# Investigating the Contribution of Peripheral versus Central Nervous System Immune Dysfunction to Cognitive Aging

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $622,369

## Abstract

Project Summary/Abstract
The overarching hypothesis of this project is that peripheral immune dysregulation, independent of central
nervous system (CNS) immune dysregulation, is a critical driver of cognitive decline, and this relationship is
exacerbated by higher Alzheimer's Disease (AD)-related pathology and by recent immune health events.
Epidemiological studies indicate that elevated levels of peripheral immune markers are evident years prior to
clinical manifestation of Alzheimer's Disease. Although peripheral immune dysfunction is a risk factor for
cognitive decline, many key unanswered how to effectively measure peripheral
and CNS immune changes; 2) how to disentangle the mechanistic role of peripheral and CNS immune
dysregulation on aging outcomes, and 3) how to evaluate the effect of immune-related health events on
cognitive decline. To address gaps in the field, we propose to use longitudinal, multimodal measurements
of peripheral and CNS immune markers. In addition to examining immune markers in circulating blood and
CSF, we will employ a cutting-edge method to analyze immune markers carried by periphery- and CNS-
derived extracellular vesicles (EVs). EVs play key roles in cell-to-cell communication and EV methodologies
also allow for specification of the originating cells. Our primary aims for this study are: to determine how
peripheral immune markers relate to CNS immune markers over time (Aim 1); to determine whether peripheral
and CNS immune markers show independent associations with cognitive outcomes, and to delineate how AD-
related pathology influences these associations (Aim 2); and to evaluate the role of immune health history on
the relationship between peripheral and CNS immune markers and cognitive decline (Aim 3). To test our
hypotheses, we will prospectively assess 180 AOAs enriched for preclinical AD (i.e., AOAs with positive
amyloid PET brain scans) with baseline and 24-month follow-up measurements of peripheral immune markers
(i.e., in circulating blood and in periphery-derived blood EVs) and of CNS immune markers (i.e., in CSF and in
CNS-derived blood EVs), and correlate these markers with metrics of cognition and biomarkers of AD (i.e.,
amyloid and p-tau). We will employ both a targeted and an exploratory immune marker panel, and will record
recent immune health events to determine their potential impact on the relationship between immune
dysregulation and cognitive decline. Importantly, this study will establish the most comprehensively
immunophenotyped aging cohort to date and will allow us to address critical questions regarding the role of the
peripheral immune system in typical and pathological aging. By determining the contribution(s) of peripheral-
versus CNS-derived immune signals to cognitive aging trajectories, we will be poised to better understand,
predict, and ultimately treat early pathogenic immune events that may drive AD pathogenesis.
questions remain, including: 1)

## Key facts

- **NIH application ID:** 10061516
- **Project number:** 5R01AG058772-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Brianne Magouirk Bettcher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $622,369
- **Award type:** 5
- **Project period:** 2019-02-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10061516

## Citation

> US National Institutes of Health, RePORTER application 10061516, Investigating the Contribution of Peripheral versus Central Nervous System Immune Dysfunction to Cognitive Aging (5R01AG058772-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10061516. Licensed CC0.

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