Mass spectrometry measures of plasma Aβ, tau and P‐tau isoforms’ relationship to amyloid PET, tau PET, and clinical stage of Alzheimer’s disease

Abstract

AbstractBackgroundRecent advances in understanding the links between amyloid‐beta (Aβ) and specific tau isoforms in brain, cerebrospinal fluid (CSF), and blood indicate that a cascade of events of Alzheimer’s disease (AD) pathophysiology begin with detection of altered CSF and blood Aβ 42/40 ratio, followed by increases in amyloid plaques by Positron Emission Tomography (PET) scan, associated with increased phosphorylation of specific CSF tau isoforms (e.g. p‐tau217 and p‐tau181), before increases in p‐tau205, hypometabolism, and atrophy. Finally, CSF total tau increases before tau aggregation by tau PET and onset of clinical symptoms. The longitudinal tau and Aβ changes which occur in brain and CSF are now being understood in blood, enabling interpretation and understanding of AD progression in much larger and more robust populations.MethodWe compared plasma Aβ 42/40 ratios measured by mass spectrometry to measures of amyloid, tau, and clinical and cognitive status in ADNI, AIBL, Biofinder and the Knight ADRC. In order to improve racial, ethnic, educational, socioeconomic, and comorbid disease diversity, we launched the Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD), a community‐ and clinic‐based study (goal n=1120) to mirror the demographics of the Saint Louis metropolitan area. We mapped the entire blood plasma tau protein with 15 specific regions and analyzed several plasma p‐tau isoforms (e.g. p‐tau217 and p‐tau181) by mass spectrometry and compared with CSF and PET results across two sporadic AD studies.ResultSEABIRD participants had an initial blood collection and 25% underwent confirmatory amyloid PET. Consistent with ADNI, AIBL, Biofinder and ADRC, we found plasma Aβ 42/40 ratios had high concordance with amyloid PET. In blood plasma tau, we found that some, but not all, plasma p‐tau isoforms had a strong concordance with CSF and PET measures and that p‐tau217 was more concordant for amyloid status compared to p‐tau181. Further, plasma Aβ 42/40 and p‐tau measures identify the stage of disease as measured by PET and CSF measures, Figure 1.ConclusionThese findings indicate that blood plasma Aβ and p‐tau measures are highly precise biomarkers of brain amyloidosis, tauopathy, and can identify stages of clinical and preclinical AD.