Pathophysiological mechanisms and clinical value of novel blood-based tau biomarkers

Abstract

The use of fluid biomarkers, which serve as biological signatures of physiological processes or disease states, has a great impact on the field of neurology when it comes to providing tools to better understand, diagnose, and monitor various neurological disorders. Blood-based biomarkers are particularly valuable in conditions where clinical symptoms overlap or when diagnosis relies on invasive procedures such as cerebrospinal fluid analysis or neuroimaging. In Alzheimer’s disease (AD), blood-based tau biomarkers enable the early detection of pathology, even before significant clinical symptoms arise, potentially facilitating timely interventions. Moreover, tau biomarkers have demonstrated utility in acute neurological conditions such as traumatic brain injury and acute ischemic stroke, where blood levels of different tau variants are associated with the severity of central nervous system injury and clinical outcomes. This thesis focuses on two newly developed immunoassays, Brain-derived tau (BD-tau) and the University of Gothenburg p-tau217, explores their clinical utility across a spectrum of neuro-logical disorders, with particular emphasis on AD. We present plasma BD-tau as a biomarker for AD-type neurodegeneration showing strong associations with amyloid pathology and neuro-degenerative changes across the AD continuum. In acute ischemic stroke, plasma BD-tau levels strongly correlate with cerebral infarct volume and clinical outcomes, supporting its use as a marker to monitor brain injury following stroke. Plasma p-tau217, on the other hand, demonstrates excellent performance in identifying individuals at the earliest stages of AD, namely, preclinical and prodromal AD. It performs on par with commercially available p-tau217 assays and outperforms markers such as plasma p-tau181 and p-tau231 in the early diagnosis and prognosis of future cognitive decline, further establishing it as a robust diagnostic and prognostic tool in AD. Finally, we evaluated the versatility of BD-tau and p-tau217 in other neurological conditions. Plasma p-tau217 was found to be elevated in Niemann-Pick disease type C (NPC), pointing to shared mechanisms of tau pathology and tangle formation between AD and NPC. Similarly, plasma BD-tau and p-tau217 show both diagnostic and prognostic value in Creutzfeldt–Jakob disease (CJD), distinguishing it from other rapidly progressive dementias. Altogether, the findings presented in this thesis underscore the clinical value and versatility of blood-based tau biomarkers, while also offering insights into the mechanisms underlying tau pathology in various conditions. In AD, they can complement clinical evaluation and serve as accessible tools for early diagnosis and monitoring. In other neurological conditions, they provide important mechanistic insights and show potential for assessing disease severity, particularly in acute conditions, and as prognostic and progression biomarkers in disorders such as NPC and CJD.