The memory and thinking changes characteristic of Alzheimer disease (AD) are now known to be preceded by over a decade of brain amyloid deposition in cognitively normal older adults. The overarching goal of this renewal application is to characterize the indicators of the transition from cognitive normality to the earliest stages of symptomatic AD. However, the substantial heterogeneity in the cognitive abilities of older adults can blur this threshold. To address this concern, Project 1 proposes to identify the cognitive indicators (collected through Core B: Clinical) of the transition and to substantiate these cognitive markers with resting state functional connectivity MRI (rs-fcMRI;collected through Core E: Imaging). We hypothesize that the irreversible transition from cognitive normality to symptomatic AD can be detected by impairment in attentional control, impaired learning on cognitive measures and disruption in resting state networks (RSNs). To test this hypothesis, we propose the following Specific Aims: 1) To evaluate sensitive measures of cognitive performance as indicators of preclinical AD and as predictors of the development of symptomatic AD. 2) To evaluate alterations in RSNs using rs-fcMRI as indicators of preclinical AD and as predictors of the development of symptomatic AD. 3) To examine the relationship between the cognitive performance measures in SA1 with the RSN alterations in SA2, both cross-sectionally and longitudinally on the rate of change. 4) To relate the cognitive and rs-fcMRI findings in Project 1 with findings from all other Projects and Cores to develop a model that optimally characterizes the transition from cognitive normality to symptomatic AD. In particular, Project 1 findings will be examined in relation to the sleep variables and cerebrospinal fluid measures obtained in Project 2, genetic variants of AD progression in Project 3, volumetric and amyloid imaging data in Core E: Imaging, [and the molecular pathology of AD and markers of synaptic integrity and neuronal number (particularly in the relevant brain regions such as the dorsal anterior cingulate) obtained in Core D: Neuropathology]. .

Public Health Relevance

As instructed by the funding opportunity announcement for this application (PAR-13-329), only the Overall component contains a project narrative. Cores and projects were instructed not to include this section.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-4 (M1))
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Washington University
Saint Louis
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Lucey, Brendan P; Mawuenyega, Kwasi G; Patterson, Bruce W et al. (2016) Associations Between β-Amyloid Kinetics and the β-Amyloid Diurnal Pattern in the Central Nervous System. JAMA Neurol :
Esparza, Thomas J; Wildburger, Norelle C; Jiang, Hao et al. (2016) Soluble Amyloid-beta Aggregates from Human Alzheimer's Disease Brains. Sci Rep 6:38187
McKee, Ann C; Cairns, Nigel J; Dickson, Dennis W et al. (2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131:75-86
Reiman, Eric M; Langbaum, Jessica B; Tariot, Pierre N et al. (2016) CAP--advancing the evaluation of preclinical Alzheimer disease treatments. Nat Rev Neurol 12:56-61
Jin, Sheng Chih; Benitez, Bruno A; Deming, Yuetiva et al. (2016) Pooled-DNA Sequencing for Elucidating New Genomic Risk Factors, Rare Variants Underlying Alzheimer's Disease. Methods Mol Biol 1303:299-314
Hohman, Timothy J; Cooke-Bailey, Jessica N; Reitz, Christiane et al. (2016) Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk. Alzheimers Dement 12:233-43
Van Schependom, Jeroen; Jain, Saurabh; Cambron, Melissa et al. (2016) Reliability of measuring regional callosal atrophy in neurodegenerative diseases. Neuroimage Clin 12:825-831
Hohman, Timothy J; Bush, William S; Jiang, Lan et al. (2016) Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium. Neurobiol Aging 38:141-50
Su, Yi; Rubin, Brian B; McConathy, Jonathan et al. (2016) Impact of MR-Based Attenuation Correction on Neurologic PET Studies. J Nucl Med 57:913-7
Ebbert, Mark T W; Boehme, Kevin L; Wadsworth, Mark E et al. (2016) Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk. Alzheimers Dement 12:121-9

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