# Mechanisms and Moderators of the Effects of Physical Activity in Preclinical Alzheimer Disease

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2022 · $240,391

## Abstract

Project 4: Project Summary/Abstract
Physical activity is emerging as a potential non-pharmacological intervention to reduce the risk of developing
symptomatic AD. However, there are several unresolved issues regarding the potential role of physical activity.
First, the neurobiological mechanisms by which physical activity may be protective are unclear. While there is
evidence from rodent studies that exercise-induced increase in trophic factors reduce AD pathology, enhance
hippocampal neuroplasticity and improve hippocampal-dependent memory, this pathway has not been fully
tested in humans. Second, there is limited understanding of the factors that contribute to individual differences
in the effectiveness of physical activity. Third, the majority of studies have used self-report measures with
variable evidence of reliability and validity, which could lead to biased estimation of effects. Lastly, the effect of
physical activity on core AD pathology has been less examined with mixed findings in the literature. Project 4
will address these gaps and limitations by testing the mechanistic model supported by animal work in humans
and determining factors that may moderate the beneficial effects of physical activity, both cross-sectionally and
longitudinally. Aim 1 will test the hypothesis that higher levels of physical activity will be associated with
benefits for neuronal/synaptic integrity and hence medial temporal lobe structure and episodic memory both
directly by reduced amyloid deposition and tau phosphorylation (via increased trophic factors) and indirectly by
mitigating the negative effects of AD pathology. Aim 2 will test the hypothesis that vascular health and the
response of trophic factors to an acute bout of exercise moderate the effects of physical activity on AD
biomarkers, medial temporal lobe structure and episodic memory. Exploratory Aim 3 will examine the role of
stress exposure (Clinical Core) and reactivity, inflammation (Projects 1 & 2), and the gut microbiome (Project
3) in the effects of physical activity. Physical activity will be robustly characterized with objective measures of
cardiorespiratory fitness and actigraphy-derived estimates of physical activity over 7 days. We will incorporate
blood measures of trophic factors, CSF measures of neuronal integrity (Fluid Biomarker Core), structural MRI
and DTI measures of medial temporal lobe structure (Project 1) as well as CSF and PET measures of AD
biomarkers (Projects 1 & 2). Importantly, this Project represents a critical initial step in a line of research to
determine the degree to which physical activity, directly and/or indirectly, influences the transition from
cognitive normality to symptomatic AD.

## Key facts

- **NIH application ID:** 10437772
- **Project number:** 5P01AG026276-17
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** DENISE HEAD
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $240,391
- **Award type:** 5
- **Project period:** 2005-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437772

## Citation

> US National Institutes of Health, RePORTER application 10437772, Mechanisms and Moderators of the Effects of Physical Activity in Preclinical Alzheimer Disease (5P01AG026276-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10437772. Licensed CC0.

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