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Fluid‐based biomarkers to facilitate clinical trial execution and interpretation
Author(s) -
Zetterberg Henrik
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.039031
Subject(s) - neuroimaging , medicine , biomarker , dementia , neurodegeneration , positron emission tomography , cerebrospinal fluid , disease , clinical trial , population , pathology , oncology , amyloid (mycology) , bioinformatics , radiology , psychiatry , biochemistry , chemistry , environmental health , biology
Background Most clinical trials in dementia prevention or disease modification have failed to meet their primary outcomes. During recent years, improved fluid‐ and imaging‐based biomarkers for Alzheimer’s disease (AD) pathologies have been developed. These can be used to increase the likelihood that the included patient population carries the pathology that the treatment is intended to ameliorate. However, the approach can be costly and results in frequent screen failures. Here, improved recruitment strategies that employ staged testing, from simple blood tests as pre‐screening tools to cerebrospinal fluid (CSF) analysis and neuroimaging for final diagnosis, are described and discussed. Methods The literature on blood‐, CSF‐, and imaging‐based biomarkers for amyloid and tau pathologies, as well as neurodegeneration, was reviewed. A number of staged testing scenarios were developed. Results The best‐established blood‐based biomarker for AD pathology is phosphorylated tau (P‐tau). Plasma P‐tau distinguishes AD patients from cognitively normal controls with areas under the curve (AUCs) above 90% and detects both tau and amyloid pathology, as determined by positron emission tomography (PET), with AUCs around 90%, already in pre‐dementia stages of the disease. This diagnostic performance exceeds that of plasma Aβ42/Aβ40 ratio. Plasma neurofilament light (NfL) concentration is increased in AD and correlates with neuroimaging evidence of neurodegeneration. Employing plasma P‐tau181 as a pre‐screening biomarker in the recruitment of patients to clinical trials of amyloid‐ or tau‐targeting therapies would reduce the number of screen failures by at least 50% and virtually remove the costs for negative PET examinations. Plasma NfL, being a general marker of neuronal injury, has the potential to detect side effects of drugs, e.g ., clinically relevant encephalitis. Conclusions We propose that future clinical trials of drug candidates against AD‐related pathologies are designed so that a pre‐screening with plasma P‐tau takes place, increasing the likelihood that patients with AD pathology are included and subjected to costly but important examinations, such as amyloid and/or tau PET at baseline. In addition to yearly PET examinations, more frequent testing of blood biomarkers during the trial could also help identifying positive effects of the drug candidate (P‐tau and NfL), and side effects detrimental to neuronal health (NfL).