Olfactory Dysfunction as a Clinical Marker of Early Glymphatic Dysfunction in Neurodegenerative Diseases

An abnormal accumulation of misfolded proteins is a common feature shared by most neurodegenerative disorders. Olfactory dysfunction (OD) is common in elderly population and is present in 90% of patients with Alzheimer’s or Parkinson’s disease, usually preceding the cognitive and motor symptoms onset by several years. Early Aβ, tau and α-synuclein protein aggregates have been observed in brain structures involved in odor processing (olfactory bulb and tract, piriform cortex, amygdala, entorhinal cortex, and hippocampus) and seem to underly OD. Glymphatic system is a glial-associated fluid transport system that facilitates the movement of CSF and ISF and removes brain waste during specific brain waste sleep stages. Noteworthy, glymphatic system became less functional in aging and is impaired in several conditions, including neurodegenerative diseases. As the nasal pathway has been recently described as the main outflow pathway of cerebrospinal fluid and solutes, we hypothesized that OD may be indeed a clinical marker of early glymphatic dysfunction that entails abnormal accumulation of pathological proteins in olfactory structures. Here we review the physiological, anatomical, and chronological evidence supporting this suggestion. If this hypothesis is confirmed, olfactory dysfunction could be considered as a clinical proxy of glymphatic dysfunction in neurodegenerative diseases.