Cosmochemistry techniques shed light on potential new Alzheimer’s disease biomarker

Minimally invasive test assesses relative levels of potassium isotopes in human blood serum and shows potential to diagnose Alzheimer’s disease before symptoms become apparent

A recent study in Metallomics examined stable potassium (K) isotope ratios (δ⁴¹K) in serum samples from individuals with Alzheimer’s disease (AD).

Background

Brain biometal changes in individuals with Alzheimer’s disease have led to increased scientific interest in isotope metallomics, which uses analytical geochemistry to characterize biometal isotopes in biological systems.

In neurodegenerative diseases such as Alzheimer’s, metals such as calcium, iron, copper and zinc build up in the brain. Metal accumulation correlates with amyloid b (Aβ) protein buildup and plaque development. In contrast, studies report that potassium levels decline in the Alzheimer’s brain, with a concomitant increase in serum levels in middle age. Serum metal levels may thus serve as a non-invasive biomarker for Alzheimer’s disease.

About the study

The current study researchers investigated whether serum δ⁴¹K ratios could predict Alzheimer’s disease.

Researchers compared twenty serum samples, ten from patients with Alzheimer’s disease and ten from age-matched and cognitively normal control subjects. In addition, they analyzed serum samples anticoagulated with K-EDTA and Li-heparin from two patients with Alzheimer’s disease to investigate differences in serum concentrations. The Australian Biomarker and Lifestyle Flagship Study of Aging (AIBL) participants provided serum samples.

Researchers digested the samples in polyfluoroalkyl (PFA) vials containing 30% hydrogen peroxide and 70% nitric acid at a ratio of 1:10. To digest 3.5 ml of serum, they used 400 ml of hydrogen peroxide and 3.1 ml of nitric acid. The Mini-Mental State Exam (MMSE) scores, National Institute of Neurological and Communicative Disorders and Stroke and AD and Related Disorders Association (NINCDS-ADRDA) criteria, and positron emission tomography (PET) biomarker scores confirmed the diagnosis of AD.

Researchers separated potassium using cation exchange chromatography and standard sample bracketing (SSB) to measure the composition of potassium isotopes. Inductively coupled plasma mass spectrometry (ICP-MS) determined mean potassium concentrations. Researchers have examined the average δ mechanically⁴¹ K changes. From the beginning calculations predicted the fractionation of potassium isotopes between hydrated potassium and its organic form bound to glutamate and aspartate. Cartesian coordinates of optimized potassium-bearing species were used in the calculations.

Density Functional Theory (DFT) calculations determined the vibrational frequencies of metal complexes. To calculate the vibrational frequencies, researchers replaced potassium ions with isotopes 39K and 41K with mass values ​​of 38.97 and 40.96, respectively. They calculated amino acid metal complexes in vacuo with potassium bound to carboxyl groups. They also derived beta factors or reduced functional partition ratios for analysis.

D’Agostino & Pearson normality tests examined Alzheimer’s disease and checked data deviations from Gaussian distributions. F-tests examined the variance between data from Alzheimer’s patients and controls, and Welch’s t-test compared the means between the two data sets. Receiver operating characteristic (ROC) curves indicated the specificity and sensitivity of δ⁴¹ K ratios as AD biomarkers.

Results

Patients with Alzheimer’s disease showed a significantly lower mean δ⁴¹K ratios than controls. Hydrated potassium also showed lower δ⁴¹K ratios than organically bound potassium. Serum δ⁴¹K values ​​and DFT findings are consistent with literature suggesting efflux of hydrated potassium ions from the brain into the blood (due to Aβ accumulation). This corresponded to a measurable reduction in serological δ⁴¹K.

The findings suggest a link between altered potassium metabolism and Alzheimer’s disease, probably in its early stages. The study indicates that serum δ⁴¹K values ​​could be minimally invasive biomarkers to detect Alzheimer’s disease. It is more scalable, stable and cost-effective than current techniques.

The δ⁴¹K values ​​ranged between -0.15 and -0.97%. The average δ⁴¹K values ​​were -0.55% in patients with Alzheimer’s disease and -0.32% in controls (mean difference 0.2%). Samples treated with K-EDTA and Li-heparin showed significantly different δ⁴¹K values. They were heavier than their serum counterparts. ROC curves yielded an area under the curve (AUC) value of 0.8, a sensitivity of 70%, and a specificity of 89% in detecting Alzheimer’s disease. Hydrated potassium was the isotopically lightest species in the study. Aspartate and glutamate increase the weight of potassium isotope compositions by 0.4% and 0.2%, respectively. The findings indicated that potassium in hydrated form exhibits a lower isotopic weight than potassium bound in organic compounds.

Conclusion

The research results showed a lighter composition of potassium isotopes or a lower δ⁴¹K values ​​in the serum of patients with Alzheimer’s disease than in healthy controls. This marker performed well in identifying Alzheimer’s disease. Future studies should investigate serum δ⁴¹K as a minimally invasive marker for Alzheimer’s disease in larger populations. Further research could determine the influence of external factors such as diet on isotope concentrations in body reservoirs such as serum, brain and organs of the human body.