Deregulation of the Glymphatic System in Alzheimer's Disease: Genetic and Non-Genetic Factors

Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by progressive degeneration of brain function. AD gradually affects the parts of the brain that control thoughts, language, behavior and mental function, severely impacting a person's ability to carry out daily activities and ultimately leading to death. The accumulation of extracellular amyloid-β peptide (Aβ) and the aggregation of intracellular hyperphosphorylated tau are the two key pathological hallmarks of AD. AD is a complex condition that involves both non-genetic risk factors (35%) and genetic risk factors (58-79%). The glymphatic system plays an essential role in clearing metabolic waste, transporting tissue fluid, and participating in the immune response. Both non-genetic and genetic risk factors affect the glymphatic system to varying degrees. The main purpose of this review is to summarize the underlying mechanisms involved in the deregulation of the glymphatic system during the progression of AD, especially concerning the diverse contributions of non-genetic and genetic risk factors. In the future, new targets and interventions that modulate these interrelated mechanisms will be beneficial for the prevention and treatment of AD.