There is substantial evidence that Autosomal Dominant Alzheimer Disease (ADAD) is caused by over- production of A?42 relative to A?40, and shares a final common pathway with later onset Alzheimer Disease (AD). The pathophysiology of AD causing mutations can be directly measured in humans with CSF A? metabolism studies. ADAD A? metabolism results with other testing will allow for better understanding of the pathophysiology, A? deposition (PET PIB), structural (MRI) and functional changes (clinical and neuropsychometrics) of the brain in ADAD. This information will likely lead to improved diagnostic testing and more precise pharmacodynamic testing of disease modifying treatments.
Aims : 36 pre-symptomatic participants between the age of 21 and 74 will be recruited and undergo CSF A? metabolism studies in addition to ACS PPG studies including PET/PIB (project 1), CSF biomarkers (project 2), attentional neuropsychometrics (project 3) and structural MRI (project 4). With these data we will achieve 3 specific aims.
Aim 1 : To determine A?40, A?42, and A?Total production and clearance rates in ADAD mutation carriers versus controls. Direct measurement of the pathophysiological changes of A? metabolism in humans in ADAD would provide a needed biological marker (biomarker) of a potential pathogenic cause of AD. A novel technique, developed at Washington University, allows for the direct measurement of production and clearance rates of A? in humans(Bateman et al. 2006).
Aim 2 : To determine changes in absolute levels of A? species in CSF and variability patterns in ADAD vs. controls. A?42 is an important biomarker for AD and has been demonstrated to be sensitive and specific. A? levels change significantly over hours in normal participants, but this normal pattern of variation may be disrupted in AD pathology.
Aim 3 : To determine changes in total levels biomarkers from initial CSF (A0, tau, and others), pathological deposition of A? by PET PIB (pathology), structural changes on MRI (pathology), and neuropsychometric changes in ADAD versus controls. These ongoing studies of the ACS PPG will be performed with each participant, in addition to a clinical evaluation (CDR) to determine any clinically relevant cognitive changes. This study will measure cognitive, imaging, physiology, and bio-marker changes in people with a causative mutation that leads to Alzheimer disease. This information will provide important data to develop better tests for Alzheimer disease. It will also likely assist in developing new treatments for Alzheimer disease that may change the course of the disease. ? ? ?
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