Plasma Biomarkers of Ad Emerging as Essential Tools for Drug Development: An Eu/Us Ctad Task Force Report

Abstract

There is an urgent need to develop reliable and sensitive blood-based biomarkers of Alzheimer’s disease (AD) that can be used for screening and to increase the efficiency of clinical trials. The European Union-North American Clinical Trials in Alzheimer’s Disease Task Force (EU/US CTAD Task Force) discussed the current status of blood-based AD biomarker development at its 2018 annual meeting in Barcelona, Spain. Recent improvements in technologies to assess plasma levels of amyloid beta indicate that a single sample of blood could provide an accurate estimate of brain amyloid positivity. Plasma neurofilament light protein appears to provide a good marker of neurodegeneration, although not specific for AD. Plasma tau shows some promising results but weak or no correlation with CSF tau levels, which may reflect rapid clearance of tau in the bloodstream. Blood samples analyzed using -omics and other approaches are also in development and may provide important insight into disease mechanisms as well as biomarker profiles for disease prediction. To advance these technologies, international multidisciplinary, multi-stakeholder collaboration is essential.

Pre-therapeutic Microglia Activation and Sex Determine Therapy Effects of Chronic Immunomodulation

“…We initiated PPARγ therapy at ages manifesting an early phase of limited fibrillar amyloidosis in both mouse models, thus emulating an early but detectable stage of the human AD continuum 28 . In consideration of emerging plasma biomarkers for AD pathology 29 , novel treatments for AD shall likely be initiated at a comparable disease stage in future clinical studies. Thus, we focused our intervention monitoring on the phase of amyloid aggregation, which revealed the greatest therapeutic response in AD model mice with a seemingly more aggressive microglial activation during early amyloid build-up.…”

Predicting Brain Amyloid Using Multivariate Morphometry Statistics, Sparse Coding, and Correntropy: Validation in 1,101 Individuals From the ADNI and OASIS Databases

“…Developing computational models for detecting Aβ pathology based on less invasive, less costly, and more readily available procedures could help identify a target population with a high prevalence of Aβ pathology. With or without more affordable BBBs as an alternative for inferring Aβ burden in the brain (Bateman et al, 2019;Janelidze et al, 2020;Palmqvist et al, 2020), especially after their diagnosis viabilities are further reduced, sMRI scans will always be an option that is largely accessible, cost-effective, and widely used as a standard-of-care procedure. Structural MRI will also identify pathologies that AD BBB's do not assess, e.g., stroke, tumor, and subdural hematoma.…”

“…Blood-based biomarkers (BBBs) are somewhat effective for inferring Aβ burden in the brain and CSF, and are less expensive than imaging (Bateman et al, 2019;Janelidze et al, 2020;Palmqvist et al, 2020). Even so, structural MRI biomarkers are largely accessible, cost-effective, and widely used in AD imaging research as well as for clinical diagnosis.…”

Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation

“…We initiated PPARγ therapy at ages manifesting an early phase of limited fibrillar amyloidosis in both mouse models, thus emulating an early but detectable stage of the human AD continuum 41 . In consideration of emerging plasma biomarkers for AD pathology 42 , novel treatments for AD shall likely be initiated at a comparable disease stage in future clinical studies. Thus, we focused our intervention monitoring on the phase of amyloid aggregation, which revealed the greatest therapeutic response in those AD model mice with a seemingly more aggressive microglial activation during the early amyloid build-up phase.…”