Stable potassium isotope ratios in human blood serum towards biomarker development in Alzheimer's disease

Abstract

The Alzheimer's disease (AD)-affected brain purges K with concurrently increasing serum K, suggesting brain-blood K transferal. Here, natural stable K isotope ratios-δ41K-of human serum samples were characterized in an AD biomarker pilot study (plus two paired Li-heparin and potassium ethylenediaminetetraacetic acid [K-EDTA] plasma samples). AD serum was found to have a significantly lower mean δ41K relative to controls. To mechanistically explore this change, novel ab initio calculations (density functional theory) of relative K isotope compositions between hydrated K+ and organically bound K were performed, identifying hydrated K+ as isotopically light (lower δ41K) compared to organically bound K. Taken together with literature, serum δ41K and density functional theory results are consistent with efflux of hydrated K+ from the brain to the bloodstream, manifesting a measurable decrease in serum δ41K. These data introduce serum δ41K for further investigation as a minimally invasive AD biomarker, with cost, scalability, and stability advantages over current techniques.

Keywords: Alzheimer's disease; biomarker; isotope; metallomics; potassium.

Graphical Abstract

Human blood serum stable K isotope compositions (δ⁴¹K) indicate statistically significant light K isotope enrichment in Alzheimer's disease (AD) relative to controls. This marker displays good performance in identifying AD (receiver operating characteristic curve analysis), introducing serum δ⁴¹K for further exploration as a minimally invasive AD biomarker.

Fig. 1

Boxplot of ⁴¹K/³⁹K isotope ratios—δ⁴¹K in per mil, ‰—for Alzheimer's disease (AD) versus control (CN) subjects, with Welch's t-test P result reported. Outlier(s) indicated by grey circles.

Fig. 2

⁴¹K/³⁹K reduced partition function for various biologically relevant species at 37°C. Relative isotopic enrichment can be predicted by subtraction; e.g. at normal body temperature, six-coordinated hydrated K⁺ is predicted to be 0.39‰ lighter than K₂-glutamate (1.92–2.31 = −0.39).