Alzheimer's disease (AD) will soon become a public health crisis if left untreated. There are currently no proven treatments that delay the onset or prevent the progression of AD, but several promising candidates are being developed. During the development of these therapies, it will be very important to have biomarkers that can identify individuals at high risk for AD in order to target them for clinical trials, diseasemodifying therapies and to monitor therapy. Early onset dominantly inherited AD accounts for a very small proportion of all AD cases (<1%) but the neuropathologic hallmarks and clinical features of these individuals are similar to the more common late onset form of the disease. Because individuals possessing the various AD mutations are destined to develop AD, and families with a given mutation develop symptoms at a relatively predictable age, such individuals may be studied from a presymptomatic stage, providing a unique opportunity to investigate the very earliest manifestations of AD. We hypothesize that evaluation of fluid biomarkers in individuals with AD causing mutations will provide a means to detect the presence of AD neuropathology prior to symptoms and predict the time it will take to convert from cognitively normal to cognitively impaired. We believe this will be relevant to late-onset AD. Our AD biomarkers program has been in existence for nine years and operates as part of the Washington University Alzheimer's Disease Research Center. Our Biomarker Core currently facilitates and supports antecedent AD biomarker research by providing the necessary infrastructure for the collection, storage, and dissemination of samples for our own research and that of the greater AD scientific community. Thus we are highly qualified and in an excellent position to extend our mission to include samples obtained from individuals with dominantly inherited forms of the disease. We propose the following aims: 1) to establish a repository of fasted cerebrospinal fluid (CSF), serum and plasma samples from individuals (gene carriers and noncarriers;presymptomatic and symptomatic) who are biological adult children of a parent with a known causative mutation for AD (obtained uniformly from 7 participating sites using protocols from the Alzheimer's Disease Neuroimaging Initiative (ADNI);2) to obtain measures of CSF Ap^o, Ap^, total tau, and phosphorylated tau (ptau18i), and plasma Ap^o, Apx.4Q, ApM2, and Apx^,2 by ELISA-based methods;and 3) to coordinate the distribution of samples to qualified investigators for further biomarker discovery studies. To the extent that our biomarker findings can be extrapolated to the more common sporadic, late onset form of AD (as current data suggest), analysis of fluid and imaging biomarkers in dominantly inherited AD may have a profound impact on overall AD diagnosis and treatment.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program--Cooperative Agreements (U19)
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Washington University
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