# Large artery stiffness and cerebrovascular dysfunction: Implications for cognitive impairment and neuropathology

> **NIH NIH R01** · UNIVERSITY OF OREGON · 2021 · $432,966

## Abstract

PROJECT SUMMARY
As the prevalence of late-onset Alzheimer’s disease continues to increase, understanding the mechanistic
causes of this disease is becoming increasingly critical. Recent clinical studies have linked increased stiffness
of the large arteries to both impaired memory and Alzheimer’s disease. It is hypothesized that these relations
are a result of large artery stiffness-induced cerebrovascular dysfunction. Increased large artery stiffness leads
to greater pulsatility of pressure and blood flow in the cerebral vasculature, which is known to cause vascular
damage. Dysfunction of the cerebral arteries and microvasculature is associated with cognitive impairment and
greater Alzheimer’s disease-related neuropathology. Furthermore, amyloid-β (Aβ) induces cerebrovascular
damage, and cerebrovascular impairment increases Aβ accumulation, thus creating a vicious cycle of
cerebrovascular dysfunction and neuropathology. The goal of the proposed studies is to provide the first proof-
of-concept evidence that age-related increases in large artery stiffness, synergistically with greater Aβ
production, lead to cognitive impairment, neuropathology, and cerebrovascular dysfunction. To accomplish this
goal, we will employ transgenic mouse models of greater large artery stiffness and greater Aβ production, as
well as use a pharmacological intervention to prevent age-related increases in large artery stiffness. In Aim 1,
we will assess the effects of large artery stiffness, in combination with Aβ, on cognitive dysfunction and
Alzheimer’s disease-related neuropathology. In Aim 2, we will determine the effect of large artery stiffness, in
combination with Aβ, on cerebral blood flow and cerebral vascular reactivity and structural integrity. In Aim 3,
we will identify candidate mechanisms by which large artery stiffness and greater cerebral artery pulsatility lead
to cerebrovascular dysfunction. To do so, we will examine the role and source(s) of vascular oxidative stress,
as well as perform transcriptome analysis of cerebral arteries and microvascular endothelial cells. The
knowledge to be gained by completing the proposed aims will inform future studies to identify novel therapeutic
targets for the prevention or attenuation of late-onset Alzheimer’s disease.

## Key facts

- **NIH application ID:** 10140260
- **Project number:** 5R01AG064016-02
- **Recipient organization:** UNIVERSITY OF OREGON
- **Principal Investigator:** Ashley Elizabeth Walker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,966
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140260

## Citation

> US National Institutes of Health, RePORTER application 10140260, Large artery stiffness and cerebrovascular dysfunction: Implications for cognitive impairment and neuropathology (5R01AG064016-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10140260. Licensed CC0.

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