Elevated Na⁺/K⁺ Ratio in Alzheimer's Disease: A Potential Biomarker for Braak Stage

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and the accumulation of amyloid plaques and neurofibrillary tangles. While prior research has focused mainly on protein aggregation and neuroinflammation, emerging evidence suggests that ionic imbalances, particularly involving sodium (Na+) and potassium (K+), may contribute to AD progression. Na+ and K+ are critical for maintaining neuronal membrane potential, regulating action potential firing, and supporting neurotransmitter function. Although studies primarily focused on absolute Na+ concentrations, the Na+/K+ ratio may provide a more sensitive marker of ionic dysregulation. Given that the Na+/K+ gradient is actively maintained by the Na/K-ATPase pump, a target known to be vulnerable in AD, we hypothesized that the Na+/K+ ratio is altered in AD. We analyzed postmortem tissue from the prefrontal cortex, thalamus, and cerebrospinal fluid (CSF) of 97 human subjects (67 AD, 30 controls). AD cases exhibited a significant increase in the Na+/K+ ratio in the thalamus and CSF, driven primarily by elevated Na+ levels. The Na+/K+ ratio positively correlated with Braak tangle stage, suggesting an association with AD progression. These findings provide novel insights into ionic dysregulation in AD and suggest that the CSF Na+/K+ ratio may serve as a valuable biomarker of disease severity and progression. Future research should explore the potential of targeting ionic homeostasis as a therapeutic strategy in AD.