Physical Activity, Alzheimer's Disease and Cognition Relative to APOE Genotype

NCT03876314 | Completed Results

• 2 other identifiers: 18-0228R01AG058919
• Study Type: interventional
• Target: 180
• Locations: 1 country
• Sites: 1

Brief Summary

Physical activity and Alzheimer's disease (PAAD-2) is a randomized control trial that will assess the effects of exercise on middle-aged (40-65 years) cognitively normal adults who have a heightened risk of Alzheimer's disease (AD) due to family history (FH+). The investigators will also assess the extent to which this effect is moderated by apolipoprotein epsilon-4 (APOE4) carrier status, and will gather critical new experimental evidence on the use of physical activity to improve cognitive performance by persons at the greatest risk of Alzheimer's disease.

Conditions

Healthy; Dementia; Alzheimer Disease; Physical Activity

Keywords

Alzheimer's; Alzheimers; Alzheimer; dementia; exercise

Outcome Measures

Primary Outcomes (18)

• Change in Performance on the Cognitive Domain of Executive Function as Measured With Stroop Interference Reaction Time (RT)

  Change in executive function will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on Stroop Interference. Stroop interference is calculated using reaction time (RT) data from correct trials and the following formula: Stroop Interference RT = Stroop Incongruent RT - (average (Stroop Congruent RT , Stroop Neutral RT)). Stroop Congruent is also known as Stroop Word, and Stroop Neutral is also known as Stroop Color. RT is recorded in msec and a larger score is indicative of greater interference (worse performance)

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Executive Function as Measured With Trail Making Test Interference

  Change in executive function will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on the Comprehensive Trail Making Test (TMT) interference. TMT interference is calculated as total time to complete TMT B (also called Trail 5) minus the total time to complete TMT A (also called Trail 1)which were both recorded in seconds. TMT interference is, therefore, recorded in seconds with a larger score indicative of greater interference (worse performance)

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Executive Function as Measured With NIH Toolbox Dimensional Change Card Sort

  Change in executive function will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on the NIH Toolbox Dimentional Change Card Sort Test (DCCS). We used the recommended outcome of the DCCS computed score. This is calculated automatically within the NIH Toolbox based upon a two-stage process combining a score of 0-5 from the accuracy data with a score of 0-5 from the reaction time data. Thus, scores range from 0-10 with a higher score indicative of better performance.

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Executive Function as Measured With the NIH Toolbox Flanker Test.

  Change in executive function will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on the NIH Toolbox Flanker Inhibitory Control and Attention Test. We used the recommended outcome of the Flanker computed score. This is calculated automatically within the NIH Toolbox based upon a two-stage process combining a score of 0-5 from the accuracy data with a score of 0-5 from the reaction time data. Thus, scores range from 0-10 with a higher score indicative of better performance.

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Executive Function as Measured With Matrix Reasoning.

  Change in executive function will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on Matrix Reasoning Accuracy from the Virginia Cognitive Aging Project (VCAP). Version O was given at pre, Version A was given at mid, and Version B was given at post. Possible scores range from 0-1 (i.e., 0% accuracy to 100% accuracy expressed on a 0.00-1.00 scale) with a higher score being indicative of better performance.

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Memory as Measured With the Auditory Verbal Learning Test.

  Change in memory will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on the Auditory Verbal Learning Test. Majdan et al. (1996) Form 1 was given at pre, the standard Rey Auditory Verbal Learning list was given at mid, and Majdan et al. (1996) Form 2 was given at post. These versions are comparable in terms of their scores (Sherman, Tan, \& Hrabok, 2022). Possible scores range from 0-15 with a bigger score being indicative of better memory.

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Memory as Measured With the Rey-Osterrieth Complex Figure Test

  Change in memory will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on the Rey Osterreith Complex Figure Test. Tests were scored using the deep learning approach for automated scoring published by Langer et al. eLife 2024;13:RP96017. DOI: https://doi.org/10.7554/eLife.96017. Possible scores range from 0-36 with higher scores being indicative of better memory.

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Memory as Measured With the NIH Toolbox Picture Sequence Test

  Change in memory will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on the NIH Toolbox Picture Sequence Memory Test - The computed score is an IRT-based theta score of the number of adjacent pairs placed for trial 1 and 2 with a higher score being indicative of better memory. This score is automatically created within the NIH Toolbox. Version A was given at pre, Version B was given at mid, and Version C was given at post. Possible scores range from 200-700 with a higher score being indicative of better performance.

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Memory as Measured With the Mnemonic Similarity Test

  Change in memory will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) Lure Discimination Index (LDI) on the Mnemonic Similarity Test (MST). The MST was created based upon the publicly available and validated instructions and stimuli provided by the creators of the task (Stark, Kirwan, \& Stark, 2019). Equivalent versions of the test are administered so participants see different stimuli at each testing session and those stimuli were counterbalanced to rotate through the different item types. The formula for calculating the LDI is: p(similar\|lure) - p(similar\|foil) where p(similar\|lure) = Total # of "similar" responses to lure items / 36 and p(similar\|foil) = Total # "similar" responses to foil items / 36. Scores range from -1 to +1 with a larger score indicating better discrimination performance.

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Attention as Measured With the Paced Auditory Serial Addition Test

  Change in attention will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on the 2-sec trial of the Paced Auditory Serial Addition Task. Scores are reported as the number of correct responses with possible scores ranging from 0-60 and larger scores being indicative of better attention.

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Attention as Measured With the Forward Digit Span Test

  Change in attention will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on the Neurological Assessment Battery (NAB) Digit Span Forward test. Scores are reported as the number of correct trials with possible scores ranging from 0-14 and larger scores being indicative of better attention.

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Working Memory as Measured With NIH Toolbox List Sort Working Memory

  Change in working memory will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on the NIH Toolbox List Sort Working Memory Test. Scores are reported as the sum of the total number of items correctly recalled and sequenced on Lists 1 and 2 with possible scores ranging from 0-26 and larger scores being indicative of better working memory.

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Working Memory as Measured With Spatial Working Memory

  Change in working memory will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) reaction time on the 4-dot trial of the Spatial Working Memory Test. Scores are reported as the average reaction time (RT) for correct responses. Smaller scores are indicative of faster performance (i.e., better performance).

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Working Memory as Measured With Backward Digit Span

  Change in working memory will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) accuracy on the Neurological Assessment Battery (NAB) Digit Span Backwards test. Scores are reported as the number of correct trial with possible scores ranging from 0-14 and larger scores being indicative of better working memory.

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Processing Speed as Measured With the Digit Symbol Modalities Test (SDMT)

  Change in working memory will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on the Digit Symbol Modalities Test (SDMT) (Smith, 1973). Scores are reported as the sum of Oral and Written Trial Raw Scores (correct responses) with possible scores ranging from 0-220 and larger scores being indicative of better working memory.

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Processing Speed as Measured With the Stroop Word Test

  Change in processing speed will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on Stroop Word condition (also known as the Stroop Congruent condition). RT is recorded in msec and a larger score is indicative of slower performance (worse performance)

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Processing Speed as Measured With the Stroop Color Test

  Change in processing speed will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on Stroop Color condition (also known as the Stroop Neutral condition). RT is recorded in msec and a larger score is indicative of slower performance (worse performance)

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

• Change in Performance on the Cognitive Domain of Processing Speed as Measured With the Trail Making Test A

  Change in executive function will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) performance on the Comprehensive Trail Making Test (TMT) A (TMT A) (also known as Trail 1). Performance is recorded in seconds with a larger score indicative of slower performance (worse performance)

  Pre-Test, Mid-Test (~6 months), and Post-Test (~12 months)

Secondary Outcomes (20)

• Change in Brain Morphology (Whole Brain Volume)

  Pre-Test and Post-Test (~12 months)

• Change in Brain Morphology (Left Hippocampus Volume)

  Pre-Test and Post-Test (~12 months)

• Change in Brain Morphology (Right Hippocampus Volume)

  Pre-Test and Post-Test (~12 months)

• Change in Blood Biomarkers (BDNF, Irisin, IGF-1, Glucose, Insulin, TNF-⍺, Serum Amyloid Protein (SAP), Albumin, ApoE and ⍺-2 Macroglobulin) - BDNF

  Pre-Test and Post-Test (~12 months)

• Change in Blood Biomarkers (BDNF, Irisin, IGF-1, Glucose, Insulin, TNF-⍺, Serum Amyloid Protein (SAP), Albumin, ApoE and ⍺-2 Macroglobulin) - Irisin

  Pre-Test and Post-Test (~12 months)

Study Arms (2)

Physical Activity Condition (PAC)

EXPERIMENTAL

Subjects will be asked to attend virtual exercise sessions 3 times a week for 1 year.

Behavioral: Physical Activity Condition

Usual Care Control (UCC)

NO INTERVENTION

Participants in the usual care control will maintain their normal health practices for 1 year. Participants will receive a bi-weekly health newsletter and will be contacted bi-weekly to answer any questions and inquire about the participant's health. Participants self-reported physical activity will be assessed monthly. In this fashion, participants will be contacted by staff every week. Usual care control participants that complete all study related activities including pre-, mid-, and post-test will receive a short-term YMCA membership after post-test.

Interventions

Physical Activity Condition BEHAVIORAL

Subjects will attend virtual group exercise sessions 3x/week for 1 year. Each subject will be encouraged to walk at a moderate intensity (target heart rate (HR)= 40-59% HR reserve) dependent on resting HR and age. Subjects will perform aerobic exercise on their own and resistance exercises will be completed in virtual exercise sessions with an instructor 1 hour/day for 3 days/week for 1 year. At the exercise sessions, these participants will be asked to record measures of the exercises completed and may be asked to provide measures of heart rate (assessed by palpation for 20-seconds) and rate of perceived exertion (RPE). They will be asked to submit exercise logs providing this information. Data from exercise logs and exercise specialist records will be reviewed for evidence of progression, consistent attainment of moderate intensity, and with respect to the prescribed duration of the aerobic and strength training components.

Physical Activity Condition (PAC)

Eligibility Criteria

• Age: 40 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Family History of Alzheimer's disease, cognitive impairment
• Able to communicate in English
• Not currently meeting recommendations for physical activity (the recommendations are to exercise 3 days/week for 30+ minutes per day for longer than 3 months)
• Willing to be randomized to either study condition
• Willing to complete all study activities for 1 year

You may not qualify if:

• Meet the criteria for clinical cognitive impairment
• Unable to perform physical activity due to known cardiovascular, metabolic, or renal disease and are symptomatic or due to orthopedic limitations
• Self-report history of confounding neurologic, psychiatric, or active severe or functionally disabling neurologic or medical diseases, or any other conditions that might limit exercise or pose a danger to the patient
• Current use of medications to treat symptoms of Alzheimer's disease, that adversely affect cognition, or that impact heart rate
• Meet the criteria for depression using the short form of the Center for Epidemiological Studies Depression Scale
• Traveling for an extended period (\>1 month) during the course of the study

Sponsors & Collaborators

• University of North Carolina, Greensboro: lead
• Wake Forest University Health Sciences: collaborator
• National Institute on Aging (NIA): collaborator

Study Sites (1)

University of North Carolina-Greensboro

Greensboro, North Carolina, 27402, United States

Location

Related Publications (2)

• Park KS, Etnier JL. An innovative protocol for the artificial speech-directed, contactless administration of laboratory-based comprehensive cognitive assessments: PAAD-2 trial management during the COVID-19 pandemic. Contemp Clin Trials. 2021 Aug;107:106500. doi: 10.1016/j.cct.2021.106500. Epub 2021 Jul 2.

  PMID: 34217888 DERIVED

• Park KS, Ganesh AB, Berry NT, Mobley YP, Karper WB, Labban JD, Wahlheim CN, Williams TM, Wideman L, Etnier JL. The effect of physical activity on cognition relative to APOE genotype (PAAD-2): study protocol for a phase II randomized control trial. BMC Neurol. 2020 Jun 6;20(1):231. doi: 10.1186/s12883-020-01732-1.

  PMID: 32503473 DERIVED

MeSH Terms

Conditions

Dementia; Alzheimer Disease; Motor Activity

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Tauopathies; Neurodegenerative Diseases; Behavior

Limitations and Caveats

The exercise program was designed to be in person with exercise data recorded, however it moved to virtual due to COVID-19 with virtual strength training and self-guided walking. Cohort 1 exercisers met in person from 8.2019-3.2020 but virtually for the last 5 months. Cohort 2 was recruited prior to 3.2020 expecting in-person exercise; however exercisers participated in virtual exercise beginning 6.2020. All remaining cohorts were recruited knowing that the exercise sessions would be virtual.

Results Point of Contact

• Title: Jennifer L. Etnier, Professor
• Organization: University of North Carolina Greensboro

jletnier@uncg.edu

3362687159

Study Officials

• Jennifer Etnier, PhD

  UNC Greensboro

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: The outcomes assessor will be masked to intervention assignment and APOE4 carrier status. The interventionist will be masked to APOE4 carrier status.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2019
• First Posted: March 15, 2019
• Study Start: May 23, 2019
• Primary Completion: December 21, 2024
• Study Completion: December 21, 2024
• Last Updated: June 12, 2026
• Results First Posted: June 12, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: Consistent with the recommendations from the Collaboration for Alzheimer's Prevention (CAP), pre-randomization data will be deposited within 12 months of enrollment completion. Consistent with the National Institutes of Health (NIH) guidelines, post-randomization data will be embargoed until publication of the main findings of the study (i.e. those findings relevant to the specific aims) or two years following study closure (whichever comes earlier). Requests for data sharing that come before the end of the embargo period will be considered on a case-by-case basis by the principal investigator.
• Access Criteria: Investigators interested in having access to the data will submit their request through GAAIN and then will be asked to submit a proposal to the principal investigator. The proposal should include institutional affiliation, a current resume or vita, source of funding (if applicable), and a detailed explanation of the research question and the data required. All applicants will also be required to sign an agreement of confidentiality. This agreement prohibits the use of the data in any way that would allow for the identification of individual participants.

Locations

US (1)