Trial Outcomes & Findings for Exercise in Adults With Mild Memory Problems (NCT NCT02814526)

Results Overview

The ADAS-Cog-Exec Composite is a weighted sum of standardized (Z-score) change on subtests from the Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog13; Immediate and Delayed Word Recall, Orientation, and Number Cancellation); box scores for the cognitive components of the Clinical Dementia Rating Scale (Memory, Orientation, Judgement \& Problem Solving); and additional tests requiring executive function (Trail Making Test A \& B, Digit Symbol Substitution, Category Fluency). See https://doi.org/10.1002/trc2.12059 for a detailed description regarding the development and validation of the ADAS-Cog-Exec. Change for the analysis of this primary outcome was calculated comparing the average of scores from month 6 and month 12 to baseline. The theoretical range for the ADAS-Cog-Exec is -3.00 to +3.00 in EXERT, with higher scores indicating improvement in cognitive function from baseline.

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

296 participants

Primary outcome timeframe

Baseline to mean (Mo 6, Mo 12)

Results posted on

2023-02-15

Participant Flow

This study was conducted at Academic Institutions and participating Y-USA Centers across the nation. Recruitment for the overall study began June 2016 and ended in October 2021. This study consisted of a four week screening period, followed by 12 months of supervised exercise (the ITT period), and an additional 6 month unsupervised exercise period.

Screening duration: From signed consent up to 4 weeks. At baseline visit, participants are randomized to trial arms. A total of 532 participants consented to participate in the trial. Of these consented, 236 participants were screening failures. 296 participants were assigned/randomized to the trial.

Participant milestones

Participant milestones
Measure	Aerobic Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
Overall Study STARTED	148	148
Overall Study COMPLETED	115	118
Overall Study NOT COMPLETED	33	30

Reasons for withdrawal

Reasons for withdrawal
Measure	Aerobic Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
Overall Study Adverse Event	4	3
Overall Study Death	1	1
Overall Study Lost to Follow-up	3	4
Overall Study non site physician decision	1	0
Overall Study participant noncompliance	1	1
Overall Study Withdrawal by Subject	20	14
Overall Study safety risk	2	1
Overall Study early termination-study terminated	1	2
Overall Study Other	0	4

Baseline Characteristics

Baseline scores for this measure only available for 294 participants out of 296 total baselined.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Aerobic n=148 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=148 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.	Total n=296 Participants Total of all reporting groups
Age, Continuous	74.26 years STANDARD_DEVIATION 5.71 • n=148 Participants	74.65 years STANDARD_DEVIATION 6.23 • n=148 Participants	74.46 years STANDARD_DEVIATION 5.96 • n=296 Participants
Sex: Female, Male Female	85 Participants n=148 Participants	84 Participants n=148 Participants	169 Participants n=296 Participants
Sex: Female, Male Male	63 Participants n=148 Participants	64 Participants n=148 Participants	127 Participants n=296 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=148 Participants	0 Participants n=148 Participants	3 Participants n=296 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	142 Participants n=148 Participants	145 Participants n=148 Participants	287 Participants n=296 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=148 Participants	3 Participants n=148 Participants	6 Participants n=296 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants n=148 Participants	1 Participants n=148 Participants	3 Participants n=296 Participants
Race (NIH/OMB) Asian	3 Participants n=148 Participants	4 Participants n=148 Participants	7 Participants n=296 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=148 Participants	0 Participants n=148 Participants	0 Participants n=296 Participants
Race (NIH/OMB) Black or African American	15 Participants n=148 Participants	14 Participants n=148 Participants	29 Participants n=296 Participants
Race (NIH/OMB) White	127 Participants n=148 Participants	129 Participants n=148 Participants	256 Participants n=296 Participants
Race (NIH/OMB) More than one race	0 Participants n=148 Participants	0 Participants n=148 Participants	0 Participants n=296 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=148 Participants	0 Participants n=148 Participants	1 Participants n=296 Participants
Region of Enrollment United States	148 participants n=148 Participants	148 participants n=148 Participants	296 participants n=296 Participants
Mini-Mental State Examination (MMSE)	27.92 units on a scale STANDARD_DEVIATION 1.91 • n=148 Participants	28.03 units on a scale STANDARD_DEVIATION 1.83 • n=148 Participants	27.97 units on a scale STANDARD_DEVIATION 1.87 • n=296 Participants
Alzheimer's Disease Assessment Scale - Cognitive Subscale 13 (ADAS-Cog 13)	13.82 units on a scale STANDARD_DEVIATION 6.62 • n=147 Participants • Baseline scores for this measure only available for 294 participants out of 296 total baselined.	14.23 units on a scale STANDARD_DEVIATION 6.81 • n=147 Participants • Baseline scores for this measure only available for 294 participants out of 296 total baselined.	14.02 units on a scale STANDARD_DEVIATION 6.71 • n=294 Participants • Baseline scores for this measure only available for 294 participants out of 296 total baselined.
Clinical Dementia Rating - Sum of Boxes (CDR-SB)	1.43 units on a scale STANDARD_DEVIATION 0.84 • n=148 Participants • Baseline scores for this measure only available for 295 participants out of 296 total baselined.	1.57 units on a scale STANDARD_DEVIATION 0.87 • n=147 Participants • Baseline scores for this measure only available for 295 participants out of 296 total baselined.	1.5 units on a scale STANDARD_DEVIATION 0.86 • n=295 Participants • Baseline scores for this measure only available for 295 participants out of 296 total baselined.

PRIMARY outcome

Timeframe: Baseline to mean (Mo 6, Mo 12)

Population: Modified Intent-to-Treat (mITT) Population: Includes all eligible participants who (1) began the exercise intervention (Intervention Session 1) and (2) completed at least one post-baseline assessment for the primary analysis at Month 6 or Month 12. All consented randomized participants are grouped according to the treatment assigned at randomization, regardless of any protocol violations.

The ADAS-Cog-Exec Composite is a weighted sum of standardized (Z-score) change on subtests from the Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog13; Immediate and Delayed Word Recall, Orientation, and Number Cancellation); box scores for the cognitive components of the Clinical Dementia Rating Scale (Memory, Orientation, Judgement \& Problem Solving); and additional tests requiring executive function (Trail Making Test A \& B, Digit Symbol Substitution, Category Fluency). See https://doi.org/10.1002/trc2.12059 for a detailed description regarding the development and validation of the ADAS-Cog-Exec. Change for the analysis of this primary outcome was calculated comparing the average of scores from month 6 and month 12 to baseline. The theoretical range for the ADAS-Cog-Exec is -3.00 to +3.00 in EXERT, with higher scores indicating improvement in cognitive function from baseline.

Outcome measures

Outcome measures
Measure	Aerobic n=124 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=126 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
ADAS-Cog-Exec Global Composite	-0.146 Change score Standard Error 0.063	-0.068 Change score Standard Error 0.063

SECONDARY outcome

Timeframe: Baseline to mean (Mo 6, Mo 12)

Population: Subset of participants who had the opportunity to complete a full 12 months of the study (i.e., 12 months of exercise and the 12 Month outcome assessments) before the COVID-19 pandemic affected trial conduct.

The ADAS-Cog-Exec Composite is a weighted sum of standardized (Z-score) change on subtests from the Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog13; Immediate and Delayed Word Recall, Orientation, and Number Cancellation); box scores for the cognitive components of the Clinical Dementia Rating Scale (Memory, Orientation, Judgement \& Problem Solving); and additional tests requiring executive function (Trail Making Test A \& B, Digit Symbol Substitution, Category Fluency). See https://doi.org/10.1002/trc2.12059 for a detailed description regarding the development and validation of the ADAS-Cog-Exec. Change for the analysis of this primary outcome was calculated comparing the average of scores from month 6 and month 12 to baseline. The theoretical range for the ADAS-Cog-Exec is -3.00 to +3.00 in EXERT, with higher scores indicating improvement in cognitive function from baseline.

Outcome measures

Outcome measures
Measure	Aerobic n=70 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=73 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
ADAS-Cog-Exec Global Composite in Subset Population	-0.18 Change score Standard Error 0.080	-0.15 Change score Standard Error 0.076

SECONDARY outcome

Timeframe: Baseline to mean (Mo 6, Mo 12)

The Executive Function Composite is the average standardized (Z-score) change on eight measures requiring attention and executive control: Trail Making, Part B; Digit Symbol Substitution; Category Fluency; Letter Fluency; Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog13) Number Cancellation; NIH Toolbox Flanker; NIH Toolbox Dimension Change Card Sort, and Cogstate One Back. Change for analysis of this secondary outcome was calculated comparing the average of scores from month 6 and month 12 to baseline. The theoretical range for the Executive Function Composite is -3.00 to +3.00, with higher scores indicating improvement in executive function from baseline.

Outcome measures

Outcome measures
Measure	Aerobic n=109 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=112 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
Executive Function Composite Score	-0.02903 Change in score Standard Error 0.03303	-0.03847 Change in score Standard Error 0.03246

SECONDARY outcome

Timeframe: Baseline to mean (Mo 6, Mo 12)

The Episodic Memory Composite is the average standardized (Z-score) change on five measures of memory: Immediate and Delayed Word Recall from the Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog13); Cogstate Face-Name Associative Memory; Cogstate Behavioral Pattern Separation of Objects; and Cogstate One Card Learning. Change for analysis of this secondary outcome was calculated comparing the average of scores from month 6 and month 12 to baseline. The theoretical range for the Episodic Memory Composite is -3.00 to +3.00, with higher scores indicating improvement in episodic memory from baseline.

Outcome measures

Outcome measures
Measure	Aerobic n=97 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=104 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
Episodic Memory Composite Score	0.005859 Change in score Standard Error 0.04137	-0.014384 Change in score Standard Error 0.03997

SECONDARY outcome

Timeframe: 12 Months

Assessment of volumetric change in the hippocampus region of the brain, measured by structural Magnetic Resonance Imaging (MRI), comparing MRI scans taken at baseline and month 12. Scans are compared and analyzed to give a percent deformation between timepoints.

Outcome measures

Outcome measures
Measure	Aerobic n=90 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=93 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
Volumetric Magnetic Resonance Imaging (MRI) of Hippocampus	-0.66 percent deformation Standard Deviation 1.12	-0.343 percent deformation Standard Deviation 0.98

SECONDARY outcome

Timeframe: 12 Months

Assessment of volumetric change in prefrontal composite regions of the brain, measured by structural Magnetic Resonance Imaging (MRI), comparing MRI scans taken at baseline and month 12. The prefrontal composite includes: superior frontal, caudal-middle frontal, rostral-middle frontal, pars opercularis, and pars triangularis regions. Scans are compared and analyzed to give a percent deformation between timepoints.

Outcome measures

Outcome measures
Measure	Aerobic n=90 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=93 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
Volumetric Magnetic Resonance Imaging (MRI) of Prefrontal Composite Region	-0.34 percent deformation Standard Deviation 1.36	-0.51 percent deformation Standard Deviation 1.11

SECONDARY outcome

Timeframe: 12 Months

Assessment of volumetric change in Alzheimer's Disease (AD) signature regions of the brain, measured by structural Magnetic Resonance Imaging (MRI), comparing MRI scans taken at baseline and month 12. The AD signature composite includes: parahippocampus, fusiform, inferior temporal, middle temporal, and inferior-parietal regions. Scans are compared and analyzed to give a percent deformation between timepoints.

Outcome measures

Outcome measures
Measure	Aerobic n=90 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=93 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
Volumetric Magnetic Resonance Imaging (MRI) of AD Signature Composite Region	-0.612 percent deformation Standard Deviation 1.02	-0.643 percent deformation Standard Deviation 0.951

SECONDARY outcome

Timeframe: Baseline to 12 Months

Assessment of change in blood flow activity in the hippocampus region of the brain, measured using Arterial Spin Labeling (ASL) magnetic resonance imaging (MRI) scans. Scans taken at baseline and month 12 are compared and analyzed to assess change in blood flow between the timepoints. The unit of cerebral blood flow from ASL is ml/100g/min, which means the amount of blood flow into 100g of tissue during one minute.

Outcome measures

Outcome measures
Measure	Aerobic n=73 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=66 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
Arterial Spin Labeling (ASL) Magnetic Resonance Imaging (MRI) of Hippocampus	0.07 ml/100g/min Standard Deviation 0.42	0.01 ml/100g/min Standard Deviation 0.224

SECONDARY outcome

Timeframe: Baseline to 12 Months

Assessment of change in blood flow activity in the prefrontal composite regions of the brain, measured using Arterial Spin Labeling (ASL) magnetic resonance imaging (MRI) scans. The prefrontal composite includes: superior frontal, caudal-middle frontal, rostral-middle frontal, pars opercularis, and pars triangularis regions. Scans taken at baseline and month 12 are compared and analyzed to assess change in blood flow. The unit of cerebral blood flow from ASL is ml/100g/min, which means the amount of blood flow into 100g of tissue during one minute.

Outcome measures

Outcome measures
Measure	Aerobic n=73 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=66 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
Arterial Spin Labeling (ASL) Magnetic Resonance Imaging (MRI) of Prefrontal Composite Region	0.04 ml/100g/min Standard Deviation 0.31	0.03 ml/100g/min Standard Deviation 0.29

SECONDARY outcome

Timeframe: Baseline to 12 Months

Assessment of change in blood flow activity in the Alzheimer's Disease (AD) signature regions of the brain, measured using Arterial Spin Labeling (ASL) magnetic resonance imaging (MRI) scans. The AD signature composite includes: parahippocampus, fusiform, inferior temporal, middle temporal, and inferior-parietal regions. Scans taken at baseline and month 12 are compared and analyzed to assess change in blood flow. The unit of cerebral blood flow from ASL is ml/100g/min, which means the amount of blood flow into 100g of tissue during one minute.

Outcome measures

Outcome measures
Measure	Aerobic n=73 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=66 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
Arterial Spin Labeling (ASL) Magnetic Resonance Imaging (MRI) of AD Signature Composite Region	0.05 ml/100g/min Standard Deviation 0.23	0 ml/100g/min Standard Deviation 0.25

SECONDARY outcome

Timeframe: 12 Months

Change in ratio of plasma amyloid beta peptides in blood plasma from baseline to12 months. A lower ab42/ab40 ratio in plasma is associated with a higher risk of dementia.

Outcome measures

Outcome measures
Measure	Aerobic n=103 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=111 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
Ratio of AD Biomarkers in Blood	0.00001 Change in ratio Standard Deviation 0.0185	-0.00062 Change in ratio Standard Deviation 0.01119

SECONDARY outcome

Timeframe: 12 Months

Change in ratio of amyloid beta peptides in cerebrospinal fluid (CSF) from baseline to 12 months. A lower ab42/ab40 ratio is associated with a higher risk of dementia.

Outcome measures

Outcome measures
Measure	Aerobic n=14 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=10 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
AD Biomarkers in CSF (ab42/ab40)	-0.00348 Change in ratio Standard Deviation 0.00784	-0.00413 Change in ratio Standard Deviation 0.00611

SECONDARY outcome

Timeframe: 12 Months

Change in ratio of key peptides in cerebrospinal fluid (CSF) from baseline to 12 months. A lower ab42/tau ratio is associated with a higher risk of dementia.

Outcome measures

Outcome measures
Measure	Aerobic n=14 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=10 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
AD Biomarkers in CSF (ab42/Tau)	-0.22 Change in ratio Standard Deviation 0.445	-0.299 Change in ratio Standard Deviation 0.729

SECONDARY outcome

Timeframe: 12 Months

Change in ratio of key peptides in cerebrospinal fluid (CSF) from baseline to 12 months. A lower ab42/p-tau ratio is associated with a higher risk of dementia.

Outcome measures

Outcome measures
Measure	Aerobic n=14 Participants Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=10 Participants The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
AD Biomarkers in CSF (ab42/P-tau)	-2.48 Change in ratio Standard Deviation 2.70	-3.39 Change in ratio Standard Deviation 5.47

Adverse Events

Aerobic

Serious events: 23 serious events

Other events: 148 other events

Deaths: 1 deaths

Stretching/Balance/Range of Motion

Serious events: 23 serious events

Other events: 148 other events

Deaths: 2 deaths

Serious adverse events

Serious adverse events
Measure	Aerobic n=148 participants at risk Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA . Aerobic exercise: Moderate/high intensity aerobic exercise will involve training at 70-80% heart rate reserve for 30 min, with an additional 10 minutes for warm-up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA .	Stretching/Balance/Range of Motion n=148 participants at risk The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA. Stretching/balance/range of motion exercise: The stretching/balance/range of motion program will involve exercise at or below 35% heart rate reserve for 30 min, with an additional 10 minutes for warm up and 5 minutes for cool-down, 4 times per week, for 12 months while supervised twice per week by a study-certified trainer at a participating YMCA.
Cardiac disorders Cardiac disorders	2.7% 4/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.	2.0% 3/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.
Gastrointestinal disorders Gastrointestinal disorders	0.00% 0/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.	0.68% 1/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.
Infections and infestations Infections and infestations	3.4% 5/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.	2.7% 4/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.
Injury, poisoning and procedural complications Injury, poisoning and procedural complications	2.7% 4/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.	1.4% 2/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.
Investigations Investigations	0.00% 0/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.	1.4% 2/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (cysts and polyps) 1 1	0.68% 1/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.	0.68% 1/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.
Nervous system disorders Nervous system disorders	1.4% 2/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.	2.7% 4/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.
Psychiatric disorders Psychiatric disorders	1.4% 2/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.	0.00% 0/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.
Renal and urinary disorders Renal and urinary disorders	0.00% 0/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.	0.68% 1/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders 0 1	0.00% 0/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.	0.68% 1/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.
Surgical and medical procedures Surgical and medical procedures 4 4	2.7% 4/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.	2.7% 4/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.
Vascular disorders Vascular disorders 1 0	0.68% 1/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.	0.00% 0/148 • Adverse event data is collected from the time of consent through the 12 month supervised exercise period and through the following 6 month unsupervised exercise period. Adverse Event (AE)reporting begins at the time of consent. Collection of AEs was done through participant reporting using both systematic and non-systematic assessment of AEs. Systematic collection of AEs occurred at each scheduled participant visit capturing the events in source documents and electronic case report forms (eCRF). Non-systematic AE reporting, spontaneous reporting by participant between visits, was also implemented.

Other adverse events

Additional Information

Clinical Operations

Alzheimer's Disease Cooperative Study (ADCS)

Phone: 858-246-1333

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place