# Imaging Beta-Amyloid Clearance Mechanisms in the Aging Brain

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $375,655

## Abstract

Summary/Abstract
Function of the P-glycoprotein (P-gp) efflux pump at the blood-brain barrier (BBB) is reduced in Alzheimer’s
disease (AD). Evidence suggests that cerebrospinal fluid (CSF) and interstitial fluid (ISF) flow, i.e., brain fluid
dynamics (BFD), are also reduced in AD. P-gp function and BFD are both likely critical contributors to the
clearance of beta-amyloid (Ab), and intriguing evidence suggests that P-gp and BFD have complementary,
possibly dependent roles in the clearance of Ab. However, it is not known where in the AD pathophysiological
spectrum P-gp function and BFD become critically reduced. It is further not established if reduced P-gp function
and BFD are initiating factors of impaired Ab clearance and therefore Ab plaque deposition. These physiologic
and biomechanical processes remain largely unexamined in vivo in humans, particularly early in the AD
pathophysiological spectrum. Our preliminary data demonstrate that ventricular CSF dynamics are associated
with Ab plaque deposition and are likely reduced prior to cognitive decline. The overarching goal of this study is
to further understanding of the relationships between P-gp function, BFD, and Ab plaque deposition in the earliest
AD pathophysiological stages, prior to the onset of dementia. To achieve this goal, we will leverage ongoing
longitudinal neuroimaging studies of aging and AD to recruit non-demented older adults with known levels of Ab
plaque load from existing 11C-PiB PET imaging. We will examine (1) P-gp function from (R)-11C-verapamil and
15O-H2O PET imaging; (2) ventricular CSF influx from 15O-H2O PET imaging; and (3) brain fluid pulsatility at
physiologic relevant frequencies, including cardiac, respiratory, and vasomotion using a novel 7T MRI fast echo-
planar imaging (EPI) sequence. We will examine these PET and 7T MRI neuroimaging markers both cross-
sectionally and longitudinally relative to Ab plaque load and status from 11C-PiB PET imaging. Cross-sectionally,
we hypothesize that P-gp function will be associated with BFD (ventricular CSF influx and brain fluid pulsatility)
and that P-gp function and BFD will be reduced in non-demented participants with significant Ab plaque
deposition (Ab+) relative to those without (Ab-). Longitudinally, we hypothesize that neuroimaging markers of P-
gp function and BFD will predict future Ab deposition. These proposed findings will potentially identify PET and
7T MRI neuroimaging markers of P-gp function and BFD as earlier indicators of risk of AD than Ab PET imaging.
These findings, in turn, may identify P-gp function and BFD as therapeutic targets for the prevention of Ab plaque
deposition and therefore the onset of AD-related cognitive decline.

## Key facts

- **NIH application ID:** 10431260
- **Project number:** 1R21AG076861-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** CHARLES LAYMON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $375,655
- **Award type:** 1
- **Project period:** 2022-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10431260

## Citation

> US National Institutes of Health, RePORTER application 10431260, Imaging Beta-Amyloid Clearance Mechanisms in the Aging Brain (1R21AG076861-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10431260. Licensed CC0.

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