Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies

Abstract

Clinical trial results presented in 2019 suggest that antibody-based removal of cerebral amyloid β (Aβ) plaques may possibly clear tau tangles and modestly slow cognitive decline in symptomatic Alzheimer's disease (AD). Although regulatory approval of this approach is still pending, preparing the healthcare system for the advent of disease-modifying therapies against AD is imperative. In particular, it will be necessary to identify the most suitable biomarkers to facilitate appropriate treatment of AD. Here, we give an update on recent developments in fluid and imaging biomarkers for AD-related pathologies and discuss potential approaches which could be adopted to screen for and clarify the underlying pathology in people seeking medical advice because of cognitive symptoms. We succinctly review recent data regarding biomarkers for Aβ and tau pathology, neurodegeneration, synaptic dysfunction and inflammation, highlight the need for further research into common co-pathologies, and suggest how different biomarkers could be used (most likely in combination) to facilitate the development and clinical implementation of novel drug candidates against AD.

Discordant Alzheimer's neurodegenerative biomarkers and their clinical outcomes

“…Altogether, our findings suggest that discordant neurodegenerative status points to a stage of cognitive function which is intermediate between concordant-negative and concordant-positive. Neurodegenerative pathology can be reliably measured in vivo with neuroimaging technology, CSF assessments, or blood tests, 28 but substantial discordance exists when utilizing different methods to evaluate the "N" biomarkers in the same person. 5,[12][13][14][15] Researchers have compared the prevalence of biologically defined AD with clinically defined probable AD, 29 and evaluated the correspondence between clinical syndromes and biological biomarkers as well as between CSF tau and tau-PET.…”

“…Thus, it is difficult to determine the sequence of "N" biomarker abnormality and find which specific "N" biomarker might reflect an earlier pathological stage, which is in line with the recently proposed temporal pattern of AD biomarkers. 28 Further research on this topic is needed. Second, "N" biomarker abnormalities can be caused by neuronal injury in several diseases, and thus, these biomarkers are not specific for neurodegenerative changes in AD.…”

An optimized quantitative proteomics method establishes the cell type‐resolved mouse brain secretome

“…In contrast, little is known about the proteins that are secreted from brain cells and whether-in parallel to their broad expression in different brain cell types-they are secreted from multiple brain cell types or instead are secreted in a cell type-specific manner in vitro, ex vivo (e.g., organotypic slice culture), and in vivo. Cerebrospinal fluid (CSF) constitutes an in vivo brain secretome and is an easily accessible body fluid widely used for studying brain (patho-)physiology and measuring and identifying disease biomarkers (Olsson et al, 2016;Johnson et al, 2020;Zetterberg & Bendlin, 2020), but it is largely unknown which cell type the CSF proteins are secreted from, because no systematic brain cell type-specific protein secretion studies are available.…”

In the blood: biomarkers for amyloid pathology and neurodegeneration in Alzheimer’s disease

“…Over the past decade, cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers have dominated neurodegeneration research and guided drug design. CSF amyloid beta 1-42 (Aβ42), total tau (T-tau) and phosphorylated tau 181 (P-tau 181 ) and 11 C Pittsburgh Compound B, florbetapir and florbetaben PET for Aβ pathology are now well validated for Alzheimer’s disease with 85–95% sensitivity and specificity ( Zetterberg and Bendlin, 2020 ). Important recent developments are the introduction of certified reference methods and materials for Aβ42, and second-generation tau PET.…”