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Grant Abstract

Grant Number: 5R01AT006668-02
PI Name: Fitzpatrick
Project Title: Domains of Inflammation and Risk of Dementia

Abstract: DESCRIPTION (provided by applicant): The lack of understanding of Alzheimer's disease (AD) etiology limits the ability to develop preventive measures or to detect early development of this destructive disease. Recent theory suggests that the development and/or progression of AD involves vascular as well as neurodegenerative components. New focus has been directed toward investigating the associations between inflammatory biomarkers and AD to provide evidence of the vascular origin. The findings in these studies are inconsistent due to the limited availability of longitudinal data and lack of simultaneous measurement of different inflammatory markers which may reflect different aspects of inflammation. This study proposes to examine biomarkers representing different domains of vascular disease to increase understanding of how they vary in the development of dementia and AD among participants of the Ginkgo Evaluation of Memory Study (GEMS) cohort. We will also investigate the association between levels of these biomarkers and changes in cognition as well as brain pathology in MRI images. Stored blood samples of the GEMS cohort will be used to measure biomarkers of inflammatory disease representing different domains: IL-6 (general systemic inflammation), pentraxin 3 and serum amyloid P (vascular inflammation), PAI-1 and adiponectin (metabolic function), receptor for advanced glycation endproduct - RAGE (oxidative stress) and endothelin-1 (endothelial function). The GEMS Study is ideal for examining these relationships as it is a prospective multi-site study of adults age 75 or older who were evaluated every six month for cognitive decline and dementia onset over 7 years of follow-up. Subtype of dementia, i.e. AD and vascular dementia, were determined using MRI images and standardized criteria. The clinical trial resulted in no differences between Ginkgo biloba and placebo for primary outcomes of dementia, AD, MCI, mortality and CVD endpoints. This ancillary study to GEMS is a case-cohort design of 523 participants with incident dementia and 1046 non-demented controls. Stored blood will be accessed to assay biomarkers at baseline and for up to two additional time points during follow-up. Statistical approaches will include Cox proportional hazards regression, multiple linear regression, and mixed models regression for longitudinal analysis of data. Inclusion of time-dependent variables, risk factors for vascular disease, and cardiovascular morbidities in models will help elucidate pathways involving these biomarkers along the progression to dementia and AD. The large number of incident cases that were found in GEMS provides adequate power for these analyses overall and within subgroups such as gender and ApoE genotype. These findings will provide new knowledge that can be used to develop effective screening tools to focus on prevention as well as early detection of dementia and AD. PUBLIC HEALTH RELEVANCE: This project proposes to evaluate associations between different domains of inflammation and dementia, Alzheimer's disease, and mild cognitive impairment (MCI) using biomarkers measured longitudinally in 1569 participants of the Ginkgo Evaluation of Memory cohort. Assessment of these biomarkers to predict risk of dementia prior to cognitive symptoms emerging will increase ability to develop strategies of prevention and early detection.

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