PAAD-2: Physical Activity, Alzheimer's Disease and Cognition Relative to APOE Genotype

Sponsor

University of North Carolina, Greensboro (Other)

Overall Status

Recruiting

CT.gov ID

NCT03876314

Collaborator

Wake Forest University Health Sciences (Other), National Institute on Aging (NIA) (NIH)

240

Enrollment

Location

Arms

45.3

Anticipated Duration (Months)

5.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy Dementia Alzheimer Disease Physical Activity	Behavioral: Physical Activity Condition	N/A

Detailed Description

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 Design

Study Type:

Interventional

Anticipated Enrollment :

240 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Care Provider, Outcomes Assessor)

Masking Description:

The outcomes assessor will be masked to intervention assignment and APOE4 carrier status. The interventionist will be masked to APOE4 carrier status.

Primary Purpose:

Basic Science

Official Title:

The Effect of Physical Activity on Cognition Relative to APOE Genotype (PAAD-2)

Actual Study Start Date :

May 23, 2019

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Physical Activity Condition (PAC) Subjects will be asked to attend virtual exercise sessions 3 times a week for 1 year.	Behavioral: Physical Activity Condition 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.
No Intervention: Usual Care Control (UCC) 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.

Arm

Intervention/Treatment

Experimental: Physical Activity Condition (PAC)

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

Behavioral: Physical Activity Condition

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.

No Intervention: Usual Care Control (UCC)

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.

Outcome Measures

Primary Outcome Measures

Change in performance on the cognitive domain of executive function as measured with Stroop Interference [Pretest, 6 months, and 12 months]
Change in executive function will be assessed by comparing post-, mid-, and pre-test performance on Stroop Interference.
Change in performance on the cognitive domain of executive function as measured with Trail Making Test Interference [Pretest, 6 months, and 12 months]
Change in executive function will be assessed by comparing post-, mid-, and pre-test performance on Trail Making Test interference.
Change in performance on the cognitive domain of executive function as measured with Dimensional Change Card Sort [Pretest, 6 months, and 12 months]
Change in executive function will be assessed by comparing post-, mid-, and pre-test performance on Dimensional Change Card Sort
Change in performance on the cognitive domain of executive function as measured with the Flanker test. [Pretest, 6 months, and 12 months]
Change in executive function will be assessed by comparing post-, mid-, and pre-test performance on the Flanker test.
Change in performance on the cognitive domain of executive function as measured with Matrix Reasoning. [Pretest, 6 months, and 12 months]
Change in executive function will be assessed by comparing post-, mid-, and pre-test performance on Matrix Reasoning.
Change in performance on the cognitive domain of memory as measured with the Auditory Verbal Learning Test. [Pretest, 6 months, and 12 months]
Change in memory will be assessed by comparing post-, mid-, and pre-test performance on the Auditory Verbal Learning Test.
Change in performance on the cognitive domain of memory as measured with the Rey-Osterrieth Complex Figure Test [Pretest, 6 months, and 12 months]
Change in memory will be assessed by comparing post-, mid-, and pre-test performance on the Rey-Osterrieth Complex Figure Test
Change in performance on the cognitive domain of memory as measured with the Picture Sequence test [Pretest, 6 months, and 12 months]
Change in memory will be assessed by comparing post-, mid-, and pre-test performance on the Picture Sequence test.
Change in performance on the cognitive domain of memory as measured with the Mnemonic Similarity Test [Pretest, 6 months, and 12 months]
Change in memory will be assessed by comparing post-, mid-, and pre-test performance on the Mnemonic Similarity Test
Change in performance on the cognitive domain of attention as measured with the Paced Auditory Serial Addition Test [Pretest, 6 months, and 12 months]
Change in attention will be assessed by comparing post-, mid-, and pre-test performance on the Paced Auditory Serial Addition Test
Change in performance on the cognitive domain of attention as measured with the Forward Digit Span test [Pretest, 6 months, and 12 months]
Change in attention will be assessed by comparing post-, mid-, and pre-test performance on the Forward Digit Span
Change in performance on the cognitive domain of working memory as measured with List Sort Working Memory [Pretest, 6 months, and 12 months]
Change in working memory will be assessed by comparing post-, mid-, and pre-test performance on the List Sort Working Memory
Change in performance on the cognitive domain of working memory as measured with Spatial Working Memory [Pretest, 6 months, and 12 months]
Change in working memory will be assessed by comparing post-, mid-, and pre-test performance on the Spatial Working Memory
Change in performance on the cognitive domain of working memory as measured with Backward Digit Span [Pretest, 6 months, and 12 months]
Change in working memory will be assessed by comparing post-, mid-, and pre-test performance on the Backward Digit Span
Change in performance on the cognitive domain of processing speed as measured with the Wechsler Adult Intelligence Scale (WAIS-IV) Digit Symbol Task [Pretest, 6 months, and 12 months]
Change in working memory will be assessed by comparing post-, mid-, and pre-test performance on the Wechsler Adult Intelligence Scale (WAIS-IV) Digit Symbol Task
Change in performance on the cognitive domain of processing speed as measured with the Stroop Color Test [Pretest, 6 months, and 12 months]
Change in working memory will be assessed by comparing post-, mid-, and pre-test performance on the Stroop Color Test
Change in performance on the cognitive domain of processing speed as measured with the Stroop Word Test [Pretest, 6 months, and 12 months]
Change in working memory will be assessed by comparing post-, mid-, and pre-test performance on the Stroop Word Test
Change in performance on the cognitive domain of processing speed as measured with the Trail Making Test A [Pretest, 6 months, and 12 months]
Change in working memory will be assessed by comparing post-, mid-, and pre-test performance on the Trail Making Test A

Secondary Outcome Measures

Change in brain morphology (whole brain and hippocampal volumes) [Pretest and 12 months]
MRI will be used to measure brain morphology including whole brain and hippocampal volumes and change will be assessed from pre-test to post-test.
Change in brain activity (resting-state connectivity) [Pretest and 12 months]
Functional MRI will be used to measure brain activity including resting-state connectivity and change will be assessed from pre-test to post-test.
Change in blood biomarkers (BDNF, irisin, IGF-1, glucose, insulin, TNF-⍺, serum amyloid protein (SAP), albumin, ApoE and ⍺-2 macroglobulin) [Pretest and 12 months]
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.
Change in cardiorespiratory fitness [Pretest, 6 months, and 12 months]
Fitness will be assessed using a submaximal graded aerobic exercise test performed on a treadmill. Oxygen uptake (VO2) will be measured during a ramped exercise protocol performed until volitional exhaustion or test termination due to symptom limitations. Change across time will be assessed.

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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