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

By Pooja Toshniwal PahariaReviewed by Danielle Ellis, B.Sc.Sep 9 2024

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

A recent study in Metallomics investigated stable potassium (K) isotope ratios (δ⁴¹K) in serum samples of individuals with Alzheimer's disease (AD).

Background

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

In neurodegenerative diseases like Alzheimer's disease, metals such as calcium, iron, copper, and zinc accumulate within the brain. Metal accumulation correlates with amyloid b (Aβ) protein buildup and plaque development. In contrast, studies report that potassium levels decrease in Alzheimer's disease brains with a concomitant increase in serum at midlife. Metal levels in serum may thus serve as a non-invasive biomarker for Alzheimer's disease.

About the study

The present study researchers investigated whether serum δ⁴¹K ratios could predict Alzheimer's disease.

Researchers compared 20 serum samples, ten from Alzheimer's disease patients and ten from age-matched and cognitively normal controls. In addition, they analyzed K-EDTA and Li-heparin anticoagulated serum samples from two Alzheimer's disease patients to investigate differences in serum concentrations. The Australian Biomarker and Lifestyle Flagship Study of Ageing (AIBL) participants provided serum samples.

Researchers digested the samples in polyfluoralkyl (PFA) vials containing 30% hydrogen peroxide and 70% nitric acid in a 1:10 ratio. 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, the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association (NINCDS-ADRDA) criteria, and positron emission tomography (PET) scores for biomarkers confirmed AD diagnosis.

Researchers separated potassium through cation-exchange chromatography and standard-sample bracketing (SSB) to measure potassium isotope compositions. Inductively Coupled Plasma Mass Spectrometry (ICP-MS) determined the mean potassium concentrations. Researchers mechanistically explored mean δ⁴¹ K changes. Ab initio calculations predicted potassium isotope fractionation between hydrated potassium and its organic form bound to glutamate and aspartate. The calculations used Cartesian coordinates of optimized potassium-bearing species.

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 partition functional ratios for analysis.

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

Results

Alzheimer's disease patients showed significantly lower average δ⁴¹K ratios than controls. Hydrated potassium also showed lower δ⁴¹K ratios than organically bound potassium. Serum δ⁴¹K values and DFT findings align with literature suggesting the outflow of hydrated potassium ions from the brain to blood (due to Aβ accumulation). This aligned with a measurable reduction in serological δ⁴¹K.

The findings suggest an association between altered potassium metabolism and Alzheimer's disease, likely in its early stage. 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 mean δ⁴¹K values were -0.55% in Alzheimer's disease patients and -0.32% among controls (mean difference, 0.2%). Samples treated with K-EDTA and Li-heparin showed markedly different δ⁴¹K values. They were heavier than their serum counterparts. ROC curves yielded an area under the curve (AUC) value of 0.8, 70% sensitivity, and 89% specificity 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 study findings showed lighter potassium isotope composition or lower δ⁴¹K values in the serum of Alzheimer's disease patients than in healthy controls. This marker performed well in identifying Alzheimer's disease. Future studies must explore 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 isotopic concentrations in bodily reservoirs such as serum, brain, and organs of the human body.