# The relationship of AD risk factors to reactive astrogliosis along the Alzheimer's disease continuum

> **NIH NIH P01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $100,159

## Abstract

Project 2 Summary/Abstract
Health risk factors such as cardiovascular risk factors (CVRF) and poor sleep are thought to increase the risk
of Alzheimer’s disease (AD). While the mechanisms linking CVRF and poor sleep with AD pathology remain
unclear, neuroinflammation such as astrogliosis, may be one such pathway.
CVRF has consistent links to AD pathology: during the past 10 years of this program project, we explored the
relationship of Aβ deposition alone and in combination with vascular modulators to neuronal dysfunction, and
their association with progression to cognitive impairment and AD. We identified associations of increased
arterial stiffness, systolic blood pressure, and cholesterol homeostasis with increases in Aβ burden
In addition to CVRF, sleep is implicated as a risk factor for AD. Sleep has well-established links to brain
structures and pathways implicated in AD, and is essential to cognitive, immune, and other physiological
functions. Age- and disease-related sleep changes may influence the accumulation of AD pathology21, 22.
Sleep loss is associated with increased levels of Aβ in the interstitial space, and influences kinetics of Aβ and
tau in the cerebrospinal fluid. We and others have demonstrated that poor sleep quality and lower objective
sleep efficiency (see preliminary data) are associated with greater Aβ burden. Moreover, through this program
project, we found a stronger association between Aβ and forgetting in those with poorer sleep efficiency.
Together, these data suggest that CVRF and poor sleep may create a state of vulnerability to AD pathology.
Nonetheless, the mechanisms by which these health factors can create this increased vulnerability to AD
remain unclear. One potential mediating factor is neuroinflammation. Cellular inflammation plays a well-
established role in AD pathology. Inflammation has established links with CVRF, hypertension, and stroke risk.
Similarly, sleep loss induces a 3-fold increase in pro-inflammatory cytokines, which contribute to the
homeostatic drive for SWA. Moreover, chronic poor sleep leads to a cascade of chronic neuroinflammation
including astrogliosis and microglial activation. Together, these data suggest that CVRF and poor sleep may
accelerate the process of Aβ deposition partially through neuroinflammation. The overarching goal Project 2
is to understand the role of astrogliosis, as a marker of neuroinflammation, in the relationship between
health risk factors (CVRF and sleep) and the trajectory of AD pathophysiology. In 300 participants we will
complete longitudinal assessments of: 1) Clinical vascular measures of CVRF and sleep efficiency and SWA
assessed with actigraphy and polysomnography; 2) Astrogliosis using PET (SMBT-1) and plasma (GFAP); and
3) AD pathology including Aβ-PET, plasma Aβ, tau PET, and plasma tau. We will examine cross-sectional and
longitudinal associations of CVRF and sleep with pathology and the mediating role of astrogliosis. We will
explore whether chan...

## Key facts

- **NIH application ID:** 10410729
- **Project number:** 2P01AG025204-16
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ann D. Cohen
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $100,159
- **Award type:** 2
- **Project period:** 2004-12-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410729

## Citation

> US National Institutes of Health, RePORTER application 10410729, The relationship of AD risk factors to reactive astrogliosis along the Alzheimer's disease continuum (2P01AG025204-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10410729. Licensed CC0.

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