Elucidating the role of endothelial dysfunction in alzheimer disease: towards a new data-driven disease model

Ended Project Grant Awarded Last action

Award ID
RF1AG083744
Recipient
Awarding agency
Obligated
$1,549,865

Award facts

Assistance listing
93.866 Aging Research
Completion date
Place of performance
St. Louis, MO 63103, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Structural and functional alterations in brain endothelium are observed in =90% of alzheimer disease (ad) brains in the absence of cerebrovascular disease or AMYLOID angiopathy. Despite its prevalence, the role of endothelial dysfunction in ad pathogenesis has not been adequately investigated due to the absence of reliable endothelial biomarkers. We have identified a novel panel of endothelial biomarkers whose brain ribonucleic acid (RNA) and cerebrospinal fluid (CSF) protein levels are significantly altered in ad compared to controls. Exciting preliminary data suggest that these proteins offer promise as novel diagnostic and prognostic biomarkers of brain endothelial dysfunction and strongly correlate with cognitive and radiological outcomes in ad. Importantly, our preliminary ad models suggest that endothelial dysfunction is an early pathological substrate which may precede AMYLOID and TAU. We here propose to conduct the first in-depth comprehensive translational study of endothelial dysfunction in ad. In this study, we will utilize proteomics and transcriptomics to measure CSF protein and brain RNA levels of these endothelial markers in 3 large well-characterized longitudinal cohorts of late-onset sporadic ad, healthy controls, and non-ad dementias (combined N>3,400) who have been followed for 20-25 years and for whom we have detailed longitudinal cognitive, CSF, magnetic resonance imaging (MRI including ASL, flair, and DTI), AMYLOID-positron emission tomography (AMYLOID-pet), and TAU-pet imaging data. In aim 1, we will examine the diagnostic and prognostic utility of CSF endothelial markers in ad and their ability to predict cognitive decline and brain atrophy over time, independently of AMYLOID and TAU. We will also characterize baseline and longitudinal associations of endothelial dysfunction with CSF and/or imaging markers of AMYLOID, TAU, inflammation, and neuronal/synaptic injury over 20-25 years of follow-up, including 10-15 years prior to symptom onset. In aim 2, we will leverage event-based modeling (EBM; aim 2A) in our cross-sectional cohorts and multifactorial data driven analyses (mfdda; aim 2B) in our longitudinal cohorts to propose new data-driven predictive models for ad which will elucidate the temporal ordering of fluid and imaging ad markers and the spatiotemporal progression of ad imaging markers (cerebral blood flow, AMYLOID and TAU pet, and brain atrophy) across 37 brain regions and over 10-15 years prior to symptom onset. Functional pathway analyses of proteomic and RNA-SEQ data from our cohort and others will identify novel mechanisms by which endothelial dysfunction contributes to neurodegeneration, and influences synaptic plasticity, axonal repair, and abnormal protein aggregation in ad (aim 2C). Through in-depth multi-omics analyses of endothelial dysfunction and the integration of multimodal data from large well-characterized longitudinal multiracial ad cohorts, we aim to propose a new disease model which will be the first to integrate endothelial dysfunction into the ad paradigm and will capture the molecular and pathological heterogeneity of ad beyond AMYLOID and TAU. Findings from this study will provide novel insights into disease mechanisms and new molecular targets for ad drug discovery.

Transactions

Action Obligated Date
Amendment $0
Amendment -$36,075
Amendment $36,075
Amendment $36,075
Amendment -$36,075
Amendment $590,265
Amendment $590,265
Amendment -$590,265
Amendment -$590,265
Amendment -$590,265
Original award $2,140,130
Show all 11

Subawards

Subrecipient Amount Awarded
The Ohio State University  Event-based modelling (EBM) to generate AD models that predict temporal biomarker ordering in LOAD using cross- sectional multi-omic data from n=3,387… $36,420
University Of New Mexico Dr Kang will be directly involved performing the following:  Statistical analyses for Aim 1A-C which include examining the diagnostic and predictive value of… $71,147
Lovelace Biomedical Research Institute Dr Vakhtin will perform the following: Processing MRI images to measure whole brain and regional white matter injury including measuring white matter… $6,778
The Washington University The scope of work for Dr Cruchaga’s laboratory in this project includes:  Performance of RNA extraction and transcriptomic studies of n=557… $40,797
Mind Research Network Scope of Work for Dr. Caprihan Dr Caprihan will perform the following:  Processing MRI images to measure whole brain and regional white matter injury… $58,009
Mind Research Network $40,598

Quick answers

Who received award RF1AG083744?

RF1AG083744 was awarded to University Of New Mexico by National Institute on Aging (National Institutes of Health) on September 1, 2023.

How much is award RF1AG083744 worth?

$1,549,865 has been obligated on RF1AG083744.

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