Despite advances in our knowledge of Alzheimer's disease (AD) course, our understanding of the pathogenesis of this devastating illness is lagging behind. This application, in response to RFA-AG-15-010, aims to identify the contribution of vascular dysfunction and its associated molecular mechanisms related to the endothelium and angiotensin pathways in AD. We propose to assess systemic and cerebral vascular functions and identify their molecular regulators in prodromal AD and use experimental models to define the precise contribution of these pathways and potential therapeutic interventions. We leverage existing cohorts (Emory Cardiovascular Biobank and Predictive Health Studies); excellent infrastructure for molecular and translational vascular phenotyping; ongoing NIH funded projects (Emory ADRC) at our institution; and a strong interdisciplinary team with expertise in cardiology, vascular biology, cognitive aging, neurosciences, neuroimaging, metabolomics and bioinformatics. To achieve this goal of studying the role of vascular function in AD, we will study 100 individuals with prodromal AD (MCI with AD-signature cerebrospinal fluid (CSF) profile, MCI-AD) and 100 matched cognitively normal individuals for 2 years and use a novel AD rat model (TgF344) that exhibits changes in both amyloid and tau also followed for 2 years.
Our Aims are to investigate the role of vascular function and regenerative capacity in MCI-AD (AIM1); Identify CSF and plasma markers in vascular other metabolic pathways using explorative unbiased metabolomic profiling in MCI-AD (AIM2); and use a rat AD animal model to establish the chronological order between vascular dysfunction and AD trajectory and study the impact of modifying vascular dysfunction via angiotensin II blockade on AD trajectory (AIM3). Our preliminary work suggests that (i) systemic and cerebral vascular dysfunction contribute to cognitive impairments, and that (ii) molecular/cellular modulators of vascular function (oxidative stress (OS), renin angiotensin aldosterone system, endothelial activity and vascular regeneration) are related to cognitive function and neuropathological indicators of AD. We intend to build on this prior work and will leverage ongoing studies to ensure recruitment of the proposed sample (n=200). We incorporate a set of parallel measures in the human and rat studies enhancing 2-way translational capabilities: object location cognitive paradigm, A?/tau levels, and comparable measures of vascular. To uncover underlying known and unknown molecular regulators, we have a cutting edge metabolomic facility and use novel metabolomic analysis of CSF and plasma of our participants. We validate the role of significant metabolite in AD in (i) our AD rats using gene expression and (ii) in an independent CSF sample (N=800). Our infrastructure of a strong vascular phenotyping program and a highly accomplished interdisciplinary team put us in a unique place to achieve the goals of this RFA: identify novel vascular biomarkers and provide new vascular-targeted therapies in early AD.

Public Health Relevance

Although great advances have been made in understanding Alzheimer's disease (AD), underlying vascular mechanisms are still not fully described. This study investigates the vascular effects and mechanisms in early stages of AD. This project would offer new targets for future therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
3RF1AG051633-01S1
Application #
9231712
Study Section
Program Officer
Petanceska, Suzana
Project Start
2015-09-30
Project End
2020-08-31
Budget Start
2016-04-15
Budget End
2020-08-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Shokouhi, Mahsa; Qiu, Deqiang; Samman Tahhan, Ayman et al. (2018) Differential Associations of Diastolic and Systolic Pressures With Cerebral Measures in Older Individuals With Mild Cognitive Impairment. Am J Hypertens 31:1268-1277
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Pimple, Pratik; Hammadah, Muhammad; Wilmot, Kobina et al. (2018) Chest Pain and Mental Stress-Induced Myocardial Ischemia: Sex Differences. Am J Med 131:540-547.e1
Samman Tahhan, Ayman; Hammadah, Muhammad; Raad, Mohamad et al. (2018) Progenitor Cells and Clinical Outcomes in Patients With Acute Coronary Syndromes. Circ Res 122:1565-1575
Hajjar, Ihab; Hayek, Salim S; Goldstein, Felicia C et al. (2018) Oxidative stress predicts cognitive decline with aging in healthy adults: an observational study. J Neuroinflammation 15:17
Samman Tahhan, Ayman; Hammadah, Muhammad; Kelli, Heval Mohamed et al. (2018) Circulating Progenitor Cells and Racial Differences. Circ Res 123:467-476
Ghasemzedah, Nima; Hayek, Salim S; Ko, Yi-An et al. (2017) Pathway-Specific Aggregate Biomarker Risk Score Is Associated With Burden of Coronary Artery Disease and Predicts Near-Term Risk of Myocardial Infarction and Death. Circ Cardiovasc Qual Outcomes 10:
Hayek, Salim S; Ko, Yi-An; Awad, Mosaab et al. (2017) Cardiovascular Disease Biomarkers and suPAR in Predicting Decline in Renal Function: A Prospective Cohort Study. Kidney Int Rep 2:425-432
Cai, Qingpo; Alvarez, Jessica A; Kang, Jian et al. (2017) Network Marker Selection for Untargeted LC-MS Metabolomics Data. J Proteome Res 16:1261-1269
Samman Tahhan, Ayman; Hayek, Salim S; Sandesara, Pratik et al. (2017) Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes. Atherosclerosis 264:108-114

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