Molecular imaging and fluid biomarkers of Alzheimer’s disease neuropathology: an opportunity for integrated diagnostics

Abstract

Alzheimer’s disease (AD) gold standard diagnosis is the detection of amyloid plaques and neurofibrillary aggregates of hyperphosphorylated tau at autopsy. The developments in the diagnostic field over the last two decades have made these neuropathological processes partly accessible in vivo by two main classes of biomarkers: molecular imaging and laboratory measures. Molecular imaging, using specific PET radiotracers, allows visualizing the presence of amyloid and tau in the brain; laboratory assessments provide indirect evidence measuring the release or retention of specific amyloid and tau isoforms in the cerebrospinal fluid (CSF) and more recently, with the development of high-sensitivity systems, also in plasma. Over the past few years, there have been major advances both in the molecular imaging and fluid biomarker research. In order to be employed in clinical practice, biomarkers should be investigated systematically for their validity, i.e., their ability to discriminate true-positive from true-negative cases accurately and consistently across clinical contexts. The main steps of the validation process of AD biomarkers have been formalized in a Strategic Biomarker Roadmap, resulting from the collaborative work of a group of experts in the diagnosis of cognitive disturbances and biomarkers [1]. The roadmap, updated based on recent theoretical advancement [2], outlines the methodology required to produce and assess evidence of analytical validity, clinical validity, and clinical utility for each biomarker. This framework provides therefore a systematic tool to identify the gaps in knowledge that should be filled with priority to allow evidence-based clinical and policy decisions. Only once the analytical and clinical validity of a biomarker are proven can its utility (i.e., the impact of the biomarker-based diagnosis on clinically relevant outcomes) be properly assessed. PET tracers specific for amyloid pathology, tested in clinical studies since 2004, have already proven their analytical validity and are currently evaluated in large-scale phase 4 studies testing clinical validity and collecting data for clinical utility [3, 4]. Tracers specific for tau pathology represent a more recent advance. The first ligands described, the so-called first-generation tracers, have been introduced in clinical studies in 2013. Among these, 18F-flortaucipir (Tauvid) was approved for use by the Food and Drug Administration earlier this year (https:// www.fda.gov/drugs/drug-approvals-and-databases/drugtrial-snapshot-tauvid). In parallel, a number of new ligands (second-generation tracers), purportedly with greater sensitivity and specificity, are currently under evaluation. Their level of maturity within the Strategic Biomarker Roadmap structure is summarized in the contributions by Wolters, Chiotis, and Bischof [5–7]. Laboratory assessments of amyloid and tau pathology have also significantly advanced over the last years. CSF measures, currently routinely used in clinical practice, have improved their standardization across centers through unified protocols for sampling, handling, and storage and the introduction of fully automated assays [8]. The introduction of novel technologies with greatly increased sensitivity has also allowed the This article is part of the Topical Collection on Neurology – Dementia