# Sex hormones, inflammation, and cognitive decline in older men and women

> **NIH NIH R21** · PENNSYLVANIA STATE UNIVERSITY, THE · 2020 · $199,825

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD) is the most common form of dementia in older adults, has no known cure, and
increasingly impacts society in terms of its human toll and healthcare costs. AD disproportionately affects
women, even when accounting for women’s greater longevity and other sex-linked factors. This research
focuses on the predominant sex hormones in older women and men (estradiol, estrone, testosterone) as
protective factors against pre-clinical cognitive decline and mild cognitive impairment (MCI), which may be
prodromal states of AD. Sex hormones reduce risk for AD and protect against cognitive decline in women and
men and may do so through associations with reduced pro-inflammatory and increased anti-inflammatory
signaling. Research rarely studies women and men concurrently and rarely examines the effects of ‘opposite-
sex’ hormones (i.e., estrogens in men, testosterone in women) to compare the relative strength of sex
hormones’ protective effects. Research on cognitive decline likewise has ignored age-related changes in
estrone, the predominant estrogen in older women that may represent a separate protective pathway against
cognitive decline. Moreover, studies linking sex hormones to cognitive decline lack rigorous assessments of
inflammation as a pathway by which testosterone exerts its protective effects. This project investigates sex
hormones’ (estradiol, estrone, and testosterone) influence on cognitive outcomes in adults aged 70+ years (n =
610) who are enrolled as part of the Einstein Aging Studies (EAS), an ongoing longitudinal cohort study. The
EAS examines cognitive functioning via highly sensitive ambulatory assessments (6/day, 14 days/wave)
across 3 annual waves, and via MCI prevalence at Wave 1. Blood collected before and after each assessment
burst is assayed for a panel of pro- and anti-inflammatory cytokines, including basal circulating levels and
stimulated responses. We propose to assay sex hormones from these same blood samples. We hypothesize
that sex hormones will relate to better cognitive outcomes in Wave 1 in men and women, and that levels of pro-
and anti-inflammatory biomarkers will partly mediate this effect. Similarly, we expect sex hormones will protect
against cognitive decline and may do so via their effects on inflammation. This research broadens the impact
of the ongoing, longitudinal EAS by linking sex hormones to sensitive measurement of cognitive states
associated with AD. We will also examine sex hormones association with inflammatory load across the full two-
week burst, and with individuals’ inflammatory responses in blood, which may be a more sensitive measure for
the development of AD. The work is a necessary and timely investigation of sex hormones’ links to cognitive
decline and MCI, which may be part of the long prodromal periods inherent to AD. Integrating this proposal into
the EAS will provide a pipeline of new data that will inform and invigorate new research on the rou...

## Key facts

- **NIH application ID:** 10017865
- **Project number:** 5R21AG066140-02
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** CHRISTOPHER G ENGELAND
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $199,825
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017865

## Citation

> US National Institutes of Health, RePORTER application 10017865, Sex hormones, inflammation, and cognitive decline in older men and women (5R21AG066140-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10017865. Licensed CC0.

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