Exercise in Adults With Mild Memory Problems | NCT02814526

ID	Type	Description	Link
U19AG010483-22	U.S. NIH Grant/Contract		View source

Name	Class
National Institute on Aging (NIA)	NIH
Wake Forest University Health Sciences	OTHER

Description Module

Detailed Description

Overall Study Design:

The EXERT trial was a multicenter phase 3 randomized, single-blind study that examined the effects of aerobic exercise on cognition, functional status, whole and regional cerebral blood flow, and cerebrospinal fluid biomarkers of Alzheimer's disease in approximately 300 adults with amnestic MCI. EXERT included an 18-month behavioral intervention trial, with a 12-month supervised exercise intervention phase with its primary endpoints, followed by a 6-month unsupervised exercised phase.

Subject Populations and Group Assignments:

The study population included male and female subjects aged 65 to 89 diagnosed with test scores and clinical ratings consistent with amnestic Mild Cognitive Impairment (MCI).

Assignment to study groups:

involved randomization to either treatment or active control, and study staff performing assessments were blinded to intervention assignment to maintain the single-blind structure of the trial.

Participants were to complete EXERT interventions at participating YMCAs located near the selected clinic sites across the U.S. The YMCA provided 18-month memberships at no cost to participants. In the first 12 months, a study-certified YMCA Trainer supervised all participants for the first 8 exercise sessions completed (weeks 1 and 2), and for 2 of 4 weekly sessions thereafter through Month 12. At Month 12, participants transitioned to independent exercise and were instructed to continue their assigned exercise programs for the final 6 months of the study without supervision. To encourage adherence and optimize cost efficiency, Trainers provided supervision to small groups of participants (2-4 individuals) randomized to the same intervention whenever possible. Compliance was evaluated using multiple mechanisms including heart rate monitoring, participant ratings of perceived exertion, entries in participants' Physical Activity Logs, Trainer assessment of effort, and weekly data review by the YMCA-Project Manager (Y-PM) and the Intervention Oversight Team (includes the Project Directors, Wake Forest team of exercise trial specialists, and Y-USA). These mechanisms provided multiple and regular opportunities to discuss participant progress, identify and resolve barriers, and encourage high levels of adherence to study protocols. The Intervention Oversight Team had the necessary expertise to successfully accomplish this objective in EXERT.

Label	Type	Description	Intervention Names
Aerobic	Experimental	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 .	Behavioral: Aerobic exercise
Stretching/balance/range of motion	Active Comparator	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.	Behavioral: Stretching/balance/range of motion exercise

Name	Type	Description	Arm Group Labels	Other Names
Aerobic exercise	Behavioral	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 .

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
ADAS-Cog-Exec Global Composite	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.	Baseline to mean (Mo 6, Mo 12)

Secondary Outcomes

Measure	Description	Time Frame
ADAS-Cog-Exec Global Composite in Subset Population	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.

Other Outcomes

Measure	Description	Time Frame
Intervention Effects on Secondary Outcomes in a Subset of Participants Who Completed 12 Months of the Study Prior to the COVID-19 Pandemic.	To examine intervention effects on secondary outcomes listed above in participants who had the opportunity to complete a full 12 months of the study before the pandemic affected trial conduct.	12 months

Eligibility Module

Eligibility Criteria

Inclusion Criteria

Age between 65 and 89 years old, inclusive
MMSE: ≥24 for participants with 13 or more years of education; ≥22 for participants with 12 or fewer years of education
Global CDR score of 0.5 with a memory score of at least 0.5
Profile of test scores and clinical ratings is consistent with amnestic mild cognitive impairment
Speaks English fluently
Visual and auditory acuity adequate for cognitive testing
Completed at least 6 years of formal education or work history sufficient to exclude mental retardation
Has an informant who knows the participant well, has regular contact, and is available to accompany the participant to clinic visits or complete study partner assessments remotely.
Sedentary or underactive, determined by responses to the staff-administered EXERT Telephone Assessment of Physical Activity (TAPA) survey
Willing to be randomized to either intervention group and to complete the assigned activities as specified for 18 months
Willing and able to reliably travel to the identified YMCA, 4 times per week for 18 months
Ability to safely participate in either intervention and complete the 400 m Walk Test within 15 min without sitting or use of any assistance
Plans to reside in the area for at least 18 months
For planned travel, total time away must be no more than 2 months over the course of the study, and no more than 1 month at any one time; participants must be willing to continue the assigned exercise program if travelling out of the area for more than 1 week
In overall good general health with no disease or planned surgery that could interfere with study participation
Modified Hachinski ≤4
Stable use of cholinesterase inhibitors, memantine, vitamin E, estrogens, aspirin (81 300 mg daily), beta-blockers, or cholesterol-lowering agents for 12 weeks prior to screening (important for biomarker analyses)
Stable use of antidepressants lacking significant anticholinergic side effects for 4 weeks prior to screening as long as the participant does not meet DSM V criteria for major depression currently or in the last 12 months; GDS scores are to be used to inform clinical decisions but there is no specified cut-off score for inclusion
When applicable, willing to complete 4-week washout of psychoactive medications, including disallowed antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, and willing to avoid these medications for the duration of the trial
Able to complete all baseline assessments

Exclusion Criteria

Any significant neurologic disease, other than MCI, including any form of dementia, Parkinsons disease, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma with persistent neurologic sequelae or known structural brain abnormalities
Sensory or musculoskeletal impairment sufficient to preclude successful and safe completion of the intervention or assessment protocols; must be able to walk safely and unassisted on a treadmill
Contraindications for MRI studies, including claustrophobia, metal (ferromagnetic) implants, or cardiac pacemaker
Brain MRI at screening shows evidence of infection, infarction, or other clinically significant focal lesions, including multiple lacunes in prefrontal or critical memory regions; inconclusive findings may be subject to review by the ADCS Imaging Core
History of major depression or bipolar disorder (DSM V criteria), psychotic features, agitation or behavioral problems within the last 12 months
History of schizophrenia, as per DSM V criteria
History of alcohol or substance abuse or dependence within the past 2 years, as per DSM V criteria
Currently consumes more than 3 alcoholic drinks per day
Clinically significant or unstable medical condition, including uncontrolled hypertension or significant cardiac, pulmonary, hematologic, renal, hepatic, gastrointestinal, endocrine, metabolic or other systemic disease in the opinion of clinic medical personnel that may put the participant at increased risk, influence the results or compromise the participants ability to participate in the study (treated atrial fibrillation for more than 1 year or occasional premature ventricular contractions on ECG are not exclusions)
History in the last 6 months of myocardial infarction, coronary artery angioplasty, bypass grafting, or STENT placement
History in the last 3 months of transient ischemic attack or small vessel stroke (if more than 3 months, small vessel stroke with no residual effects are permitted)
Expected joint replacement surgery within the next 18 months
History within the last 5 years of a primary or recurrent malignant disease with the exception of non-melanoma skin cancers, resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with normal prostate-specific antigen posttreatment
Hemoglobin A1c >7.0
Clinically significant abnormalities in screening laboratory blood tests: low B12 is exclusionary, unless follow-up labs (homocysteine [HCY] and methylmalonic acid [MMA]) indicate that it is not physiologically significant
Current or past use of insulin to treat type 2 diabetes (other diabetes medications are acceptable if hemoglobin A1c ≤7)
Current use (within 60 days of screening) of psychoactive medications including tricyclic antidepressants, antipsychotics, mood-stabilizing psychotropic agents (e.g. lithium salts), psychostimulants, opiate analgesics, antiparkinsonian medications, anticonvulsant medications (except gabapentin and pregabalin for non-seizure indications), systemic corticosteroids, or medications with significant central anticholinergic activity. Limited use of antipsychotics (quetiapine ≤ 50mg/day or risperidone ≤ 0.5mg/day), and non-chronic use of opiate analgesics on an as needed basis is permitted; such medications must be avoided for 8 hours before clinic assessments
Chronic use of anxiolytics or sedative hypnotics except as follows: use of benzodiazepines for treatment on an as-needed basis for insomnia or daily dosing of anxiolytics is permitted; medications must be avoided for 8 hours before clinic assessments
Previous or current treatment involving active immunization against amyloid
Previous treatment with approved or investigational agents with anti-amyloid properties or passive immunization against amyloid are prohibited 12 months prior to screening and for the duration of the trial; treatment with other investigational agents are prohibited 3 months prior to screening and for the duration of the trial
For LP, current use of anticoagulants such as Coumadin, Plavix, or high dose Vitamin E
For LP, current blood clotting or bleeding disorder, or significantly abnormal prothrombin time (PT) or partial thromboplastin time (PTT) at screening
For LP, presence of physical distortions due to spinal surgery, severe degenerative joint disease or deformity, or obesity that could interfere with CSF collection (as per investigator judgment)
Participants whom the PI deems otherwise ineligible

Name	Affiliation	Role
Howard Feldman, MDCM FRCP(C)	Alzheimer's Disease Cooperative Study (ADCS)	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
University of California, Irvine		Irvine	California	92697	United States
VAPAHCS / Stanford University School of Medicine

PubMed Identifier	Type	Citation	Retractions
20065132	Background	Baker LD, Frank LL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, Plymate SR, Fishel MA, Watson GS, Cholerton BA, Duncan GE, Mehta PD, Craft S. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol. 2010 Jan;67(1):71-9. doi: 10.1001/archneurol.2009.307.
18768414	Background	Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM, Xiao J, Greenop KR, Almeida OP. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA. 2008 Sep 3;300(9):1027-37. doi: 10.1001/jama.300.9.1027.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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 .

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Nov 18, 2021	Jul 6, 2022

Arm/Group Information

ID	Title	Description
BG000	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 .
BG001	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.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	OG000-0.146± 0.063 OG001-0.068± 0.063

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Regression, Linear		0.29		Mean Difference (Net)	0.078			2-Sided								Superiority

Secondary

ADAS-Cog-Exec Global Composite in Subset 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.

Posted

Least Squares Mean

Standard Error

Change score

Baseline to mean (Mo 6, Mo 12)

ID	Title	Description
OG000	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 .

Secondary

Executive Function Composite Score

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.

Posted

Least Squares Mean

Standard Error

Change in score

Baseline to mean (Mo 6, Mo 12)

ID	Title	Description
OG000	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 .
OG001	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.

Secondary

Episodic Memory Composite Score

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.

Posted

Least Squares Mean

Standard Error

Change in score

Baseline to mean (Mo 6, Mo 12)

ID	Title	Description
OG000	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 .
OG001	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.

Secondary

Volumetric Magnetic Resonance Imaging (MRI) of Hippocampus

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.

Posted

Mean

Standard Deviation

percent deformation

12 Months

ID	Title	Description
OG000	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 .
OG001	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.

Secondary

Volumetric Magnetic Resonance Imaging (MRI) of Prefrontal Composite Region

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.

Posted

Mean

Standard Deviation

percent deformation

12 Months

ID	Title	Description
OG000	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 .
OG001	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.

Secondary

Volumetric Magnetic Resonance Imaging (MRI) of AD Signature Composite Region

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.

Posted

Mean

Standard Deviation

percent deformation

12 Months

ID	Title	Description
OG000	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 .
OG001	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.

Secondary

Arterial Spin Labeling (ASL) Magnetic Resonance Imaging (MRI) of Hippocampus

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.

Posted

Mean

Standard Deviation

ml/100g/min

Baseline to 12 Months

ID	Title	Description
OG000	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 .
OG001	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.

Secondary

Arterial Spin Labeling (ASL) Magnetic Resonance Imaging (MRI) of Prefrontal Composite Region

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.

Posted

Mean

Standard Deviation

ml/100g/min

Baseline to 12 Months

ID	Title	Description
OG000	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 .
OG001	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.

Secondary

Arterial Spin Labeling (ASL) Magnetic Resonance Imaging (MRI) of AD Signature Composite Region

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.

Posted

Mean

Standard Deviation

ml/100g/min

Baseline to 12 Months

ID	Title	Description
OG000	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 .
OG001	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.

Secondary

Ratio of AD Biomarkers in Blood

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.

Posted

Mean

Standard Deviation

Change in ratio

12 Months

ID	Title	Description
OG000	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 .
OG001	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.

Secondary

AD Biomarkers in CSF (ab42/ab40)

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.

Posted

Mean

Standard Deviation

Change in ratio

12 Months

ID	Title	Description
OG000	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 .
OG001	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.

Secondary

AD Biomarkers in CSF (ab42/Tau)

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.

Posted

Mean

Standard Deviation

Change in ratio

12 Months

ID	Title	Description
OG000	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 .
OG001	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.

Secondary

AD Biomarkers in CSF (ab42/P-tau)

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.

Posted

Mean

Standard Deviation

Change in ratio

12 Months

ID	Title	Description
OG000	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 .
OG001	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.

Other Pre-specified

Intervention Effects on Secondary Outcomes in a Subset of Participants Who Completed 12 Months of the Study Prior to the COVID-19 Pandemic.

To examine intervention effects on secondary outcomes listed above in participants who had the opportunity to complete a full 12 months of the study before the pandemic affected trial conduct.

Not Posted

12 months

Participants

Other Pre-specified

Exploratory Magnetic Resonance Imaging (MRI) Volumes and Perfusion and Individual AD Biomarkers in CSF and Blood Measures

To test whether 12 months of aerobic exercise, relative to the control, favorably affects MRI whole brain, ventricular and entorhinal volumes; perfusion in whole brain, gray matter and white matter; and individual AD biomarkers in CSF (ab42, ab40, total tau, p-tau, BDNF) and blood (ab42, ab40).

Not Posted

12 Months

Participants

Other Pre-specified

Clinical Dementia Rating Scale-Sum of Boxes (CDR) and Alzheimers Disease Assessment Scale-Cognitive 13-item (ADAS-Cog13)

To test whether 12 months of aerobic exercise, relative to the control, reduces clinical ratings of cognitive impairment as measured by the CDR Sum of Boxes, and total score on the ADAS Cog13.

Not Posted

12 Months

Participants

Other Pre-specified

Measures of Cognitive Function and Well-being Including (1) ADCS-ADL-MCI); (2) BRIEF-A; (3) GDS; (4) NPI; SF-36; EuroQol: 5-Item Health Questionnaire; (5) CCI: Cognitive Change Index); and (6) Study Partner Self-Assessment

To test whether 12 months of aerobic exercise, relative to the control, improves self-report measures of cognitive function and well-being, including (1) daily living skills (ADCS-Activities of Daily Living-MCI); (2) BRIEF-A: Behavior Rating Inventory of Executive Function-Adult Version); (3) mood (GDS); (4) health-related quality of life (NPI: Neuropsychiatric Inventory; SF-36: 36-Item Short Form Health Survey; EuroQol: 5-Item Health Questionnaire); (5) subjective memory concerns (CCI: Cognitive Change Index); and (6) Study Partner Self-Assessment Questionnaire

Not Posted

12 Months

Participants

Other Pre-specified

ADAS-Cog-Exec, Executive Function, and Episodic Memory Composites

To examine enduring cognitive effects (measured by ADAS-Cog-Exec, Executive Function and Episodic Memory Composites) of the intervention following a 6-month extension (through Month 18) when the prescribed exercise is continued without supervision.

Not Posted

18 Months

Participants

Other Pre-specified

Subgroup Treatment Responder Analyses

To explore whether sex, age, baseline AD biomarker profile in CSF (ab42/ab40, ab42/tau, ab42/p-tau) and blood (ab42/ab40), and ApoE4 genotype (e4+, e4-) predict treatment response.

Not Posted

12 Months

Participants

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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 .	1	148	23	148	148	148
EG001	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.	2	148	23	148	148	148

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Cardiac disorders	Cardiac disorders	MedDRA (18.0)	Systematic Assessment	EG0004 affected148 at risk EG0013 affected148 at risk
Gastrointestinal disorders	Gastrointestinal disorders	MedDRA (18.0)	Systematic Assessment	EG0000 affected148 at risk EG0011 affected148 at risk
Infections and infestations	Infections and infestations	MedDRA (18.0)	Systematic Assessment	EG0005 affected148 at risk EG0014 affected148 at risk
Injury, poisoning and procedural complications	Injury, poisoning and procedural complications	MedDRA (18.0)	Systematic Assessment	EG0004 affected148 at risk EG0012 affected148 at risk
Investigations	Investigations	MedDRA (18.0)	Systematic Assessment	EG0000 affected148 at risk EG0012 affected148 at risk
Neoplasms benign, malignant and unspecified (cysts and polyps) 1 1	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (18.0)	Systematic Assessment	EG0001 affected148 at risk EG0011 affected148 at risk
Nervous system disorders	Nervous system disorders	MedDRA (18.0)	Systematic Assessment	EG0002 affected148 at risk EG0014 affected148 at risk
Psychiatric disorders	Psychiatric disorders	MedDRA (18.0)	Systematic Assessment	EG0002 affected148 at risk EG0010 affected148 at risk
Renal and urinary disorders	Renal and urinary disorders	MedDRA (18.0)	Systematic Assessment	EG0000 affected148 at risk EG0011 affected148 at risk
Respiratory, thoracic and mediastinal disorders 0 1	Respiratory, thoracic and mediastinal disorders	MedDRA (18.0)	Systematic Assessment	EG0000 affected148 at risk EG0011 affected148 at risk
Surgical and medical procedures 4 4	Surgical and medical procedures	MedDRA (18.0)	Systematic Assessment	EG0004 affected148 at risk EG0014 affected148 at risk
Vascular disorders 1 0	Vascular disorders	MedDRA (18.0)	Systematic Assessment	EG0001 affected148 at risk EG0010 affected148 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Cardiac disorders 11 9	Cardiac disorders	MedDRA (18.0)	Systematic Assessment	EG00011 affected148 at risk EG0019 affected148 at risk
Ear and labyrinth disorders	Ear and labyrinth disorders	MedDRA (18.0)	Systematic Assessment	EG0004 affected148 at risk EG0011 affected148 at risk
Endocrine disorders	Endocrine disorders	MedDRA (18.0)	Systematic Assessment	EG0001 affected148 at risk EG0010 affected148 at risk
Eye disorders	Eye disorders	MedDRA (18.0)	Systematic Assessment	EG0004 affected148 at risk EG0014 affected148 at risk
Gastrointestinal disorders	Gastrointestinal disorders	MedDRA (18.0)	Systematic Assessment	EG0009 affected148 at risk EG00119 affected148 at risk
General disorders and administration site conditions	General disorders	MedDRA (18.0)	Systematic Assessment	EG00013 affected148 at risk EG00115 affected148 at risk
Immune system disorders	Immune system disorders	MedDRA (18.0)	Systematic Assessment	EG0003 affected148 at risk EG0013 affected148 at risk
Infections and infestations	Infections and infestations	MedDRA (18.0)	Systematic Assessment	EG00060 affected148 at risk EG00151 affected148 at risk
Injury, poisoning and procedural complications 76 59	Injury, poisoning and procedural complications	MedDRA (18.0)	Systematic Assessment	EG00076 affected148 at risk EG00159 affected148 at risk
Investigations 6 8	Investigations	MedDRA (18.0)	Systematic Assessment	EG0006 affected148 at risk EG0018 affected148 at risk
Metabolism and nutrition disorders	Metabolism and nutrition disorders	MedDRA (18.0)	Systematic Assessment	EG0002 affected148 at risk EG0010 affected148 at risk
Musculoskeletal and connective tissue disorders 78 70	Musculoskeletal and connective tissue disorders	MedDRA (18.0)	Systematic Assessment	EG00078 affected148 at risk EG00170 affected148 at risk
Neoplasms benign, malignant and unspecified (cysts and polyps) 6 6	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (18.0)	Systematic Assessment	EG0006 affected148 at risk EG0016 affected148 at risk
Nervous system disorders 18 29	Nervous system disorders	MedDRA (18.0)	Systematic Assessment	EG00018 affected148 at risk EG00129 affected148 at risk
Psychiatric disorders 4 6	Psychiatric disorders	MedDRA (18.0)	Systematic Assessment	EG0004 affected148 at risk EG0016 affected148 at risk
Renal and urinary disorders 4 6	Renal and urinary disorders	MedDRA (18.0)	Systematic Assessment	EG0004 affected148 at risk EG0016 affected148 at risk
Reproductive system and breast disorders 1 0	Reproductive system and breast disorders	MedDRA (18.0)	Systematic Assessment	EG0001 affected148 at risk EG0010 affected148 at risk
Respiratory, thoracic and mediastinal disorders 8 3	Respiratory, thoracic and mediastinal disorders	MedDRA (18.0)	Systematic Assessment	EG0008 affected148 at risk EG0013 affected148 at risk
Skin and subcutaneous tissue disorders 8 2	Skin and subcutaneous tissue disorders	MedDRA (18.0)	Systematic Assessment	EG0008 affected148 at risk EG0012 affected148 at risk
Surgical and medical procedures 19 17	Surgical and medical procedures	MedDRA (18.0)	Systematic Assessment	EG00019 affected148 at risk EG00117 affected148 at risk
Vascular disorders 9 3	Vascular disorders	MedDRA (18.0)	Systematic Assessment	EG0009 affected148 at risk EG0013 affected148 at risk

ID	Term
D060825	Cognitive Dysfunction
D008569	Memory Disorders
D009043	Motor Activity

ID	Term
D003072	Cognition Disorders
D019965	Neurocognitive Disorders
D001523	Mental Disorders
D019954	Neurobehavioral Manifestations
D009461	Neurologic Manifestations
D009422	Nervous System Diseases
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms
D001519	Behavior

ID	Term
D009043	Motor Activity
D009068	Movement
D009142	Musculoskeletal Physiological Phenomena
D055687	Musculoskeletal and Neural Physiological Phenomena