Alzheimer's disease (AD) is a chronic neurodegenerative disorder that typically manifests clinically in the elderly. Interestingly, a variety of postmortem evidence suggests that the pathological hallmarks of AD, and by inference the disease itself, begin to occur early in an individual's life. This has led to an emerging view of AD whereby a set of disparate mechanistic triggers over a life-time converge upon shared biochemical pathways to elicit a phenotypically similar clinical syndrome and neuropathological state. This convergent pathophysiological hypothesis asserts that specific downstream biochemical pathways mediate the synaptic loss, cellular injury, and death observed in AD. Furthermore, many of these pathophysiological changes will be manifest in peripheral systems, which share these signaling pathways. We hypothesize that the hematopoietic system shares many cellular signaling pathways with the nervous system and is affected by many of the same pathophysiological changes that characterize AD. Specifically, we propose that peripheral leukocytes are affected by AD pathogenic processes, which will be reflected in alterations in protein levels and functions. As such, these changes will serve as important biomarkers for AD diagnosis and progression and will provide valuable insights into its pathophysiology and potential therapeutics. We propose to identify and collect serial clinical measurements and biological samples from three cohorts: subjects at high risk for developing mild-cognitive impairment (MCI)/AD (>75 years old with a first degree relative diagnosed with AD);age-and gender-matched subjects at low risk;and newly diagnosed, drug-naive subjects with MCI/AD.
In Specific Aim 1 we will undertake an extensive clinical and biomolecular examination of all high risk subjects that progress to a diagnosis of MCI/AD compared to an appropriately matched subset of low risk subjects without MCI/AD to discover and validate a potential biomarker profile of disease.
In Specific Aim 2 we will test the specificity and sensitivity of this profile in a second subset of the low risk cohort without MCI/AD and early, drug-naive MCI/AD subjects. We hypothesize that the clinical-biomolecular profile identified in these studies will be important to our understanding of disease diagnosis, pathogenesis, and therapy in AD. With the aging of America's baby boomers the need to fully understand the pathogenesis of this disease and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and our health care systems. As such, it is necessary to develop robust, specific, and sensitive biomarkers of early AD, which would greatly facilitate the diagnosis and treatment of this disease.

Public Health Relevance

We hypothesize that the clinical-biomolecular profile identified in these studies will be important to our understanding of disease diagnosis, pathogenesis, and therapy in AD. With the aging of America's baby boomers the need to fully understand the pathogenesis of this disease and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and our health care systems. As such, it is necessary to develop robust, specific, and sensitive biomarkers of early AD, which would greatly facilitate the diagnosis and treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG030753-05
Application #
8278568
Study Section
Special Emphasis Panel (ZRG1-CND-E (90))
Program Officer
Hsiao, John
Project Start
2008-05-15
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$573,745
Indirect Cost
$64,712
Name
Georgetown University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Fiandaca, Massimo S; Kapogiannis, Dimitrios; Mapstone, Mark et al. (2015) Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study. Alzheimers Dement 11:600-7.e1
Mapstone, Mark; Cheema, Amrita K; Fiandaca, Massimo S et al. (2014) Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med 20:415-8
Yasar, Sevil; Xia, Jin; Yao, Wenliang et al. (2013) Antihypertensive drugs decrease risk of Alzheimer disease: Ginkgo Evaluation of Memory Study. Neurology 81:896-903