# Cognitive Vulnerability to Stress in Individuals at Risk for Alzheimer's Disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $650,697

## Abstract

PROJECT SUMMARY/ABSTRACT
In the wake of discouraging results from treatment trials in Alzheimer’s disease (AD), the need to identify novel
approaches is urgent. There is emerging consensus that the lack of efficacy in AD clinical trials is attributable
to disease heterogeneity. Accordingly, identifying predictors of specific AD endophenotypes that could become
targets for intervention is of great interest. Among potential options, compelling evidence implicates the stress
response as a promising candidate. Indeed, findings from numerous studies converge on the notion that
individuals with a heightened sensitivity to stress are at greater risk of developing AD, suggesting that these
individuals may represent a group who could be targeted in AD treatment trials. Translating these findings into
clinical application has been hampered, however, by a lack of integration between studies that use rigorous
experimental interrogation of the endocrine stress response and studies that include sophisticated
characterization of patient samples. We aim to address this crucial gap. In this application, we propose to
conduct a prospective study to examine the associations among the endocrine stress response, the negative
cognitive effects of acute stress, and subsequent cognitive decline in 60 men and 60 women with mild
cognitive impairment due to AD (MCI). For our basic study design, we will induce acute stress with the Trier
Social Stress Test (TSST), and then measure the endocrine hormone and cognitive responses. The domains
of memory and executive functioning will be the primary cognitive outcomes. Salivary samples collected at
fixed intervals throughout the TSST will be used to measure stress hormone response; cortisol will be the
primary hormone outcome. We will also examine the influence of the APOE gene and polygenic risk scores for
AD and collect blood-based biomarkers associated with AD pathophysiology. Specific Aim #1: To determine
the association between endocrine response to acute stress and memory and executive test performance
following acute stress in individuals with MCI due to AD. Specific Aim #2: To examine the moderating effect of
APOE genotype and polygenic risk score on the association between endocrine response to acute stress and
cognitive test performance following acute stress in individuals with MCI due to AD. Specific Aim #3: To
determine predictors of cognitive decline and neurodegeneration at 2-year follow-up. Secondary Aim: Conduct
the analyses from Specific Aims 1-3 in men and women separately in order to identify sex-specific predictors
of stress-induced cognitive impairment and cognitive decline and neurodegeneration after 2 years.
Public health significance: Given the many recent failures of amyloid-lowering therapies in AD, it is important
to identify new potential treatment mechanisms. The proposed study could lay the groundwork for future AD
prevention trials targeting stress vulnerability and HPA-axis reactivity in at-risk i...

## Key facts

- **NIH application ID:** 10774198
- **Project number:** 5R01AG065171-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** CYNTHIA Ann MUNRO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $650,697
- **Award type:** 5
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10774198

## Citation

> US National Institutes of Health, RePORTER application 10774198, Cognitive Vulnerability to Stress in Individuals at Risk for Alzheimer's Disease (5R01AG065171-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10774198. Licensed CC0.

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