Exercise in Adults With Mild Memory Problems

Inclusion Criteria:

- Age between 65 and 89 years old, inclusive

- Mini-Mental State Exam (MMSE): ≥24 for participants with 13 or more years of
education; ≥22 for participants with 12 or fewer years of education

- CDR =0.5

- Impaired delayed verbal recall as indicated by scores meeting at least one of the
following criteria: Logical Memory II ≤ 8; Auditory Verbal Learning Test, Trial 7 ≤4

- 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 at least weekly contact, and is
available to accompany the participant to clinic visits

- Sedentary or underactive, determined by responses to the staff-administered 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 (up to 400 IU daily),
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; Geriatric Depression Score (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,
Parkinson's 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 participant's 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 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 lumbar puncture (LP), current use of anticoagulants such as Coumadin or Plavix

- 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