Journal ArticleDOI
Biomarkers in Alzheimer's disease drug development
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TLDR
Surrogate markers that can function as outcomes in pivotal trials and reliably predict clinical outcomes are needed to facilitate primary prevention trials of asymptomatic persons where clinical measures may be of limited value.Abstract:
Developing new therapies for Alzheimer's disease (AD) is critically important to avoid the impending public health disaster imposed by this common disorder. Means must be found to prevent, delay the onset, or slow the progression of AD. These goals will be achieved by identifying disease-modifying therapies and testing them in clinical trials. Biomarkers play an increasingly important role in AD drug development. In preclinical testing, they assist in decisions to develop an agent. Biomarkers in phase I provide insights into toxic responses and drug metabolism and in Phase II proof-of-concept trials they facilitate go/no-go decisions and dose finding. Biomarkers can play a role in identifying presymptomatic patients or specific patient subgroups. They can provide evidence of target engagement before clinical changes can be expected. Brain imaging can serve as a primary outcome in Phase II trials and as a key secondary outcome in Phase III trials. Magnetic resonance imaging is currently best positioned for use in large multicenter clinical trials. Cerebrospinal fluid (CSF) measures of amyloid beta protein (Aβ), tau protein, and hyperphosphorylated tau (p-tau) protein are sensitive and specific to the diagnosis of AD and may serve as inclusion criteria and possibly as outcomes in clinical trials targeting relevant pathways. Plasma measures of Aβ are of limited diagnostic value but may provide important information as a measure of treatment response. A wide variety of measures of detectable products of cellular processes are being developed as possible biomarkers accessible in the cerebrospinal fluid and plasma or serum. Surrogate markers that can function as outcomes in pivotal trials and reliably predict clinical outcomes are needed to facilitate primary prevention trials of asymptomatic persons where clinical measures may be of limited value. Fit-for-purpose biomarkers are increasingly available to guide AD drug development decisions.read more
Citations
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Journal ArticleDOI
The Preclinical Alzheimer Cognitive Composite Measuring Amyloid-Related Decline
Michael C. Donohue,Reisa A. Sperling,David P. Salmon,Dorene M. Rentz,Rema Raman,Ronald G. Thomas,Michael W. Weiner,Michael W. Weiner,Paul S. Aisen +8 more
TL;DR: Analyses of at-risk cognitively normal populations suggest that the authors can reliably measure the first signs of cognitive decline with the ADCS-PACC, and suggest the feasibility of secondary prevention trials.
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Alzheimer's disease drug development pipeline: 2017
TL;DR: There is an urgent need to develop new treatments for Alzheimer's disease (AD) and to understand the drug development process for new AD therapies.
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Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects.
Robert Vassar,Peer-Hendrik Kuhn,Peer-Hendrik Kuhn,Christian Haass,Christian Haass,Matthew E. Kennedy,Matthew E. Kennedy,Lawrence Rajendran,Philip C. Wong,Stefan F. Lichtenthaler +9 more
TL;DR: This review highlights the recent progress in understanding cell biology, substrates, and functions of BACE proteases and discusses the therapeutic options and potential mechanism‐based liabilities, in particular for BACE inhibitors in Alzheimer's disease.
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New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs
TL;DR: In a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success, it is crucial to have biomarkers for early detection of AD-related brain dysfunction, usable before clinical onset.
Journal ArticleDOI
The future of blood-based biomarkers for Alzheimer's disease
Kim Henriksen,Sid E. O'Bryant,Harald Hampel,John Q. Trojanowski,Thomas J. Montine,Andreas Jeromin,Kaj Blennow,Anders Lönneborg,Tony Wyss-Coray,Holly Soares,Chantal Bazenet,Magnus Sjögren,William T. Hu,Simon Lovestone,Morten A. Karsdal,Michael W. Weiner +15 more
TL;DR: The points addressed include: the major challenges in the development of blood‐based biomarkers of AD, including patient heterogeneity, inclusion of the “right” control population, and the blood–brain barrier; the need for standardization of preanalytical variables and analytical methodologies used by the field.
References
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Journal ArticleDOI
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TL;DR: Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein containing a Lys670 → Asn, Met671 → Leu mutation had normal learning and memory but showed impairment by 9 to 10 months of age.
Journal ArticleDOI
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Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles: Intracellular Aβ and Synaptic Dysfunction
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