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)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Saint Louis
United States
Zip Code
Adel, Tameem; Cohen, Taco; Caan, Matthan et al. (2017) 3D scattering transforms for disease classification in neuroimaging. Neuroimage Clin 14:506-517
Schindler, Suzanne E; Jasielec, Mateusz S; Weng, Hua et al. (2017) Neuropsychological measures that detect early impairment and decline in preclinical Alzheimer disease. Neurobiol Aging 56:25-32
Zhao, Yue; Raichle, Marcus E; Wen, Jie et al. (2017) In vivo detection of microstructural correlates of brain pathology in preclinical and early Alzheimer Disease with magnetic resonance imaging. Neuroimage 148:296-304
Su, Yi; Vlassenko, Andrei G; Couture, Lars E et al. (2017) Quantitative hemodynamic PET imaging using image-derived arterial input function and a PET/MR hybrid scanner. J Cereb Blood Flow Metab 37:1435-1446
Deming, Yuetiva; Li, Zeran; Kapoor, Manav et al. (2017) Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers. Acta Neuropathol 133:839-856
Day, Gregory S; Lim, Tae Sung; Hassenstab, Jason et al. (2017) Differentiating cognitive impairment due to corticobasal degeneration and Alzheimer disease. Neurology 88:1273-1281
Monsell, Sarah E; Mock, Charles; Fardo, David W et al. (2017) Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology. Alzheimer Dis Assoc Disord 31:232-238
Mez, Jesse; Chung, Jaeyoon; Jun, Gyungah et al. (2017) Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans. Alzheimers Dement 13:119-129
Khajehnejad, Moein; Saatlou, Forough Habibollahi; Mohammadzade, Hoda (2017) Alzheimer's Disease Early Diagnosis Using Manifold-Based Semi-Supervised Learning. Brain Sci 7:
Holth, Jerrah; Patel, Tirth; Holtzman, David M (2017) Sleep in Alzheimer's Disease - Beyond Amyloid. Neurobiol Sleep Circadian Rhythms 2:4-14

Showing the most recent 10 out of 831 publications