Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis

Abstract

INTRODUCTION CSF analysis and other measurements of amyloidosis, such as amyloid-binding positron emission tomography (PET) studies, are limited by cost and availability. There is a need for a more practical Aβ biomarker for central nervous system (CNS) amyloid deposition. METHODS We adapted our previously reported Stable Isotope Labeling Kinetics (SILK) protocol to analyze the turnover kinetics and concentrations of Aβ38, Aβ40, and Aβ42 in human plasma. RESULTS Aβ isoforms have a half-life of approximately three hours in plasma. Aβ38 demonstrated faster turnover kinetics compared to Aβ40 and Aβ42. Faster fractional turnover of Aβ42 relative to Aβ40 and lower Aβ42 and Aβ42/Aβ40 concentrations in amyloid positive participants were observed. DISCUSSION Blood plasma Aβ42 shows similar amyloid-associated alterations as we have previously reported in CSF, suggesting a blood-brain transportation mechanism of Aβ. The stability and sensitivity of plasma Aβ measurements suggests this may be a useful screening test for CNS amyloidosis.

Aging and APOE‐ε4 are determinative factors of plasma Aβ42 levels

“…With a longer follow‐up, repeated measurement of plasma A β may be useful as a simple and minimally invasive screening procedure to detect brain A β amyloidosis 14, 15, 16. A β in plasma does not only originate in the brain because it is also involved in amyloid precursor protein (APP) metabolism in peripheral organs, it binds to several proteins and lipoproteins, is partially released from activated platelets, and is metabolized in the liver and cleared through the kidneys 19.…”

“…APOE‐ε4 is the strongest genetic risk factor for sporadic late onset AD, and markedly accelerates A β amyloid deposition in the brain and the onset age of dementia by approximately 10 years 10, 17. Recent studies have revealed that CNS‐derived A β is cleared into the CSF28 and peripheral blood,29 and that the clearance rate is decreased in late onset AD,30 and is differently regulated by age and presence of A β amyloidosis 15, 31. Association of plasma A β levels and cortical amyloid burden is also modulated by APOE isoforms 32.…”

“…Recent studies have clarified that the plasma A β 42/40 ratio is inversely correlated with cortical amyloid burden in AD, which can be converted into MCI,12, 13 and that the plasma A β 42/40 ratio is a useful screening marker for brain A β amyloidosis in normal individuals 14, 15. Approximately 30–50% of A β in the plasma originates from the brain 15. Age, APOE‐ε4, and AD pathology are specific determinants of A β turnover kinetics from the brain to CSF, and finally to plasma 15, 16…”

“…Approximately 30–50% of A β in the plasma originates from the brain 15. Age, APOE‐ε4, and AD pathology are specific determinants of A β turnover kinetics from the brain to CSF, and finally to plasma 15, 16…”

Current state of Alzheimer’s fluid biomarkers

“…Using an ultrasensitive immunoassay technique (Simoa platform), levels of Aβ42 and the ratio of Aβ42/Aβ40 in plasma were shown to correlate with CSF levels and with Aβ deposition measured by PET [160, 377], and plasma Aβ42/Aβ40 associated with risk of progression to MCI or dementia in cognitively normal individuals with subjective cognitive decline [377]. Ovod et al used mass spectrometry to demonstrate lower levels of plasma Aβ42 and Aβ42/Aβ40 in subjects with an Aβ-positive PET [273]. In addition to the use of novel technologies, plasma samples could be chemically treated to reduce degradation of Aβ and improve the accuracy of plasma Aβ measurements [278].…”