# Exercise for Brain Health with Increased Genetic Risk for Alzheimer's Disease

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2021 · $607,955

## Abstract

PROJECT SUMMARY. Apolipoprotein E epsilon4 (APOE-e4) allele carriers are known to be at substantially
greater risk for cognitive decline and Alzheimer’s disease (AD). Yet, APOE-ε4 allele inheritance is an imperfect
predictor of who will develop clinical symptoms of the disease, suggesting that modifiable lifestyle factors such
as exercise may moderate its influence on disease progression. Our team is uniquely qualified, and we have
published several preliminary studies showing that physical activity may offer protection for APOE-ε4 allele
carriers from AD-related neurodegeneration and cognitive decline. Interventions, such as exercise, that even
modestly delay the onset of cognitive impairment or improve cognitive function in healthy APOE-e4 carriers will
have a major public health impact. It is not yet known, however, if exercise prospectively modifies the disease
trajectory in healthy asymptomatic older adults who are at increased genetic risk for AD. The focus and
innovative aspect of our proposal is to test the hypothesis that exercise training will improve the efficiency of neural
networks during memory retrieval, increase resting cerebral blood flow, neural network connectivity, and cortical
thickness, and improve episodic memory performance in APOE-e4 allele carriers. There are three key knowledge
gaps regarding exercise as a primary prevention of cognitive decline in those at genetic risk for AD. First, it has not
yet been firmly established that exercise improves the function and efficiency of neuronal networks during cognition,
including memory retrieval, in APOE-e4 allele carriers. Second, it is unknown if the neurotrophic and increased
resting cerebral blood flow effects of exercise extend to APOE-e4 allele carriers. Third, it has not been demonstrated
that an exercise intervention will have lasting effects that delay cognitive decline or conversion to MCI. The novel and
distinguishing feature of our proposal is to address the first two knowledge gaps with MRI and cognitive outcomes
after exercise training in cognitively intact older APOE-e4 allele carriers. Cognitively intact APOE-e4 allele carriers
will be randomly assigned to 6-months of either supervised moderate intensity aerobic exercise training (ET) or
supervised flexibility exercise control (FC). The ET and FC each contain a group-based exercise component
and are run in retirement communities. Our primary aims are to compare pre-intervention to post-intervention
changes in 1) MRI biomarkers; and 2) episodic memory performance measured by the Rey Auditory Verbal
Learning Test (RAVLT). We hypothesize that after ET compared to FC, brain activation during memory
retrieval will be reduced, resting cerebral blood flow and functional connectivity will increase in frontal regions,
and episodic memory performance will improve. Outcomes in response to the intervention will be measured at
baseline and 6 months. Our famous name discrimination task has several advantages to track the effe...

## Key facts

- **NIH application ID:** 10407361
- **Project number:** 3R01AG057552-05S1
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** JEROME CARSON SMITH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $607,955
- **Award type:** 3
- **Project period:** 2021-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407361

## Citation

> US National Institutes of Health, RePORTER application 10407361, Exercise for Brain Health with Increased Genetic Risk for Alzheimer's Disease (3R01AG057552-05S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10407361. Licensed CC0.

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