This proposal will pursue in cognitively normal individuals from the Adult Children Study (ACS;POI AG026276) detailed, quantitative cross-sectional and longitudinal measurements of regional brain circulation, oxygen consumption and glucose use (total as well as the fraction devoted to aerobic glycolysis (AG;glucose use outside of oxidative phosphorylation)), and compare for the first time these more comprehensive measurements of brain circulation and metabolism with state-of-the-art biomarkers and clinical assessments in the same individuals. This work is motivated by our observation that while AG represents about 15% of the total glucose metabolized by the normal adult human brain it is strikingly nonuniform in its distribution being highest the brain's default mode network (DMN). The DMN is noteworthy from a disease perspective in that it represents a primary site of beta-amyloid (A?) plaque accumulation in Alzheimer's disease (AD). This apparent association between AG and AD prompted us to explore further this relationship in transgenic mice where we found that AG (but not total glucose consumption) and AP vary together not only regionally but with changes in synaptic activity. Furthermore, reducing synaptic activity chronically not only reduces AG and A? levels but also retards plaque deposition. Here we propose measuring for the first time AG in individuals in whom A? plaque distribution will be assessed with [11C]PIB PET imaging along with other state-of-the-art biomarkers and clinical assessments. The overarching aim of this application is to substantially enhance our knowledge of the pathophysiology of preclinical AD and specifically to more fully characterize AG as a biomarker of synaptic activity, a potential aggravating factor in the development of AD pathology. We will determine the chronology (cross-sectionally and longitudinally) of changes in AG and its relationship to clinical assessments and other biomarkers of AD. This project will not only provide novel and important information about development of preclinical AD and its transition to clinical stages, but also may provide a useful marker of the efficacy of anti-Abeta treatments especially those designed to modify synaptic function.

Public Health Relevance

The focus of the ACS and this project is the discovery of predictive and diagnostic biomarkers of AD. A more complete view of brain metabolism, specifically as it relates to synaptic function, and AD pathology would be extremely helpful in achieving a better understanding of AD pathophysiology and assisting in the design and control of appropriate preventive treatments which may seek to modify synaptic function.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Hsiao, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Schindler, Suzanne E; Sutphen, Courtney L; Teunissen, Charlotte et al. (2018) Upward drift in cerebrospinal fluid amyloid ? 42 assay values for more than 10 years. Alzheimers Dement 14:62-70
Sato, Chihiro; Barthélemy, Nicolas R; Mawuenyega, Kwasi G et al. (2018) Tau Kinetics in Neurons and the Human Central Nervous System. Neuron 98:861-864
Millar, Peter R; Balota, David A; Bishara, Anthony J et al. (2018) Multinomial models reveal deficits of two distinct controlled retrieval processes in aging and very mild Alzheimer disease. Mem Cognit 46:1058-1075
Babulal, Ganesh M; Chen, Suzie; Williams, Monique M et al. (2018) Depression and Alzheimer's Disease Biomarkers Predict Driving Decline. J Alzheimers Dis 66:1213-1221
Vlassenko, Andrei G; Gordon, Brian A; Goyal, Manu S et al. (2018) Aerobic glycolysis and tau deposition in preclinical Alzheimer's disease. Neurobiol Aging 67:95-98
Gangishetti, Umesh; Christina Howell, J; Perrin, Richard J et al. (2018) Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer's disease. Alzheimers Res Ther 10:98
Stout, Sarah H; Babulal, Ganesh M; Ma, Chunyu et al. (2018) Driving cessation over a 24-year period: Dementia severity and cerebrospinal fluid biomarkers. Alzheimers Dement 14:610-616
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:
Day, Gregory S; Musiek, Erik S; Morris, John C (2018) Rapidly Progressive Dementia in the Outpatient Clinic: More Than Prions. Alzheimer Dis Assoc Disord 32:291-297
Chen, Jason A; Fears, Scott C; Jasinska, Anna J et al. (2018) Neurodegenerative disease biomarkers A?1-40, A?1-42, tau, and p-tau181 in the vervet monkey cerebrospinal fluid: Relation to normal aging, genetic influences, and cerebral amyloid angiopathy. Brain Behav 8:e00903

Showing the most recent 10 out of 352 publications