# Cognitive and Brain Changes in Preclinical Alzheimer's Disease

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2021 · —

## Abstract

The pathogenesis of Alzheimer’s disease (AD) remains unclear, though there is growing support for a
synergistic relationship between vascular dysfunction and accumulation of amyloid-β and neurofibrillary
tangles. Cerebrovascular disease (CVD) risk factors are prevalent in the VA population, have been linked to
cognitive decline and higher risk for dementia, and may represent potential targets for remediating age-related
cognitive decline. [CVD risk factors are associated with peripheral vascular (e.g., increased pulse wave velocity
[PWV] indicating arterial stiffness) and cerebrovascular changes (e.g., reduced cerebral blood flow [CBF];
decreased cerebrovascular reactivity [CVR] indicating reduced ability of the cerebral vasculature to adjust
CBF).] Cerebral blood flow (CBF) is tightly coupled with metabolism underlying cognition by increasing local
delivery of oxygen and glucose to support neural function, and as such is an indirect measure of neural activity
and vascular function. [Animal models suggest reduced CBF (aka, hypoperfusion) contributes to AD-like
neurodegeneration by increasing amyloid-β accumulation and tau phosphorylation--the hallmark
neuropathology of AD. Translating these findings to humans is critical to identify and refine biomarkers of AD
and ultimately improve early detection and treatment.] We have shown altered CBF in prefrontal and medial
temporal lobe regions in older adults at genetic (APOE ε4 carriers) or cognitive (mild cognitive impairment;
MCI) risk for AD that is associated with memory and executive function, implicating CBF as a potential
biomarker of AD. This application aims to elucidate the link between the vascular and neurodegenerative
pathophysiological process of AD and the emergence of clinical symptoms to lead to an improved mechanistic
understanding of cognitive decline. Thus, the current application: [1) examines the association between
neurovascular (CBF) and cerebrovascular (CVR) function and cognition in at-risk older Veterans and tests
potential AD-related mechanisms (e.g., cerebral spinal fluid [CSF] AD biomarkers) that mediate this
relationship, 2) examines whether cerebrovascular function moderates the relationship between CBF and CSF
biomarkers, and 3) examines moderating effects of individual risk factors (e.g., increased arterial stiffness,
elevated sedentary time, APOE ε4).] This study will examine cognitive, vascular, and brain function in 120
English-speaking non-demented Veterans aged 65+ with at least 2 CVD risk factors, placing them at increased
risk for cognitive decline. Assessments include well-validated and standardized cognitive testing (e.g., NIH
Toolbox), state-of-the-art MR imaging (to measure CBF and CVR), comprehensive vascular function
assessment (including carotid-femoral pulse wave velocity, blood pressure, carotid ultrasound), lumbar
puncture to assay CSF AD biomarkers (including Aβ42, p-tau181, and total tau), accelerometry to assess
physical activity/sedentary level, and...

## Key facts

- **NIH application ID:** 9892974
- **Project number:** 5I01CX000565-08
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** CHRISTINA E WIERENGA
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-01-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892974

## Citation

> US National Institutes of Health, RePORTER application 9892974, Cognitive and Brain Changes in Preclinical Alzheimer's Disease (5I01CX000565-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9892974. Licensed CC0.

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