![]() We also summarize the many challenges that have been encountered in efforts to integrate fluid biomarkers in clinical trials, and the barriers that have begun to be overcome. Then, we provide a comprehensive overview of current and future application of fluid biomarkers in clinical trials for AD. In this review, we first succinctly outline a panel of fluid biomarkers for neuropathological changes in AD. Fluid biomarkers measured in cerebrospinal fluid and circulating blood, which can reflect the pathophysiological process in the brain, are becoming increasingly important in AD clinical trials. 6815 ortelius trial#These many trial failures have highlighted a need for the incorporation of biomarkers in clinical trials to help improve the trial design. However, almost all drug candidates have failed in clinical trials over the past 30 years. ![]() We discuss the potential COUs for each biomarker.Īlzheimer’s disease (AD) research is entering a unique moment in which enormous information about the molecular basis of this disease is being translated into therapeutics. ![]() In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. The number of people living with AD is predicted to increase however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. The purpose of this paper is to review the literature regarding the existing and emerging fluid biomarkers and to examine how fluid biomarkers have been incorporated into clinical trials.Īlzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. Fluid biomarkers are important because they can provide information regarding the underlying biochemical processes that are occurring in the brain. Three biomarkers are neuroimaging measures - hippocampal atrophy measured by magnetic resonance imaging (MRI), amyloid uptake as measured by Pittsburg compound B positron emission tomography (PiB-PET), and decreased fluorodeoxyglucose (18F) uptake as measured by PET (FDG-PET) - and three are sampled from fluid sources - cerebrospinal fluid levels of amyloid β42 (Aβ42), total tau, and phosphorylated tau. Six biomarkers have now been included in diagnostic criteria for AD and are regularly incorporated into clinical trials. With the focus on disease modification, biomarkers promise to play an increasingly important role in clinical trials. In the last decade, few therapeutic agents designed to modify the underlying disease process have progressed to clinical trials and none have been brought to market. Insights gained from decades of research have begun to unlock the pathophysiology of this complex disease and have provided targets for disease-modifying therapies. Therapies that prevent or slow the progression of the disease are urgently needed to avoid this growing public health emergency. Current treatments provide symptomatic relief but do not affect the underlying pathology of the disease. ![]() With the demographic shift of the global population toward longer life expectancy, the number of people living with Alzheimer's disease (AD) has rapidly expanded and is projected to triple by the year 2050. ![]()
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