Combined Dysfunction of Glymphatic System and Mitochondria: A Noval Causal Contributor to Alzheimer’s Disease?

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is traditionally attributed to amyloid-beta (Aβ) accumulation and tau pathology. However, emerging evidence suggests that broader systemic dysfunctions may underlie or contribute to these hallmark features. Two biological systems—the glymphatic clearance pathway and mitochondrial energy metabolism—have independently gained attention for their roles in neurodegeneration. The glymphatic system facilitates cerebrospinal fluid (CSF) flow and waste clearance, including Aβ, while mitochondria regulate neuronal bioenergetics and redox homeostasis. By interlinking impaired clearance of neurotoxins and disrupted cellular energy metabolism, a vicious cycle may emerge that accelerates cognitive decline. We argue that integrated dysfunction could serve as an upstream event contributing to disease onset and progression. Understanding this combined pathology may not only redefine causality in AD but also offer novel therapeutic strategies targeting the neurovascular-energetic interface.