Potassium Isotope Ratios: A Potential Biomarker for Early Alzheimer's Disease Diagnosis

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMSep 16 2024

Alzheimer's disease has been linked to changes in the concentration of biometals in the brain. The accumulation of amyloid β and the formation of amyloid plaques in the brain is associated with the accumulation of zinc, copper, iron, and calcium in the brain.

In contrast, some metals, such as potassium, have been found at low concentrations in the brains of individuals with Alzheimer's disease.

In a recent study published in Metallomics, a team of scientists characterized the composition of potassium isotope ratios (δ⁴¹K) in the serum samples obtained from Alzheimer's disease patients and age-matched healthy controls to identify whether serum potassium isotope compositions could potentially be used as Alzheimer's disease biomarkers.

​​​​​​​Study: Stable potassium isotope ratios in human blood serum towards biomarker development in Alzheimer's disease. Image Credit: Jo Panuwat D/Shutterstock.com

Background

Isotope metallomics is a field of science that uses geochemical methods to characterize the distribution and abundance of metal isotopes in biological systems.

Growing research in the field has identified an increase in the concentration of metals such as zinc, copper, calcium, and iron in the brains of individuals with Alzheimer's disease, which has been linked to the aggregation of amyloid β plaques.

Numerous studies have also reported a decrease in potassium levels in the brain and a corresponding increase in serum potassium levels.

A greater than 20% decrease in the total potassium concentration in brain homogenate samples from individuals with Alzheimer's disease has been found to correlate with an approximately 2.6% increase in serum potassium levels.

This link between brain or serum potassium levels and Alzheimer's disease indicates its potential use as a biomarker for Alzheimer's disease.

About the Study

In the present study, the researchers analyzed ten blood serum samples from Alzheimer's disease patients and ten from age-matched, but not gender-matched, healthy controls.

Since lithium heparin and potassium ethylenediaminetetraacetic acid (K-EDTA) were both used as anticoagulants for the plasma samples, the researchers also compared one sample for each anticoagulant type to determine whether the plasma potassium values differed based on the coagulant used.

The Alzheimer's disease patients were selected based on the clinical diagnosis involving positron emission tomography (PET) scores for amyloid plaques, Mini-Mental State Exam assessments, and other established criteria.

The controls were selected based on healthy cognitive levels and normal PET scans. Given the absence of samples and the evidence that sex does not impact potassium isotope dynamics in mammals, the controls were not sex-matched in this study.

The samples were digested using a mix of nitric acid and hydrogen peroxide, and aliquots of the digested samples were analyzed using inductively coupled plasma mass spectrometry (ICP-MS) to determine the potassium concentrations. The aliquots were also used for the potassium isotope analysis.

Cation-exchange chromatography was used to isolate the potassium, and a mass spectroscopy method involving a collision/reaction cell with a multi-collector inductively coupled plasma mass spectrometer was used to measure the potassium isotopes.

Subsequently, ab initio calculations, a first-principles method based on quantum mechanics that involves the interactions between the nuclei and electrons in an atom and their movements, were used to predict the potassium isotope fractionation.

The interactions of the potassium isotopes are involved in the functioning of the sodium-potassium-adenosine triphosphatase (Na/K ATPase) enzyme, which plays a role in Alzheimer's disease.

The ab initio calculations were based on the Density Functional Theory, which models the binding of potassium with various other molecules, such as amino acids.

These models used potassium's hydration numbers and vibrational frequencies to provide insights into how potassium isotopes behaved under different conditions.

Major Findings

The study found that the potassium isotope compositions varied significantly between the serum samples from the Alzheimer's disease patients and those from the control group.

The Alzheimer's disease patients had lighter potassium isotope concentrations on average compared to the control group, with the difference being statistically significant.

Furthermore, the area under the receiver operating characteristic curve suggested that δ⁴¹K was a good predictor of Alzheimer's disease, with a specificity and sensitivity of 89% and 70%, respectively. These performance values of δ⁴¹K are comparable with those of modern proteomics-based biomarkers.

The results from the ab initio calculations revealed that hydrated potassium ions were isotopically lighter than the potassium bound to organic compounds such as aspartate and glutamate, which are associated with the activity of Na/K ATPase in the brain.

Therefore, the lighter potassium isotope concentrations observed in the serum samples of Alzheimer's disease patients were hypothesized to result from an efflux of the hydrated potassium ions from the brain, possibly due to the accumulation of amyloid β.

Conclusions

Overall, the study showed that δ⁴¹K was a promising biomarker for Alzheimer's disease, with significant potential for use in its early detection.

The use of δ⁴¹K as a biomarker also provides a cost-effective and minimally invasive method for detecting Alzheimer's disease, which can be scaled for widespread clinical use.