# Project 1 - Biomarkers of Neurovascular Function

> **NIH NIH P01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $751,684

## Abstract

The focus of P01 and Project 1 remains on the ‘neurovascular hypothesis’, which holds that changes in the
cerebrovascular system contribute to cognitive decline, dementia and AD. We propose to test the hypothesis in
APOE4 carriers (ε3/ε4; ε4/ε4) that are at high genetic risk for AD and develop with age accelerated
cerebrovascular changes relative to APOE3 homozygotes (ε3/ε3) that are at lower risk for AD and develop slower
cerebrovascular changes. Specifically, we hypothesize that cerebrovascular changes and breakdown in the
blood-brain barrier (BBB) precede and predict preclinical cognitive decline and clinical progression from
cognitively unimpaired (CU) to mild cognitive impairment (MCI), and MCI to dementia, in APOE4 carriers >
APOE3 homozygotes independently of Aβ and tau AD biomarker changes, and prior to neurodegeneration. To
test this, we will follow longitudinally 402 APOE4 and 465 APOE3 participants (ages 45-90), initially enrolled
as CU (75%) and MCI (25%). We will use: 1) Advanced molecular biomarker assessment of BBB and NVU cell-
specific biomarkers measured simultaneously in CSF and plasma with Aβ and tau biomarkers; 2) Advanced MRI
assessment of regional BBB permeability in relation to CBF changes; 3) Preclinical AD staging using AT(N)
biomarkers system; and 4) Cognitive decline by UDS 3.0 CDR and neuropsychological tests across different
cognitive domains. Three aims will test our hypothesis in APOE4 carriers and APOE3 homozygotes to 1)
Evaluate longitudinally biomarkers of BBB breakdown by serial CSF analysis in relation to serial Aβ and tau AD
biomarker (CSF, PET) changes and cognitive decline (AIM 1); 2) BBB permeability by serial DCE-MRI
measurements in relation to serial CSF biomarkers of BBB breakdown, Aβ and tau AD biomarker (CSF, PET)
changes and cognitive decline (AIM 2); 3) BBB breakdown by serial DCE-MRI measurements in relation to serial
CBF pCASL-MRI measurements, Aβ and tau AD biomarker (CSF, PET) changes and cognitive decline (AIM 3).
We expect to show that BBB/vascular dysfunction plays a major role in preclinical and early cognitive decline in
APOE4 carriers > APOE3 homozygotes, and that biomarkers of BBB breakdown in biofluids, and BBB and CBF
MRI measures will serve as reliable new prognostic biomarkers for cognitive impairment, dementia and early
AD. The results of this work may lead to new ways of thinking about pathogenesis, treatment and early
prevention of cognitive impairment, dementia and AD for which we still do not have effective therapies.

## Key facts

- **NIH application ID:** 10331684
- **Project number:** 2P01AG052350-06
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Berislav V Zlokovic
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $751,684
- **Award type:** 2
- **Project period:** 2016-09-30 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10331684

## Citation

> US National Institutes of Health, RePORTER application 10331684, Project 1 - Biomarkers of Neurovascular Function (2P01AG052350-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10331684. Licensed CC0.

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