Amyloid-Beta Clearance, Alzheimer's Disease, and the Interstitial Fluid–Fascia Connection: A Review of Current Evidence and Neurogenetic Tools

The interstitial fluid (ISF) system is essential for maintaining tissue homeostasis and transporting solutes between cells, while the brain possesses specialized pathways for fluid movement and waste clearance. The discovery of the glymphatic system demonstrated that cerebrospinal fluid (CSF) can enter the brain along periarterial spaces, interact with interstitial fluid, and facilitate clearance of extracellular solutes, including amyloid-β (Aβ). Subsequent studies have provided evidence for related clearance processes in humans and have connected impaired fluid clearance with neurodegenerative disease. In parallel, research on the peripheral interstitium and fascia has challenged the traditional view of these tissues as passive structural compartments. Anatomical studies describe fluid-filled interstitial spaces throughout connective tissues, including fascia, while research on fasciacytes suggests that specific fascial cell populations regulate the hyaluronan-rich extracellular matrix. This review examines the anatomical and functional relationships between ISF, the glymphatic system, meningeal lymphatics, and fascia, with particular emphasis on Aβ clearance and Alzheimer's disease. It further evaluates currently available neurogenetic approaches, including Cre/loxP systems, viral gene delivery, and Drosophila GAL4/UAS technologies. Although these approaches enable highly specific manipulation of neuronal and glial populations, they are not designed specifically to manipulate individual fascial cell populations while simultaneously measuring fluid dynamics. This gap provides a rationale for developing tools capable of selectively identifying and manipulating specific fascial cell types and determining their contribution to interstitial fluid dynamics and neurological disease.