In the current budget period, the Adult Children Study (ACS) transitioned from cross-sectional to longitudinal analyses, many of which are ongoing. With this application, the ACS now incorporates new biomarkers to address the overarching hypothesis that disrupted neural integrity is the proximate cause of the transition from preclinica to symptomatic Alzheimer disease (AD). Two corollary hypotheses will be addressed: 1) cerebral amyloidosis and tauopathy individually are necessary but insufficient to cause the transition from cognitive normality to impairment; and 2) the spread of tauopathy from the medial temporal lobe to the neocortex is the tau imaging correlate of the transition from preclinical to symptomatic AD. Predicting individual-level development of symptomatic AD will be enormously important for the field and may accelerate secondary prevention trials of anti-AD therapies by permitting the enrollment of only cognitively normal individuals who have near certainty of progressing to symptomatic AD. The ACS investigators and its cohort are uniquely qualified to accomplish the following Specific Aims: 1. Recruit, enroll, and maintain the ACS cohort (N?300) 2. At entry and every 3 years thereafter comprehensively assess all participants with: 1) well-established clinical and cognitive instruments (annually for participants >65 years); 2) blood for genotyping for apolipoprotein E and other susceptibility genetic variants; 3) PET scans with amyloid and tau tracers (florbetapir and T807); 4) lumbar puncture (LP) for the collection of CSF; 5) an attentional battery; and 6) structural and functional MRI. 3. In ACS participants who transition from cognitive normality to impairment, correlate phenoconversion with: a. The regional distribution and density of tau retention (Project 1) b. CSF markers of neural (tau, p-tau181) and synaptic (SNAP-25, neurogranin) injury (Project 2) c. Longitudinal rates of change on measures of global cognition and episodic memory (Clinical Core, Project 1) and attentional control (Project 3), cross sectional event-related fMRI as a function of AD markers, and the relation among A?42, sleep, and memory consolidation mechanisms (Project 3) d. The regional distribution and density of amyloid retention, and changes in brain structure and function (hippocampal volume, cortical thickness, functional connectivity) (Project 4) e. CSF concentrations of A?42, and also novel analytes (YKL-40, VILIP 1) (Project 2) 4. Analyze associations among rates of change of all AD markers from all Cores and Projects (Data Management and Biostatistics Core).

Public Health Relevance

The Adult Children Study has created a cohort of middle age and older individuals, with and without a family history of Alzheimer disease (AD), who longitudinally undergo a comprehensive battery of biological, clinical and cognitive tests to identify the earliest brain changes of AD prior to any clinical symptoms. This renewal will focus on defining the 'trigger(s)' that leads to symptomatic AD, possibly sufficient for individual prediction. Predicting individual-level development of symptomatic AD will be enormously important for the field and may accelerate secondary prevention trials of anti-AD therapies by permitting the enrollment of only cognitively normal individuals who have near certainty of progressing to symptomatic AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG026276-11
Application #
9071701
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6 (J4))
Program Officer
Hsiao, John
Project Start
2005-07-01
Project End
2021-05-31
Budget Start
2016-09-30
Budget End
2017-05-31
Support Year
11
Fiscal Year
2016
Total Cost
$2,038,685
Indirect Cost
$693,580
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Schindler, Suzanne E; Gray, Julia D; Gordon, Brian A et al. (2018) Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. Alzheimers Dement 14:1460-1469
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
Weintraub, Sandra; Besser, Lilah; Dodge, Hiroko H et al. (2018) Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set (UDS). Alzheimer Dis Assoc Disord 32:10-17
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 :
Lucey, Brendan P; Hicks, Terry J; McLeland, Jennifer S et al. (2018) Effect of sleep on overnight cerebrospinal fluid amyloid ? kinetics. Ann Neurol 83:197-204
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
Gyurkovics, Mate; Balota, David A; Jackson, Jonathan D (2018) Mind-wandering in healthy aging and early stage Alzheimer's disease. Neuropsychology 32:89-101
Islam, Jyoti; Zhang, Yanqing (2018) Brain MRI analysis for Alzheimer's disease diagnosis using an ensemble system of deep convolutional neural networks. Brain Inform 5:2
Roe, Catherine M; Ances, Beau M; Head, Denise et al. (2018) Incident cognitive impairment: longitudinal changes in molecular, structural and cognitive biomarkers. Brain 141:3233-3248
Ihara, Ryoko; Vincent, Benjamin D; Baxter, Michael R et al. (2018) Relative neuron loss in hippocampal sclerosis of aging and Alzheimer's disease. Ann Neurol 84:741-753

Showing the most recent 10 out of 352 publications