# Older women with interstitial lung disease have more dementia

> **NIH NIH R21** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $257,663

## Abstract

Age, the APOE ε4 allele, and chromosomal sex appear to place women at increased risk for
Alzheimer’s Dementia (AD) compared to age-matched men. The APOE gene is associated with
an altered FEV1/FVC ratio in women and may influence the development of Alzheimer’s and
other forms of dementia in the setting of interstitial lung disease. As part of the current R21, we
published that decreased estrogen receptor (ER)β may promote disease promoting pathways in
lung tissue and myofibroblasts isolated from patients with a fatal form of interstitial lung disease,
idiopathic pulmonary fibrosis and the bleomycin (BLM) model of interstitial lung disease. Recent
studies also highlight the role of ER regulation of APOE ε4 in brain tissue and cultured neurons.
In preliminary data, we confirm that in the National (Nationwide) Inpatient Sample (NIS)
database, older women with interstitial lung disease are at increased risk for the development of
AD. Decreased ERβ signaling may contribute to the increased risk of AD in elderly women
leading to our hypothesis that modulating sex steroid hormone receptor activation by
specifically stimulating ERβ activation may slow the development of AD in the susceptible
patient with interstitial lung disease. To test this hypothesis, we will utilize a mouse model that
incorporates the ε4 variant of the gene APOE, which is closely associated with an increased risk
of the sporadic form of AD and has an influence on lung disease. We will determine whether:
A) BLM-induced lung disease accelerates amyloid deposition in APOE ε4 mice, a
confirmed model of AD and B) the intervention of ERβ agonist on the progression of
BLM-induced lung disease influences the development of amyloid deposition in APOE ε4
mutant mice.
This proposal has high impact since sex hormone receptor activation in the setting of lung
disease could potentiate detrimental factors in females or protective factors in males on the
subsequent development of AD. Discovery of these mechanisms may lead to new therapies that
not only ameliorate age-associated lung disease, but also affect the course of dementia. We are
uniquely positioned to carry out the proposed studies as we have a longstanding track record of
research on the effects of gonadal hormones in aging and fibrotic diseases and AD.

## Key facts

- **NIH application ID:** 10123823
- **Project number:** 3R21AG060338-02S1
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** SHARON J ELLIOT
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $257,663
- **Award type:** 3
- **Project period:** 2020-04-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123823

## Citation

> US National Institutes of Health, RePORTER application 10123823, Older women with interstitial lung disease have more dementia (3R21AG060338-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10123823. Licensed CC0.

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