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

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2021 · $1,444,213

## Abstract

Apolipoprotein E epsilon 4 (APOE-ε4) 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-ε4 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-ε4 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-ε4 allele carriers. Second, it is unknown if the neurotrophic and increased resting
cerebral blood flow effects of exercise extend to APOE-ε4 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-ε4 allele carriers. This pilot clinical trial will inform a future trial
addressing the critical question on the long-term effects of exercise in ε4 carriers. Cognitively intact APOE-ε4 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 interven...

## Key facts

- **NIH application ID:** 10144346
- **Project number:** 5R01AG057552-05
- **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:** $1,444,213
- **Award type:** 5
- **Project period:** 2017-09-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144346

## Citation

> US National Institutes of Health, RePORTER application 10144346, Exercise for Brain Health with Increased Genetic Risk for Alzheimer's Disease (5R01AG057552-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144346. Licensed CC0.

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