# Characterizing the interaction of genetic vulnerabilities and chronic peripheral inflammation for AD risk

> **NIH NIH U19** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $400,787

## Abstract

ABSTRACT
Not all persons who have a high genetic risk for Alzheimer's disease (AD) become symptomatic, even those
who reach extreme old age (e.g., 90+ years old). This observation suggests that genetic vulnerability to AD is
moderated by other factors. Identifying these factors, particularly those that are modifiable, could lead to
effective AD treatments and risk reduction strategies. We conjecture that peripheral chronic low-grade
inflammation is a major factor that influences expression of AD-related genes. Further, we hypothesize that
AD risk genes affect proinflammatory reactions in both peripheral and central systems that accelerate
accumulation of AD-related pathologies in the brain. This idea is supported by our recent Framingham Heart
Study (FHS) investigation of longitudinal measurements of C-reactive protein (CRP) from which we derived a
threshold to define chronic low-grade inflammation (CLI) as a chronic proinflammatory burden. We found that
CLI was associated with increased risk and earlier onset of AD among APOE ε4 carriers [1]. In addition, some
AD risk genes influence both AD risk and peripheral inflammation. For example, PLXNA4 variants are
associated with AD risk [2] and PlxnA4 also has a role in inflammatory processes. The central hypothesis
for this study is that genetic vulnerability in concert with CLI has an important role in AD pathogenesis.
To test this hypothesis, we will capitalize on the comprehensively characterized FHS cohort and its associated
brain bank and prospective serial AD-related brain MRI and biomarker data to evaluate the correlation of CLI
with changes in cognition and brain structure, as well as with incident AD, up to several decades later.
Specifically, we will 1) Evaluate the association of genetic variants with AD risk in the presence of chronic
peripheral inflammation in the FHS cohort; 2) Identify blood biomarkers associated with AD among FHS
participants with AD genetic risk variants and CLI, and evaluate their correlation with AD-related brain
pathology; 3) Validate associations established in Aims 1 and 2 between AD-related peripheral and brain
inflammation in other datasets including the Alzheimer Disease Genetic Consortium cohorts, the Alzheimer
Disease Neuroimaging Initiative, Knight Alzheimer's Disease Research Center at Washington University, and
the Korean National Center for Research in Dementia. If we find differences in the incidence of AD based on
biomarker profiles between carriers and non-carriers of particular AD-associated genetic variants among
persons who have CLI, our study will provide rationale for the mechanisms of AD genetic risk for the disease.
We anticipate that results from this study will provide insight for developing a personalized approach for treating
and preventing AD.

## Key facts

- **NIH application ID:** 10047359
- **Project number:** 1U19AG068753-01
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** WEI QIAO Wendy QIU
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,787
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047359

## Citation

> US National Institutes of Health, RePORTER application 10047359, Characterizing the interaction of genetic vulnerabilities and chronic peripheral inflammation for AD risk (1U19AG068753-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10047359. Licensed CC0.

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