Fluid biomarkers for neurodegenerative diseases

Lead Research Organisation: University College London

Abstract

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Technical Summary

The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019.

Amyloid ß (A?), the key component of extracellular senile plaques in Alzheimer’s disease (AD) brains, is produced from amyloid precursor protein (APP) by proteolytic processing via the ?-site APP-cleaving enzyme 1 (BACE1) and the ?-secretase complex in all human beings. According to the Aß cascade hypothesis, AD is caused by abnormal accumulation of Aß in the brain [1]. This process is thought to induce, by unknown means, hyperphosphorylation of the axonal protein tau, formation of intra-neuronal tau inclusions (neurofibrillary tangles) and frank neurodegeneration.
The ultimate proof of the Aß cascade hypothesis would be if an Aß-targeting drug successfully slows down AD in a clinical trial. However, this has not yet happened. Instead, the hypothesis has been challenged by negative results in several phase III clinical trials aimed at inhibiting Aß production (secretase inhibitors), or increasing its clearance from the brain (anti-Aß immunotherapy). I argue that recent trial failures were not adequate tests of the Aß cascade
hypothesis: a major limitation of our understanding and a key barrier to progress is that we do not know whether dosages were high enough (likely not) to engage their targets; we do not know (in vivo in humans) what the effects of whatever (possibly limited) target engagement were on the multiple pathological factors in AD, nor do we know what the downstream effects on intermediates between molecular pathology and clinical decline were – the potential to examine brain tissue histopathologically during or immediately after such trials is extremely limited – and therefore improved biomarkers and improved interpretation of biomarkers are critical. Furthermore, trials in pre-clinical disease stages, e.g., such that are planned in the Dominantly Inherited Alzheimer Network (DIAN), will at least be needed to address the Aß cascade hypothesis – these trials bring a greater importance to biomarkers since by definition the clinical effects are difficult or slow to discern in a population that is not clinically affected. The negative trial outcomes
have also highlighted the need for more translational research on disease models to study AD pathogenesis, screen for and evaluate new drug candidates and establish pharmacodynamic biomarkers to verify target engagement and translate model findings to valid readouts in clinical trials. Along similar lines, we need new biomarker tools to study the pathophysiological relevance of and cellular responses to a number of non-A? pathologies that are common in AD and highly relevant to several other neurodegenerative diseases, namely tau, ?-synuclein and TDP-43.

Publications

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Banerjee G (2020) Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy. in Journal of Alzheimer's disease : JAD