The overarching aim of this application is to determine the indicators that characterize the progression from cognitive normality to the earliest stages of cognitive impairment caused by Alzheimer disease (AD). The AD field is shifting toward the goal of prevention strategies, but these efforts depend not only on therapeutic development, but also on a detailed understanding of which individuals are at high risk for symptomatic AD in order to target them for clinical trials, disease-modifying therapies, and to monitor therapy success. The overall Specific Aims in this renewal application are to: 1. Follow current participants in HASD and add new enrollees to maintain the sample size at ~250. 2. Obtain longitudinal data from the HASD participants on an annual basis for clinical and psychometric measures and at 3 year intervals with the following measures: a. Novel measures of attentional control and neural network integrity (Project 1) b. Amyloid imaging with [18F] florbetapir (Imaging Core) c. Assays of CSF analytes (Project 2) d. Structural MRI and resting state functional connectivity MRI (Imaging Core) e. Measures of sleep efficiency (Project 2) f. SNPs that predict rate of progression (Project 3) g. At autopsy, correlate measures of A? and tau burden, synaptic integrity, and neuronal loss with variables from Projects 1 and 2 and from the Imaging Core 3. Characterize the cognitive, imaging, molecular biomarker, and genetic factors that distinguish cognitively normal older adults, with and without preclinical AD, and individuals with symptomatic AD. 4. Analyze associations among rates of change of all disease markers from all Cores and Projects (Biostatistics Core).

Public Health Relevance

Alzheimer disease (AD) is preceded by at least a decade of clinically silent brain changes (termed preclinical AD) that ultimately result in declines in memory and thinking. The current application proposes to determine the indicators that identify individuals with preclinical AD at the cusp of developing clinical symptoms so that these individuals can best be targeted for eventual preventative therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG003991-31A1
Application #
8739007
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (M1))
Program Officer
Hsiao, John
Project Start
1997-01-01
Project End
2019-04-30
Budget Start
2014-08-15
Budget End
2015-04-30
Support Year
31
Fiscal Year
2014
Total Cost
$1,869,280
Indirect Cost
$639,281
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
La Joie, Renaud; Bejanin, Alexandre; Fagan, Anne M et al. (2018) Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90:e282-e290
Roe, Catherine M; Babulal, Ganesh M; Stout, Sarah H et al. (2018) Using the A/T/N Framework to Examine Driving in Preclinical AD. Geriatrics (Basel) 3:
Suárez-Calvet, Marc; Capell, Anja; Araque Caballero, Miguel Ángel et al. (2018) CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM2, neurodegeneration and cognitive decline. EMBO Mol Med 10:
Swarup, Vivek; Hinz, Flora I; Rexach, Jessica E et al. (2018) Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia. Nat Med :
Besser, Lilah; Kukull, Walter; Knopman, David S et al. (2018) Version 3 of the National Alzheimer's Coordinating Center's Uniform Data Set. Alzheimer Dis Assoc Disord 32:351-358
Bussy, Aurélie; Snider, B Joy; Coble, Dean et al. (2018) Effect of apolipoprotein E4 on clinical, neuroimaging, and biomarker measures in noncarrier participants in the Dominantly Inherited Alzheimer Network. Neurobiol Aging 75:42-50
Su, Yi; Flores, Shaney; Hornbeck, Russ C et al. (2018) Utilizing the Centiloid scale in cross-sectional and longitudinal PiB PET studies. Neuroimage Clin 19:406-416
Kawamura, Naoki; Yokota, Tatsuya; Hontani, Hidekata (2018) Super-Resolution of Magnetic Resonance Images via Convex Optimization with Local and Global Prior Regularization and Spectrum Fitting. Int J Biomed Imaging 2018:9262847
Cruchaga, Carlos; Del-Aguila, Jorge L; Saef, Benjamin et al. (2018) Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms. Alzheimers Dement 14:205-214
Maxwell, Taylor J; Corcoran, Chris; Del-Aguila, Jorge L et al. (2018) Genome-wide association study for variants that modulate relationships between cerebrospinal fluid amyloid-beta 42, tau, and p-tau levels. Alzheimers Res Ther 10:86

Showing the most recent 10 out of 911 publications