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
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
Kinnunen, Kirsi M; Cash, David M; Poole, Teresa et al. (2018) Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study. Alzheimers Dement 14:43-53
Brainstorm Consortium (see original citation for additional authors) (2018) Analysis of shared heritability in common disorders of the brain. Science 360:
Ibanez, Laura; Dube, Umber; Davis, Albert A et al. (2018) Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease. Front Neurosci 12:230
Schultz, Stephanie A; Gordon, Brian A; Mishra, Shruti et al. (2018) Widespread distribution of tauopathy in preclinical Alzheimer's disease. Neurobiol Aging 72:177-185
Broce, Iris; Karch, Celeste M; Wen, Natalie et al. (2018) Correction: Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies. PLoS Med 15:e1002504
Javaherian, Kavon; Newman, Brianne M; Weng, Hua et al. (2018) Examining the Complicated Relationship Between Depressive Symptoms and Cognitive Impairment in Preclinical Alzheimer Disease. Alzheimer Dis Assoc Disord :
Liao, Fan; Li, Aimin; Xiong, Monica et al. (2018) Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J Clin Invest 128:2144-2155
Jansen, Willemijn J; Ossenkoppele, Rik; Tijms, Betty M et al. (2018) Association of Cerebral Amyloid-? Aggregation With Cognitive Functioning in Persons Without Dementia. JAMA Psychiatry 75:84-95

Showing the most recent 10 out of 911 publications