Alzheimer’s Research And Therapy | May 13, 2020

Ehrenberg AJ, Khatun A, Coomans E, Betts MJ, Capraro F, Thijssen EH, Senkevich K, Bharucha T, Jafarpour M, Young PNE, Jagust W, Carter SF, Lashley T, Grinberg LT, Pereira JB, Mattsson-Carlgren N, Ashton NJ, Hanrieder J, Zetterberg H, Schöll M and Paterson RW.

Alz Res Therapy 12, 56 (2020)

DOI: https://doi.org/10.1186/s13195-020-00601-w

Abstract

Background

The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer’s disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field.

Purpose of review

Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer’s Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care.

Background

With 50 million individuals affected worldwide, neurodegenerative diseases remain without disease-modifying treatments. Neuropathological investigations are critical for closing intellectual gaps regarding pathophysiologic mechanisms, as postmortem examination serves as a gold standard and provides adequate resolution to observe the elements of pathophysiological cascades. However, they are limited to cross-sectional assessment. The use of antemortem biomarkers renders possible the detection of hallmarks longitudinally, throughout disease stages. Even in situations where conclusions drawn from antemortem biomarkers might differ from postmortem observations, antemortem biomarkers still offer utility. Here, we will illustrate ways that evidence can be weighed to understand neurodegenerative diseases holistically, focusing on methodology and the limitations and strengths of different modalities.

Despite sometimes indirect associations with lesions, neuropathologically validated biomarkers can be used to assess disease course, particularly as degeneration relates to clinical manifestations. For trials, biomarkers are of paramount importance. They are key for efficiently identifying and tracking cohorts by defining inclusion criteria and outcome variables [1]. As shown in a follow-up to an amyloid-β (Aβ) immunization trial [2], neuropathology can be informative for trials; however, the timelines associated with postmortem donation hinder drug development. As treatments emerge, biomarkers will become even more valuable as diagnostic tools.

There are numerous biomarkers for neurodegenerative diseases readily available or under development (Tables 1, 2, 3 and 4). In this issue of Alzheimer’s Research and Therapy, separate articles will discuss fluid (Obrocki et al.) and imaging (Young et al.) biomarkers for neurodegenerative diseases. Priming this, it is important to consider how one assesses the utility and biases of different modalities. We will discuss ways that biomarkers are utilized in neurodegenerative disease research and care, commenting on appropriate use, interpretation, and implementation. Finally, we will consider where major knowledge gaps lie and how novel biomarkers may fill them. This review will primarily focus on Alzheimer’s disease, due to a significant deficit in biomarkers useful for other neurodegenerative diseases; however, we will comment on emerging techniques for other diseases. Many of the themes discussed here on utility can be readily applied across neurodegenerative diseases.