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

University of North Carolina, Greensboro180 enrolled

Overview

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.

In this study, the investigators follow up on their past research exploring the effects of physical activity on cognitive performance and underlying mechanisms. In particular, the investigators are interested in the potentially different effects that might be realized as a function of a person's genetic risk for Alzheimer's disease. In this study, the investigators extend past work by proposing a randomized clinical trial to: (a) test the causal link between physical activity and cognitive performance in middle-aged adults (40-65 years) with a family history, and (b) determine if the effect is moderated by apolipoprotein epsilon-4 (APOE4) carrier status. The investigators will collect neuroimaging measures of cerebral structure, white matter integrity, and resting state connectivity; assess putative biological markers; and (using moderated mediation analyses) increase understanding of underlying mechanisms and of the extent to which effects are moderated by APOE4 carrier status. To test hypotheses, the investigators will randomly assign 240 cognitively normal, middle-aged adults to a 1-year virtual physical activity program or a usual care control. Those in the intervention will participate in a year-long physical activity program including aerobic exercise performed on your own and resistance exercises led in virtual exercise sessions with an instructor 1 hour/day for 3 days/week for 1 year. Those in the usual care control condition will be asked to maintain their normal lifestyle for one year and then will be given a short-term fitness center membership (contingent upon completion of testing sessions). The investigators will assess cognitive performance at pre-, mid-, and post-test, and obtain MRI scans and blood samples at pre-, mid- and post-test. The investigators will examine the effects of physical activity on cognitive performance and on neurological and biological mechanisms and will explore the moderating role of APOE4.

Study Type

INTERVENTIONAL

Interventions

Physical Activity ConditionBEHAVIORAL

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.

Eligibility

Sex: ALLMin age: 40 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * 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 Exclusion Criteria: * 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

Outcomes

Primary Outcomes

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)

Time frame: 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)

Time frame: 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.

Time frame: 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.

Time frame: 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 are proportions that 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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)

Time frame: 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)

Time frame: 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)

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

Secondary Outcomes

Change in Brain Morphology (Whole Brain Volume)

Change in whole brain morphology will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) for total segmented brain volume (i.e., total brain separated from non-brain structures). This is measured as volume (mm3), with volumes ranging from 1,050,000 to 1,350,000, and with higher values being interpreted as better.

Time frame: Pre-Test and Post-Test (~12 months)

Change in Brain Morphology (Left Hippocampus Volume)

Change in Left Hippocampus Volume will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) for total segmented left hippocampus volume (i.e., left hippocampus segmented away from other regions). This is measured as volume (mm3), ranges from 2500 to 4500, and higher values are better.

Time frame: Pre-Test and Post-Test (~12 months)

Change in Brain Morphology (Right Hippocampus Volume)

Change in Right Hippocampus Volume will be assessed by comparing Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months) for total segmented right hippocampus volume (i.e., right hippocampus segmented away from other regions). This is measured as volume (mm3), ranges from 2500 to 4500, and higher values are better.

Time frame: 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

Blood samples will be taken following a 12-hour fast. Assays will be conducted for brain-derived neurotrophic factor (BDNF), irisin, insulin-like growth factor (IGF)-1, glucose, insulin, tumor necrosis factor (TNF)-⍺, serum amyloid protein (SAP), albumin, apolipoprotein E (ApoE) and ⍺-2 macroglobulin. Change from pre-test to post-test will be assessed.

Time frame: 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

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

Change in blood biomarkers (BDNF, irisin, IGF-1, glucose, insulin, TNF-⍺, serum amyloid protein (SAP), albumin, ApoE and ⍺-2 macroglobulin) - IGF-1. Blood samples will be taken following a 12-hour fast. Assays will be conducted for brain-derived neurotrophic factor (BDNF), irisin, insulin-like growth factor (IGF)-1, glucose, insulin, tumor necrosis factor (TNF)-⍺, serum amyloid protein (SAP), albumin, apolipoprotein E (ApoE) and ⍺-2 macroglobulin. Change from pre-test to post-test will be assessed. The capture antibodies in the kits we received from the company for IGF-1 were not effective. We attempted to secure new kits to conduct the assays, but did not receive the kits in a timely fashion. We intend to conduct these assays upon receipt of the kits and the availability of personnel to perform the assays. The anticipated reporting date for IGF-1 is January 2027.

Time frame: 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) - Glucose

Time frame: 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) - Insulin

Time frame: 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) - TNFa

Time frame: 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) - SAA

Time frame: 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) - ALB

Time frame: 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) - ApoE

Time frame: 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) - ⍺-2 Macroglobulin

Time frame: Pre-Test and Post-Test (~12 months)

Change in Cardiorespiratory Fitness

Fitness will be assessed by comparing predicted VO2max at Pre-Test, Mid-Test (\~6 months), and Post-Test (\~12 months). Fitness will be assessed using a submaximal graded aerobic exercise test performed on a treadmill. Oxygen uptake (VO2) at each stage is estimated based on the treadmill speed and grade during a ramped exercise protocol performed until volitional exhaustion or test termination due to symptom limitations. The VO2max estimation uses the slope of the regression line between the heart rates (HR) of the last two stages to extrapolate to the participant's predicted VO2 at their age-predicted max HR (220-age). If HR at either of the last two stages is \<110, VO2 could not be reliably calculated, and we consider the participant to have insufficient data (ID). We have explored other options for estimating VO2 max, but believe this is the best option available.

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

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes