation by modulating endogenous small molecules, thereby improving cognitive function. Our previous research demonstrated that 630-nm red light can inhibit Aβ cross-linking by clearing endogenous formaldehyde and promoting ISF drainage. Notably, Aβ accumulation exhibits distinct characteristics at different phases of AD, accompanied by varying features of glymphatic system impairment. In the early stages, deep brain regions are significantly affected, whereas in the late stages, accumulation primarily occurs in the paracentral, precentral, and postcentral cortices. Owing to the limited penetration depth of light, this may pose a challenge to the clinical efficacy of phototherapy. Therefore, different stages of AD may require tailored phototherapeutic strategies. Meanwhile, it is important to acknowledge the ongoing controversies associated with lymphovenous anastomosis, a procedure that targets the glymphatic system. Therefore, this article reviews the characteristics of glymphatic system impairment across various AD stages and the mechanisms by which effective phototherapies modulate the glymphatic system. Potential phototherapeutic strategies corresponding to different stages of Aβ accumulation are also proposed.