# Project-001

> **NIH NIH P01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $631,336

## Abstract

Vascular contributions to dementia and AD are increasingly recognized. Thus, the focus of this entire program
and Project 1 is on the ‘neurovascular hypothesis’, which holds that dysfunction in the cerebral vascular
system contributes to cognitive decline, dementia and AD. Major genetic risk factors for late-onset AD, i.e.,
apolipoprotein E-ε4 (APOE4) gene, and early-onset autosomal dominant AD, i.e., presenilin 1 (PSEN1)
mutations, exert direct toxic effects on the cerebrovascular system and neurons, and influence amyloid-β (Aβ)
metabolism and clearance, and tau pathology. However, the role of cerebrovascular changes in disease
pathogenesis, and in predicting neuronal injury, neurodegeneration and cognitive decline in individuals with
genetic risk for AD remains elusive. Based on published data and our preliminary findings, we hypothesize
that neurovascular dysfunction and breakdown in the blood-brain barrier (BBB) are detectable by molecular
and imaging biomarkers early in the disease process in APOE4 and PSEN1 mutation carriers relative to non-carriers,
and predict neuronal injury, disrupted brain connectivity and cognitive decline. To test our hypothesis
we will evaluate 294 APOE4 carriers and 340 non-carriers ages 45-90, and 44 PSEN1 mutation carriers and
44 non-carriers ages 18 and older, at early stages with no or mild cognitive impairment that will be followed
longitudinally over 4-5 years. We will use: 1) a novel molecular biomarker assessment of the neurovascular
unit (NVU) in biofluids (CSF and plasma) to determine how vascular/BBB injury relates to neuronal injury and
responses of non-neuronal neighboring cells (e.g., astrocytes, microglia, inflammatory response), Aβ and tau
biomarkers; 2) advanced neuroimaging assessment of neurovascular function using a novel dynamic contrast
enhanced magnetic resonance imaging protocol (DCE-MRI) to examine regional BBB permeability in relation
to cerebral blood flow (CBF; arterial spin labeling, ASL-MRI), white matter lesion (WML) pathology, and
structural/functional connectivity (Project 2 collaboration); 3) cognitive assessment by Uniform Data Set and
other neuropsychological measures of memory. Four aims will test our hypothesis in APOE4 and PSEN1
mutation carriers and non-carriers to 1) Evaluate NVU molecular biomarkers in biofluids in relation to cognitive
function (AIM 1); 2) Determine regional BBB permeability (DCE-MRI) in relation to NVU molecular biomarkers
and cognitive decline (AIM 2); 3) Examine the temporal relationship between BBB permeability (DCE-MRI),
CBF (ASL-MRI) and WML (AIM 3); and 4) Evaluate NVU molecular biomarkers in biofluids in relation to
structural/functional connectivity (AIM 4; Project 2 collaboration). The relationship between neurovascular
integrity, brain connectivity and cognitive function has not been explored. This project will apply a hypothesis-driven
approach to understand how neurovascular integrity changes in individuals with genetic risk for AD, and
whethe...

## Key facts

- **NIH application ID:** 9963135
- **Project number:** 5P01AG052350-05
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** ARTHUR W TOGA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $631,336
- **Award type:** 5
- **Project period:** — → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963135

## Citation

> US National Institutes of Health, RePORTER application 9963135, Project-001 (5P01AG052350-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963135. Licensed CC0.

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