Multidomain Alzheimers Risk Reduction Study (MARRS) Pilot
Phase: NA
Conditions: Dementia, Alzheimer Disease
Sponsor: Kaiser Permanente

SMARRT Protocol, Version 1.16 
 
 
Systematic Multi-Domain Alzheimer’s Risk Reduction Trial 
(SMARRT) 
 
[formerly: Multi-domain Alzheimer's Risk Reduction Study (MARRS) Pilot] 
 
 
 
 
 
 
 
 
 
 
Principal Investigators:   
 
Kristine Yaffe, MD, University of California San Francisco (contact) 
 
Sascha Dublin, MD, PhD, Kaiser Permanente Washington Health Research Institute 
 
Former PI: Eric Larson, MD, MPH, Kaiser Permanente Washington Health Research Institute 
 
 
 
 
 
Supported by: 
 
The National Institute on Aging (NIA) 
1R01AG057508 
 
 
 
National Clinical Trial (NCT) # 03683394 
 
 
  
 
Version 1.16 
 
June 26, 2023 
 
 
 

SMARRT Protocol, Version 1.16 
 
 
 
 
 
 

SMARRT Protocol, Version 1.16 
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TABLE OF CONTENTS 
Page 
PRÉCIS .......................................................................................................................................... 3 
 
Study Title ................................................................................................................................... 3 
Objectives ................................................................................................................................... 3 
Interventions and Duration ......................................................................................................... 3 
Sample Size and Population........................................................................................................ 3 
 
STUDY TEAM ROSTER and study sites .................................................................................. 4 
 
1 
Study objectives ..................................................................................................................... 2 
1.1 
Primary Objective ........................................................................................................... 2 
1.2 
Secondary Objectives...................................................................................................... 3 
 
2 
BACKGROUND AND RATIONALE ................................................................................ 3 
2.1 
Background ..................................................................................................................... 3 
2.2 
Study Rationale ............................................................................................................... 3 
 
3 
STUDY DESIGN ................................................................................................................... 4 
 
4 
Inclusion/Exclusion Criteria ................................................................................................ 5 
4.1 
Inclusion Criteria ............................................................................................................ 5 
4.2 
Exclusion Criteria ........................................................................................................... 7 
 
5 
STUDY PROCEDURES ...................................................................................................... 8 
5.1 
Schedule of Evaluations .................................................................................................. 8 
5.2 
Description of Evaluations .............................................................................................. 9 
5.2.1 Recruitment ................................................................................................................. 9 
5.2.2 Mailing ........................................................................................................................ 9 
5.2.3 Screening Evaluation .................................................................................................. 9 
5.2.4 Baseline and Randomization..................................................................................... 10 
5.2.5 Follow-up and Final Visits........................................................................................ 11 
5.3 
Outcomes ...................................................................................................................... 12 
 
6 
STUDY INTERVENTIONS .............................................................................................. 15 
6.1 
Interventions, Administration, and Duration ................................................................ 15 
6.2 
Handling of Study Interventions ................................................................................... 19 
6.3 
Concomitant Interventions ............................................................................................ 19 
6.3.1 Allowed Interventions ............................................................................................... 19 
6.3.2 Prohibited Interventions ............................................................................................ 19 
6.4 
Adherence Assessment ................................................................................................. 20 
 
7 
SAFETY ASSESSMENTS ................................................................................................. 20 
7.1 
Adverse Events and Serious Adverse Events ............................................................... 20 
7.2 
Reporting Procedures .................................................................................................... 20 

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7.3 
Follow-up for Adverse Events ...................................................................................... 21 
7.4 
Safety Monitoring ......................................................................................................... 21 
 
8 
INTERVENTION DISCONTINUATION........................................................................ 21 
 
9 
STATISTICAL CONSIDERATIONS .............................................................................. 21 
9.1 
General Design Issues ................................................................................................... 21 
9.2 
Sample Size and Randomization .................................................................................. 22 
9.2.1 Treatment Assignment Procedures ........................................................................... 22 
9.3 
Interim analyses and Stopping Rules ............................................................................ 23 
9.4 
Data Analyses ............................................................................................................... 23 
 
10 DATA COLLECTION AND QUALITY ASSURANCE ................................................ 24 
10.1 
Data Collection Forms .................................................................................................. 24 
10.2 
Data Management ......................................................................................................... 24 
10.3 
Quality Assurance ......................................................................................................... 25 
10.3.1 
Training ................................................................................................................. 25 
10.3.2 
Metrics .................................................................................................................. 26 
10.3.3 
Protocol Deviations ............................................................................................... 26 
10.3.4 
Monitoring ............................................................................................................ 26 
 
11 PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................. 26 
11.1 
Institutional Review Board (IRB) Review .................................................................... 26 
11.2 
Informed Consent Forms .............................................................................................. 26 
11.3 
Participant Confidentiality ............................................................................................ 26 
11.4 
Study Discontinuation ................................................................................................... 27 
 
12 PUBLICATION OF RESEARCH FINDINGS ................................................................ 27 
 
13 REFERENCES .................................................................................................................... 27 
 
14 SUPPLEMENTS/APPENDICES ...................................................................................... 28 
I. Informed Consent Form/ HIPAA 
  
 
 

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PRÉCIS 
Study Title  
Systematic Multi-Domain Alzheimer’s Risk Reduction Trial (SMARRT) 
[formerly: Multi-domain Alzheimer's Risk Reduction Study (MARRS) Pilot] 
Objectives  
The primary goal of this study is to pilot-test a personalized, pragmatic, multi-domain 
Alzheimer’s disease risk reduction intervention in an integrated healthcare delivery 
system. Our innovative pilot trial could provide critically needed information to support a 
future multi-site RCT, with the ultimate goal of delaying or preventing cognitive decline 
leading to Alzheimer’s disease or other dementia in higher-risk individuals. This scalable 
healthcare system-based intervention targets personalized lifestyle and medical risk 
factors that also affect overall health. 
 
Design and Outcomes   
 
SMARRT is a randomized pilot study to test a personalized, pragmatic, multi-domain 
Alzheimer’s disease risk reduction intervention in a US integrated healthcare delivery 
system. We will randomize 200 higher-risk older adults to a two-year Alzheimer’s risk 
reduction intervention (SMARRT) or a Health Education (HE) control. 
 
The primary outcome is two-year cognitive change on a cognitive test composite score. 
Secondary outcomes include: a) improvement on Alzheimer’s risk factors, b) components 
of the global cognitive composite score, c) physical performance, d) functional ability, e) 
quality of life, and f) incidence of mild cognitive impairment (MCI) and Alzheimer’s 
disease and dementia. Changes made to the protocol due to Covid-19, i.e., switching to 
telephone data collection, may limit our ability to examine cognitive change effectively, 
as several of the most important cognitive tests cannot be administered via telephone. 
Additionally, the onset of Covid-19 may affect the ability of participants to achieve risk 
factor reduction. In an exploratory outcome we will examine the effect of the Covid-19 
pandemic on risk factors.  
 
Interventions and Duration  
 
Eligible participants will be randomized to either SMARRT or HE control. Participants 
randomized to the SMARRT group will receive personalized interventions related to their 
risk factors. Participants in the HE control group will receive typical health education 
information about risk factors for Alzheimer’s disease. All participants will receive a 
screening phone call, a baseline visit, and three follow-up visits with blinded assessors (to 
assess outcomes) at approximately 6, 12, and 24 months, and the option of a telephone 
assessment or a questionnaire by mail at 18 months.  
 
Sample Size and Population  
 
200 higher-risk older adults (age 70-89 with low normal performance on cognitive screen 

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and ≥ two modifiable risk factors that will be targeted by our intervention) at baseline 
will be eligible for randomization. 100 will be randomized to SMARRT, and 100 to HE 
control. Randomization will be stratified by clinic and blocked by race (white, non-white) 
and age (70-79, 80-89) to ensure balance in these groups. Study participants will be 
recruited from selected primary care clinics of Kaiser Permanente Washington (KPWA).  
STUDY TEAM ROSTER AND STUDY SITES 
Principal Investigators:  
Kristine Yaffe, MD 
University of California, San Francisco 
4150 Clement St., Box 181 
San Francisco, CA 94121-1545 
415-221-4810 x23985 
Kristine.Yaffe@ucsf.edu 
 
Sascha Dublin, MD, PhD 
Kaiser Permanente Washington 
1730 Minor Ave., Suite 1600 
Seattle, WA 98101-1466 
206-287-2870 
Sascha.Dublin@kp.org 
Eric B.  Larson, MD, MPH (Former PI) 
Kaiser Permanente Washington 
1730 Minor Av., Suite 1600 
Seattle, WA 98101-1466 
206-287-2534 
Eric.B.Larson@kp.org 
 
Co-Investigators by Site:  
University of California, San Francisco 
4150 Clement St., Box VAMC 181 
San Francisco, CA 94121-1545 
PI: Kristine Yaffe, MD 
 
Deborah Barnes, PhD, MPH 
4150 Clement St., Box VAMC 151R 
San Francisco, CA 94121-1545 
415-221-4810 x24221 
Deborah.Barnes@ucsf.edu 
 
 
Eric Vittinghoff, PhD 
Mission Hall, Global Health and Clinical Sciences Bldg. 
550 16th St. 2nd Floor 
San Francisco, CA 94158-0560 
415-514-8025 
Eric.Vittinghoff@ucsf.edu 
 
 

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Kaiser Permanente Washington 
1730 Minor Av., Suite 1600 
Seattle, WA 98101-1466 
PI: Sascha Dublin, MD, PhD 
 
 
Dori Rosenberg, PhD, MPH 
1730 Minor Av., Suite 1600 
Seattle, WA 98101-1466 
206-287-2532 
Dori.E.Rosenberg@kp.org 
 
Kristin Adams, MD 
1730 Minor Av., Suite 1600 
Seattle, WA 98101-1466 
253-383-6134 
Kristin.J1.Adams@kp.org 
 
Benjamin Balderson, PhD 
1730 Minor Av., Suite 1600 
Seattle, WA 98101-1466 
206-287-2803 
Benjamin.H.Balderson@kp.org 
 
Retired: Evette Ludman, PhD  
1730 Minor Av., Suite 1600 
Seattle, WA 98101-1466 
206-287-2912 
Evette.J.Ludman@kp.org 
 
 
 
1 
STUDY OBJECTIVES 
1.1 Primary Objective 
To collect pilot data on the effect of SMARRT compared to Health Education (HE) 
control for our primary outcome of two-year cognitive change. We will obtain critical 
information for estimating sample sizes required for a larger multi-site trial.  
 
Changes made to the protocol due to Covid-19, i.e., switching to telephone data 
collection, may limit our ability to examine cognitive change effectively, as several of the 
most important cognitive tests cannot be administered via telephone. 
 

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1.2 Secondary Objectives 
To compare changes in Alzheimer’s risk factors over two years in those randomized to 
SMARRT vs HE. The results will determine if SMARRT can have a meaningful impact 
on cognition by demonstrating significantly greater risk factor change than HE. 
 
To gather preliminary data on the impact of SMARRT vs HE on components of the 
global cognitive composite score, physical performance, functional ability, quality of life 
and incidence of mild cognitive impairment (MCI) and Alzheimer’s disease.  
 
The onset of Covid-19 may affect the ability of participants to achieve risk factor 
reduction. In an exploratory outcome we will examine the effect of the Covid-19 
pandemic on risk factors. 
 
2 
BACKGROUND AND RATIONALE  
2.1 Background 
Alzheimer’s disease prevalence is growing, creating a critical need for prevention. The 
number of people in the U.S. living with Alzheimer’s disease and related dementias is 
expected to rise from 5 million today to 13 million by 2050(1). Current medications do 
not change the disease course, and several drugs have recently failed Phase III trials; thus, 
there is growing interest in strategies to prevent Alzheimer’s disease. We have estimated 
that up to 30% of Alzheimer’s disease may be attributable to modifiable risk factors (2, 3) 
including physical inactivity, low education, smoking, diabetes, hypertension, depression, 
and obesity. Our estimates are now being supported by several large population-based 
cohort studies, which are finding that Alzheimer’s disease prevalence is actually 
decreasing in parallel with population-level changes in risk factors, such as better 
education, lower smoking and better control of cardiovascular risk factors. In addition, 
multidomain prevention trials in Europe have found that targeting these risk factors in 
older adults slows cognitive decline and reduces cognitive impairment. (4) These studies 
raise hope that multimodal risk reduction interventions in higher-risk older adults may 
delay the onset of Alzheimer’s disease.(5) 
2.2 Study Rationale 
Despite growing evidence and tremendous promise, to date there has not been a single 
multi-domain Alzheimer’s risk reduction trial in the US. In addition, multi-domain risk 
reduction trials performed in other countries have all involved relatively intensive 
interventions that would be difficult to implement in real-world settings. An integrated 
healthcare setting provides an important potential venue to promote Alzheimer’s 
prevention and risk reduction because the goals of the intervention are consistent with the 
goals of the healthcare system. This study will enable us to test the feasibility of this 
approach for motivating behavior change in older adults with an increased risk of 
Alzheimer’s. 
 
SMARRT is a randomized pilot study to test a personalized, pragmatic, multi-domain 

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Alzheimer’s disease risk reduction intervention in a US integrated healthcare delivery 
system. We will randomize 200 higher-risk older adults (age 70-89 with low normal 
performance on cognitive testing and ≥ two modifiable risk factors that will be targeted 
by our intervention) to a two-year Alzheimer’s risk reduction intervention (SMARRT) or 
a Health Education (HE) control. 
3 
STUDY DESIGN 
This study is a pragmatic, single-blind, randomized controlled pilot trial. We will 
randomize 200 higher-risk older adults to a two-year Systematic Multi-domain 
Alzheimer’s Risk Reduction Trial (SMARRT) intervention or a Health Education (HE) 
control. The SMARRT team will work with participants to develop a tailored action plan 
to address risk reduction. Targeted areas will include: increasing physical, mental and 
social activities; controlling cardiovascular risk factors (diabetes, hypertension); quitting 
smoking; reducing depressive symptoms; improving sleep; neuroprotective diet; and 
decreasing use of potentially harmful medications. Our novel intervention uses a 
personalized, pragmatic risk reduction program in an integrated healthcare delivery 
system and state of the art technology to maximize feasibility and risk reduction. 
 
Primary outcome is two-year cognitive change on a cognitive test composite score.  
Secondary outcomes include: a) improvement on Alzheimer’s risk factors, b) components 
of the cognitive score, c) physical performance, d) functional ability, e) quality of life, 
and f) incidence of mild cognitive impairment (MCI) and Alzheimer’s disease and 
dementia.  Changes made to the protocol due to Covid-19, i.e., switching to telephone 
data collection, may limit our ability to examine cognitive change effectively, as several 
of the most important cognitive tests cannot be administered via telephone. Additionally, 
the onset of Covid-19 may affect the ability of participants to achieve risk factor 
reduction. In an exploratory outcome we will examine the effect of the Covid-19 
pandemic on risk factors. 
3. 1     Setting 
Kaiser Permanente Washington (KPWA) is an integrated healthcare delivery system 
with about 710,000 members in the Northwest United States that provides members with 
both insurance coverage and healthcare. Because KPWA provides insurance coverage, 
we have complete information about members’ healthcare utilization as well as 
diagnosis and procedure codes and medication fills. About 2/3rds of KPWA members 
receive all or nearly all clinical care from KPWA physicians at KPWA-owned clinics. 
For those members we also have information on clinical measures such as vital signs 
(e.g. blood pressure values) and laboratory test results. This study will only recruit 
members who are receiving their clinical care within KPWA’s healthcare system. The 
University of California, San Francisco (UCSF) will provide study oversight.  
3.2  
Regulatory Review and Approval 
All study procedures have been reviewed and approved by Institutional Review Boards 
(IRBs) at KPWA and UCSF, and the study will be registered on ClinicalTrials.gov. All 
study participants will provide written, informed consent before participating in 

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assessments or intervention activities. We received a consent and Health Insurance 
Portability and Accountability Act (HIPAA) waiver to use electronic health records 
(EHR) to identify and recruit potential participants. HIPAA is a national privacy 
regulation in the US that requires all research study participants to review and sign a 
form that describes what type of information is being collected and how it will be used 
prior to participating in a study. IRBs can provide researchers with permission to use 
patient data for research without their prior approval when certain conditions are met, 
such as the research involves no more than minimal risk and is of sufficient importance 
to outweigh intrusion into the privacy of research subjects. Consistent with federal and 
state laws, all KPWA patients are provided with a Notice of Privacy Practices stating 
that their information may be used for research. Patients who have previously requested 
not to be contacted or have their records reviewed for research studies will be excluded.  
 
 
4 
INCLUSION/EXCLUSION CRITERIA  
4.1 Inclusion Criteria  
Participants must meet all the inclusion criteria to participate in this study. Age 70-89 
years (to target a population at increased risk of experiencing cognitive decline that is still 
able to participate fully in a two-year intervention study); English language fluency; low-
to-normal performance as compared to participants enrolled in the Adult Changes in 
Thought (ACT) Study (median 30) on a brief telephone cognitive screen (Cognitive 
Abilities Screening Test [CASI] short version); and ≥ two additional risk factors that will 
be targeted by our intervention (the table below has additional details on definitions). 
 
Initial eligibility criteria using electronic health records (EHR) data will be based on 
having at least one targeted risk factor.*  We will recruit among those with at least one 
targeted risk factor (rather than two) because not all risk factors of interest can be 
identified from the EHR (e.g., physical activity). We expect many individuals initially 
identified as having one risk factor will ultimately have two or more based on 
information collected on the telephone interview. The final inclusion criteria of at least 
two risk factors will be determined via a combination of EHR data (for hypertension, 
diabetes and contraindicated medications) and phone screening (for the remaining risk 
factors). 
 
*Note: The targeted risk factors are defined in the table below. In addition to the targeted 
risk factor of poorly controlled hypertension as measured by elevated blood pressure 
twice in the prior 6 months, we also selected for initial eligibility people who had a 
hypertension diagnosis in the past 2 years.  This is not a change to the definition of the 
risk factor, but rather a way of broadening the pool of sampled participants who are 
screened for eligibility.  Many people have not been to their clinic twice in the past 6 
months to have documented elevated blood pressures, but do still have poorly controlled 
hypertension.  They would still need to have 2+ of the targeted risk factors below to be 
enrolled in the study, so the criteria for eligibility is unchanged. 
 

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Table. Inclusion criteria for SMARRT Trial 
 
Inclusion Criteria 
Definition 
Data source 
Older age 
70-89 years
EHR
Language  
Fluent in English 
EHR and 
telephone 
screen
KPWA enrollment 
status
≥ 12 months (allow 3-month gap) 
EHR 
Low-to-normal 
cognitive 
performance on 
cognitive screen, 
excluding top 
performers
Brief CASI score 25 to 32, inclusive 
Telephone 
screening 
≥2 targeted risk 
factors
 
 
o Poorly controlled 
hypertension
Systolic blood pressure ≥ 140 and/or diastolic blood 
pressure ≥90 twice in the past 6 months
EHR 
o Poorly controlled 
diabetes, with 
evidence of either 
hyperglycemia or 
hypoglycemia
Hyperglycemia: ≥ 1 HbA1c ≥ 8.0 in past 12 months 
Potential hypoglycemia: Diabetes, taking insulin (at 
least one fill in past 6 months) and one or more of the 
following: 1) most recent A1c in past 12 months ≤ 6.0; 
2) diagnosis code for hypoglycemia in past 1 year
EHR 
o Elevated depression 
symptoms 
Initial recruitment (EHR): Score of ≥ 3 on Patient 
Health Questionaire-2 (PHQ-2) screen in past 12 
months 
Final eligibility: Score of ≥ 10 on PHQ-8 on telephone 
screen 
EHR (initial) 
 
Telephone 
screening 
(final 
eligibility)
o Sleep difficulty 
Initial recruitment: Diagnosis code for sleep disorder 
and/or ≥ 2 fills for a sleep medication in the past 12 
months  
Final eligibility: Scoring above the cut-off on the sleep 
questionnaire in phone screening (problems with sleep 
3+ nights/week and bothered “somewhat” or more)
EHR (initial) 
 
Telephone 
screening 
(final 
eligibility)
o Risky medications 
≥ 2 fills for medications in a given class of risky 
medications in past 6 months, per modified Beers 
criteria.  
EHR 
o Low physical 
activity 
< 30 minutes moderate intensity most days (<150 
minutes/week, Surgeon General guidelines)
Telephone 
screening
o Social isolation 
Rarely or never get social and emotional support 
needed (scoring ≥ 6 out of 9 possible points)
Telephone 
screening
o Smoking 
Initial recruitment: EHR evidence of current use of 
any tobacco 
Final eligibility: self-reported current smoking on 
telephone screen
EHR (initial) 
Telephone 
screening 
(final 

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eligibility)
 
4.2 Exclusion Criteria  
Any candidates meeting any of the exclusion criteria during EHR review or the screening 
phone call will be excluded from study participation. For initial determination of 
eligibility, we will rely on information recorded in the EHR, such as International 
Classification of Diseases 10 (ICD-10) diagnosis codes and medication fills. We will 
exclude those who are currently residing in a skilled nursing or rehabilitation facility; 
receiving palliative care or hospice services (based on clinic encounters, past 2 years); 
Charlson comorbidity index score > 5 (based in ICD-10 diagnoses, past year, to exclude 
severe comorbidity likely to interfere with ability to participate in the study); bipolar 
illness or schizophrenia (any ICD-10 code, past 2 years, or receiving two or more fills for 
antipsychotic medications, past 6 months); current alcohol or drug use disorder (any ICD-
10 code, past 2 years); receiving chronic opioid therapy (enough supplied to have taken 
20 mg in morphine equivalents each day for at least 70 days out of the last 90 day 
period); Parkinson’s disease, amyotrophic lateral sclerosis, or multiple sclerosis (any 
ICD-10, past 2 years); requested not to be contacted or not to have their medical record 
reviewed for research studies (KPWA Health Research Institute database); had clinical 
visits with the study co-investigators; and evidence of dementia (based on ICD10 codes, 
past 2 years, or prescription fills for dementia medications such as donepezil or 
memantine, past 2 years. If two participants from the same household are eligible, only 
one will be randomly selected for invitation. 
 
Additional exclusion criteria will be determined as part of telephone screening and will include: 
severe hearing impairment (unable to complete telephone screen); inability to come in for 
assessments; inability to participate in an intervention and outcomes assessments conducted in 
English;  plans to disenroll from KPWA or move out of the area in the next 2 years; current 
enrollment in the Adult Changes in Thought (ACT) study; answering ‘yes’ to the question “have 
memory problems contributed to a decline in your ability to care for yourself over the past year;” 
short CASI scores ≤24 (suggestive of cognitive impairment) or ≥33 (low likelihood of 
experiencing cognitive decline over 2 years); or inability to provide informed consent. 

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5 
STUDY PROCEDURES 
5.1 
Schedule of Evaluations 
 
Assessment 
Screening 
Baseline 
Health Coach 
Sessions 
(SMARRT 
Group Only) 
Health 
Education  
(HE Control 
Only) 
6 Month 
Assessment 
12 Month 
Assessment 
18 Month 
Assessment 
24 Month 
Assessment 
Inclusion/Exclusion Criteria 
X 
  
  
 
  
  
  
  
Informed Consent Form   
 
X  
 X (first 
session) 
 
  
  
  
  
ActiGraph  
 
X  
  
 
 
 X 
  
X  
Physical Function Tests 
 
X 
  
 
X 
X 
 
X 
Blood Pressure and 
Height/Weight
 
X 
 
 
X 
X 
 
X 
Questionnaire packet 
 
X 
  
 
X 
X 
X 
X 
Neuropsychological Test Battery
 
X 
 
 
X 
X 
X* 
X 
Cognitive Abilities Screening 
Instrument (CASI)
 
X 
 
 
X 
X 
X* 
X 
Mailed Education Forms 
  
  
 
X 
 
 
 
 
Meet with Interventionist 
  
 
X 
 
 
 
 
 
Risk Factor Review 
 
 
X (at 6 
months) 
 
 
 
 
 
Adverse Events  
  
X 
X 
X 
X 
X 
X 
X 
COVID / Generalized Anxiety 
Disorder 2-item (GAD-2)
 
 
 
 
X** 
X** 
X** 
X** 
Medication Questionnaire and 
Script
 
 
 
 
 
 
 
X 
*Option for phone assessment at 18 months, to include subset of neuropsychological tests, and telephone CASI. 
**COVID/GAD-2 if applicable at follow-up; may be administered at multiple time points. 

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5.2 Description of Evaluations  
5.2.1 Recruitment 
Our goal is to target higher-risk individuals who will be motivated to make medical 
and behavioral changes to reduce their Alzheimer’s risk. Initial eligibility will be 
determined using medical risk data from the EHR. Final eligibility will be determined 
during telephone screening. 
 
Initial eligibility criteria using EHR data will be based on age, KPWA enrollment 
status, fluency in English, lack of exclusion criteria (described above), and ≥one 
targeted risk factor. We will recruit among those with ≥one targeted risk factor (rather 
than ≥two) to increase the size of the pool of people screened and minimize the risk 
of missing potentially eligible individuals who have risks that are not documented in 
the EHR. The final inclusion criteria of ≥two risk factors will be determined via 
phone screening. All potential participants will have EHR risk factor data 
(demographics, diagnoses, laboratory values and medications). In order to achieve 
greater diversity, we will use race-ethnicity information available from KPWA 
demographic files to oversample potential participants who are Hispanic or non-
white, with a goal of having at least 30% of study participants from diverse 
backgrounds.  
 
5.2.2 Mailing 
Using standardized procedures that have been successfully applied in numerous 
research studies at KPWA Health Research Institute (KPWHRI), a research specialist 
within the Survey Research Program will mail recruitment letters describing the study 
to current KPWA members who meet initial eligibility criteria. Recruitment letters 
will include a phone number participants can call to opt out of being contacted for 
recruitment into this study. 
 
5.2.3 Screening Evaluation 
Approximately one week after letters have been mailed, potentially eligible study 
participants will be called and study interviewers will describe the study activities, 
randomization, and risks and benefits of the study. They will confirm understanding 
and invite any questions. They will obtain verbal informed consent to collect 
demographic information, to continue with the screening process, and (for those 
eligible for the study) to wear the ActiGraph activity monitor for a week. Once verbal 
consent has been given, they will give a detailed description of the study and 
determine final eligibility with a standardized screening questionnaire. 
 
Because our goal is to enroll people with low normal cognitive function, we will also 
perform the short telephone version of the CASI. Enrollment will be restricted to 
those whose scores fall between 25 and 32 inclusive (see inclusion criteria section for 
rationale). Individuals who are eligible and interested will then be scheduled for in-
person written consent and baseline assessment, and will be sent an accelerometer by 

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mail to obtain a measure of baseline levels of physical activity. 
 
5.2.4 Baseline and Randomization 
Consenting Procedure 
 
At the written consent and baseline measurement visit, the assessor will discuss the 
nature of the study and review the written consent and HIPAA authorization form. 
Adequate time will be allowed to ensure comprehension and answering any 
questions. The assessor will obtain written consent from the participant and will also 
sign the consent form. A copy of the dually signed consent form will be given to the 
participant. The original will be stored in a locked filing cabinet in KPWHRI’s locked 
offices. The consent forms will be stored separately from study ID and measures. 
 
Baseline Assessments 
 
All participants will complete the assessments listed below at baseline and three 
follow-up visits spaced over 24 months (approximately 6, 12, and 24 months), plus 
the option of a phone assessment or a mailed questionnaire at 18 months. Details of 
the assessments are below, in section 5.3. 
 
o ActiGraph: objectively measures physical activity (worn for a week before 
baseline visit) 
o Physical Function Tests 
o Short Physical Performance Battery 
o Vital Signs 
o Height and weight 
o Blood pressure 
o Questionnaire packet 
o Memory and Thinking Questionnaire (Cognitive Function Instrument) 
o Health Questionnaire (PROMIS Global Health) 
o Exercise Questionnaire (Rapid Assessment of Physical Activity in Older 
Adults: RAPA) 
o Social Activities Questionnaire (PROMIS Satisfaction with Participation in 
Discretionary Social Activities) 
o Leisure Activities Questionnaire (Cognitive Activities Questionnaire) 
o Alcohol and Smoking Questionnaire (AUDIT-C and Smoking Use) 
o Diet Questionnaire (MIND Diet) 
o Mood Questionnaire (Center for Epidemiological Studies Depression Scale: 
CES-D) 
o Sleep Questionnaire (Pittsburgh Sleep Quality Index: PSQI) 
o Neuropsychological Test Battery 
o Verbal memory (WMS-R Logical Memory) 
o Verbal memory (CERAD Word List) 
o Attention/Working memory (WAIS-R Digit Span) 
o Speed (WAIS-R Digit Symbol) 

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o Speed/Executive (Trail Making Test) 
o Speed/Executive (Stroop Test) 
o Language (Category Fluency Test) 
o Language/Executive (Phonemic Fluency) 
o Cognitive Abilities Screening Instrument (baseline, 6, 12, and 24 months; 
Telephone CASI at 18 months for phone assessments) 
 
Randomization 
 
Study participants will be randomized after the baseline visit in a 1:1 ratio to 
treatment and control, using procedures described below in Section 9.2.1. The study 
intervention will begin within eight weeks of randomization. If an appointment with 
the interventionist has not been scheduled within eight weeks of randomization, a 
case review will take place between the clinical support team and the intervention 
team to decide the best way to continue with the participant. 
 
5.2.5 Follow-up and Final Visits 
Assessments given at baseline will be repeated three times over the following 24 
months (approximately 6, 12, and 24 months*), plus the option of a phone assessment 
or a mailed questionnaire at 18 months. 
 
*Participants who are unable to or decline to complete follow up in-person visits will 
be given the option to complete an abbreviated assessment by phone/mail. These 
participants will still be given the $50 incentive. 
 
 
All Follow-up Visits and 24-Month (Final) Visit 
o ActiGraph (not at 6-month visit) 
o Physical Function Tests 
o Vital Signs 
o Questionnaire packet 
o Neuropsychological Test Battery* 
o Adverse Events 
o COVID/GAD-2 (if applicable**) 
o Medication Questionnaire (24-month only)*** 
 
* Several integral tests in the Neuropsychological Test Battery could not be 
administered via telephone, so those were not collected post-March 2020, when 
Covid-19 interrupted the study. 
 
**The COVID/GAD-2 Questionnaire may be administered at one or more follow-up 
time points, if applicable based on the prevalence of COVID in the community.   
 
*** The medication questionnaire will be pilot tested at the 24-month timepoint in 
10-15 participants.  After study team debriefing for QA and additional 

SMARRT Protocol, Version 1.16 
12 
training/clarification, we will implement for all future visits.  
 
The study team will notify all participants once their participation has ended at two 
years and when the overall study has ended. The team will mail a letter thanking each 
person for their participation. The letter will include a 1-page summary of study 
findings in lay language, a “graduation” certificate, and a reference to the first article 
resulting from the study. 
 
The study does not plan to terminate anyone’s participation early. They will continue 
in the study if they develop dementia, for as long as they and their legally authorized 
representative are willing to continue. For people unable to attend follow-up 
evaluations, we will offer a phone follow-up (CASI, neuropsychological tests, survey 
questions, AEs). Possible reasons for early withdrawal include medical event, illness, 
too busy, etc. If a participant asks to withdraw, we will first ask them if we can 
contact them again in a few months. If they are unwilling, we will ask permission to 
follow via medical records only.    
 
Exit Interview (Optional) 
After completing the study, participants may be invited to complete an exit interview 
by phone about their experience with the program and any feedback they have. This 
will help us improve the program. Participation in the exit interview is optional; if 
they agree to participation, we will ask to audio-record and transcribe the interview, 
but audio-recording is also optional. 
 
5.3 Outcomes  
Primary Outcome: Two-year Cognitive Change (Composite Score):  Cognitive function 
will be measured by a global composite score from the modified Neuropsychological Test 
Battery (mNTB), a comprehensive battery including tests of memory (WMS-R Logical 
Memory, Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] Word 
List); attention (WMS-R Digit Span); executive functioning/processing speed (Trail 
Making Test, Stroop Test, WAIS-R Digit Symbol); and language [Category Fluency Test; 
Phonemic Fluency (FAS)].  
 
Outcome measures in Alzheimer’s risk reduction trials need to be sensitive to detecting 
subtle cognitive changes. We selected the mNTB to meet this need based on several lines 
of evidence for its strength as an outcome measure. Specifically, the original NTB,(6) on 
which the mNTB builds, is well-validated with strong test-retest reliability,(6,7) ability to 
distinguish between individuals at different clinical stages (i.e., normal cognition, MCI, 
AD),(7) and sensitivity to detecting cognitive change in early stages of Alzheimer’s.(6)  
 
Changes made to the protocol due to Covid-19, i.e., switching to telephone data collection, 
may limit our ability to examine cognitive change effectively, as several of the most 
important cognitive tests cannot be administered via telephone. 
 

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13 
Secondary outcomes:  
 
a) Improvement on Alzheimer’s risk factors. Because this is a pilot study, one of our goals 
is to quantify the number and type of Alzheimer’s risk factors each person has at 
baseline as well as change in each risk factor over two years in response to the 
SMARRT intervention. This will be accomplished using a combination of validated 
objective and self-report measures as well as EHR data. We chose to use individual 
measures rather than an AD risk score so that we could examine each risk factor 
independently. In addition, current AD risk scores do not include all of the risk factors 
being targeted in this study. Specific measures include:  
 
 Self-reported physical activity (Rapid Assessment of Physical Activity for Older 
Adults (RAPA):  a validated 9-item self-report inventory assessing physical activity, 
which is designed for use with older adults and based on CDC recommendations for 
physical activity.  
 Objectively measured physical activity (Actigraphy): participants will wear an 
ActiGraph wGT3X+ (Pensacola, FL) waist-worn accelerometer for 7 days prior to 
measurement visits at baseline, 12 months, and 24 months. Data from the ActiGraph 
will be aggregated using ActiLife software with counts over 1040 per minute used as 
the threshold for moderate or higher intensity activity (a cut point that appears to be 
valid for older adults).  
 Leisure / Social Activity (PROMIS Satisfaction with Participation in Discretionary 
Social Activities): 12-item questionnaire which asks individuals to rate how satisfied 
they have been with their engagement with social and other leisure activities and 
social connectedness in the past 7 days on a 5-point Likert scale (not at all … very 
much). 
 Cognitive activity (Cognitive Activity Questionnaire): 11-item questionnaire which 
asks how often an individual engages in activities such as reading the newspaper, 
playing games (e.g., crosswords, puzzles), playing a musical instrument, and other 
cognitively stimulating hobbies/leisure activities on a 6-point Likert scale (once a 
month/never … every day).    
 Control of cardiovascular risk factors (hypertension, diabetes): Blood pressure and 
HbA1c values will be ascertained from the KPWA EHR. In addition, at each 
measurement visit, height, weight, and blood pressure will be assessed.  Height and 
weight will be used to calculate body mass index (BMI). 
 Smoking: Participants will be asked to self-report current tobacco usage, including 
questionnaire items: “Have you smoked even a puff in the last 7 days?” and if yes, 
“How many cigarettes have you smoked in the last 7 days?”.  
 Diet (MIND diet score): The Mediterranean-DASH Intervention for 
Neurodegenerative Delay (MIND) diet combines elements of the Mediterranean and 
the Dietary Approach to Systolic Hypertension (DASH) diets. The15-item 
questionnaire assesses frequency of consumption of specific food types (e.g., green 
leafy vegetables, red meat) over the past 6 months.   
 Depressive symptoms (Center for Epidemiologic Studies – Depression Scale, CES-
D): 20-item questionnaire that assess both positive and negative affect over the last 
week rated on a scale from 0 (rarely or none of the time) to 4 (most or all of the time).  

SMARRT Protocol, Version 1.16 
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 Sleep quality (Pittsburgh Sleep Quality Index, PSQI): 19 item questionnaire that 
assesses sleep quality and disturbances over the past month (not at all, less than once 
a week, once or twice a week, three or more times a week).  
 Potentially harmful medications (identified from KPWA pharmacy database): based 
on a detailed list of contraindicated medications developed for the intervention (see 
Intervention section). Additionally, a medication questionnaire will assess the use of 
over-the-counter [OTC] medications containing ingredients that increase risk of 
cognitive impairment/dementia. 
 The onset of Covid-19 may affect the ability of participants to achieve risk factor 
reduction. In an exploratory outcome we will examine the effect of the Covid-19 
pandemic on risk factors. 
 
b) Individual cognitive domain scores 
c)  Physical performance (Short Physical Performance Battery, SPPB): The SPPB was 
developed by the National Institute on Aging (NIA) to provide an objective tool for 
measuring physical performance in older adults. Each component is individually scored 
on a scale of 1-4 (balance, lower extremity strength/chair stands, and gait speed/time to 
walk 4 meters) according to SPPB scoring protocols.  The total SPPB score is the sum 
of the 3 component scores and ranges from 0 to 12.  We will also examine scores on 
subscales (time to complete 5 chair stands, time to walk 4 meters). [Because this 
requires in-person observation, we have very few timepoints with this data due to 
Covid-19.] 
d)  Functional ability (Cognitive Function Instrument, CFI): 14-item self-report inventory 
of cognitive and functional difficulties in everyday tasks (e.g., remembering 
appointments, managing finances, driving). Total scores range from 0 to 14, with 
higher scores indicating greater difficulty in everyday tasks.  
e)  Quality of life (PROMIS Global Health): 10-item self-report inventory which asks 
individuals to rate their quality of life including in terms of their overall physical and 
emotional health.  
f)  Incidence of MCI and Alzheimer’s disease: While the incidence of clinically significant 
cognitive impairment is anticipated to be low, we will hold consensus conferences to 
identify MCI and dementia including Alzheimer’s in people who meet one of the 
following criteria: 1) Full-length CASI score < 86 (or < 27 on the abbreviated telephone 
CASI for those unable to complete in-person) or 2) assessors observe or ascertain a 
noticeable decline in function. For these individuals, we will follow standard guidelines 
developed and used since 1994 in the ACT study to determine cognitive status using 
DSM-IV criteria for determination of the presence and diagnostic subtype of dementia.  
The diagnosis of Alzheimer’s disease will be based on type of dementia according to 
current NINCDS-ADRDA diagnostic criteria for Alzheimer’s and other types of 
dementia. We will define MCI broadly based on the Petersen criteria for MCI. We will 
further define MCI based on cognitive domain of deficit in order to yield categories of 
amnestic MCI, single non-memory impairment MCI and multiple domain MCI.  
 

SMARRT Protocol, Version 1.16 
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6 
STUDY INTERVENTIONS  
6.1 Interventions, Administration, and Duration  
SMARRT Intervention Arm 
After baseline assessments have been completed, the intervention team (including a nurse 
care manager and a behavioral interventionist) will use a standardized procedure to develop 
an individualized Alzheimer’s Risk Profile for each patient randomized to the SMARRT 
intervention arm. This will include a graphic display of the targeted risk factors showing 
areas where the participant is doing well (green), areas where they can continue to improve 
(orange), and areas that are of particular risk for them (red). Patients will then meet in-
person with an interventionist to review their risk profile and develop a personalized risk 
reduction action plan. Interventionists will elicit participants’ values and motivators to 
reduce Alzheimer’s risk and will use a decisional balance process informed by motivational 
interviewing and confidence ratings to help them choose 1-3 specific, achievable risk 
reduction steps that they are most ready to adopt. Participants will be provided with tools to 
track their progress. At each subsequent visit, interventionists will review progress, 
problem-solve barriers, and set new goals as needed. Targeted areas will include: 
increasing physical, mental and social activities; quitting smoking; healthy diet; controlling 
cardiovascular risk factors (diabetes, hypertension); reducing depressive symptoms; 
improving sleep; and decreasing use of potentially harmful medications. Following detailed 
protocols, the intervention team will provide counseling if participants experience distress 
related to being informed of their Alzheimer’s risk. 
 
Interventionists will provide participants with a menu of options for each targeted risk 
factor, and goals will be individualized to preferences, barriers, and motivators up front to 
optimize intervention adherence (see Table below). For each target, there are options that 
leverage technology as appropriate for the participants’ interest and skill level. Non-
technology-based options are provided for each target as well.  
 
For management of medical conditions (e.g., hypertension, diabetes, depression, sleep 
disorders), a “treat-to-target” approach will be used. This will involve setting discrete goals 
for targeted conditions (e.g., blood pressure, HbA1c, depressive symptoms) in consultation 
with the primary care team, systematically monitoring patient progress, adjusting treatment 
as needed (treat-to-target) and supporting patient self-care. Each week, the intervention 
team will meet with the clinical support team (MDs and clinical psychologists) for case 
reviews. Treatment algorithms will be based on standard KPWA treatment 
recommendations synthesized from national guidelines. Approval to exercise will be 
obtained from primary care physicians (PCPs) to ensure participants can safely engage in 
exercise prior to receiving interventions. Those who are approved and interested will be 
encouraged to gradually increase their physical activity levels, focusing on walking. In 
addition, our protocol includes strategies to reduce sitting behavior as an alternative in 
those who are not interested or able to increase physical activity levels. The SMARRT 
study physician or nurse will make recommendations to the participant and their PCP about 
management of targeted medical conditions and use of specific high-risk medications via 
Epic messaging, a secure, electronic, internal messaging system that enables clinical staff 
to communicate with each other about patient care. A detailed list of contraindicated 

SMARRT Protocol, Version 1.16 
16 
medications including generic and brand names was developed using the 2015 updated 
Beers criteria for potentially inappropriate medications in older adults and a Kaiser 
reference for high-risk medications in the elderly, focusing on medications that impact 
cognitive function. Examples of targeted medications include those with strong 
anticholinergic properties, such as some antihistamines (e.g., diphenhydramine), some 
antidepressants (e.g., amitriptyline, paroxetine), and sedative-hypnotics (e.g., alprazolam, 
lorazepam). Nurses will work collaboratively with the primary care team to deprescribe 
contraindicated medications, and health coaches will work with participants on behavioral 
approaches to manage underlying conditions such as depression or insomnia.  
 
Interventionists will follow a standard protocol for delivering the SMARRT intervention 
that allows for personalization of the specific risk reduction action plan; these plans will 
evolve over time according to participant progress, motivation and preferences or newly 
identified risk factors. Staff will use a tracking database to record information for each 
participant, including date and time of session, identified risk factors, motivational barriers 
and important values, and the outcome of discussions around developing goals.  For each 
participant, the exact number and mode (phone or in-person) of contacts will differ, but we 
will aim to have at least 1 contact per month with each participant. Best practice will 
include in-person meetings twice a year during the 2-year intervention period. Even if a 
participant has relatively fewer risk factors, or successfully addresses all of their risk 
factors, interventionists will continue to check in with them to ensure that they are 
maintaining their healthy behaviors over time.  
 

SMARRT Protocol, Version 1.16 
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Table. Targeted Risk Factors and Approaches and Outcomes in SMARRT 
Risk Factor 
Goal 
Menu of Options Tailored to Individual 
Preferences & Abilities 
Outcome Measures 
Poorly 
controlled 
hypertension 
<140/90 (<130/90 in 
patients with 10-year 
atherosclerotic 
cardiovascular disease 
risk ≥10%
Exercise, diet, medication changes using stepped care 
“treat to target” approach with primary care provider 
(PCP) 
Blood pressure (study visits; 
EHR) 
Poorly 
controlled 
diabetes
HbA1c between 7 and 8 
Exercise, diet, medication changes using stepped care 
“treat to target” approach with primary care 
HbA1c (EHR) 
 
 
Physical 
inactivity 
Increase by 2500 steps 
per day or maintain if 
they are over 10,000 
steps/day, or work up to 
8,000 steps per day 
KPWA covered programs (e.g., Silver Sneakers, 
EnhanceFitness), community programs (e.g., YMCA, 
mall walking), smart phone apps (e.g., Apple Health, 
MyFitnessPal, MapMyWalk), wearable devices (e.g., 
pedometer, Fitbit), protocol to reduce sitting 
Rapid Assessment of 
Physical Activity (RAPA) 
for Older Adults; 
Actigraphy 
Lack of mental 
stimulation 
Increase engagement in 
cognitively stimulating 
activities that are 
enjoyable
Senior center activities, local college classes, 
crossword puzzles and games, cognitive training web 
programs, smart phone apps (e.g., Lumosity, Brain 
HQ), on-line classes, volunteering; mindfulness
Cognitive Activities 
Questionnaire 
Social isolation 
Increase social 
engagement 
Senior center activities, group exercise, social 
networking websites (e.g., Facebook), video chat 
tools, volunteering 
PROMIS – Satisfaction 
with Participation in 
Discretionary Social 
Activities
Depressive 
symptoms 
Fewer depressive 
symptoms  
Behavioral activation, referral to behavioral health for 
CBT, antidepressant medication via PCP, smart phone 
apps based on CBT (e.g., MoodKit) or mindfulness 
(e.g., Mindfulness Coach)
Center for Epidemiologic 
Studies – Depression Scale 
Sleep difficulty 
Improvement on self-
reported sleep quality and 
Sleep hygiene and sleep restriction education, CBT for 
Insomnia (CBT-I), smartphone apps (e.g. Sleepio), 
Pittsburgh Sleep Quality 
Index

SMARRT Protocol, Version 1.16 
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sleep duration
physical activity, behavioral activation
Smoking 
Reduction/cessation  
Referral to Quit for Life, comprehensive program at 
no cost to KPWA members delivered by phone, web, 
and/or smart phone app; mobile tools (NCI QuitPal)
Self-reported current 
tobacco usage 
Unhealthy diet 
Increase adherence to 
MIND diet 
Education about neuroprotective foods, self-
monitoring neuroprotective food intake with paper 
food logs or websites/apps (e.g. Fitbit, MyFitnessPal, 
MyPlate) 
Mediterranean-DASH 
Intervention for 
Neurodegenerative Delay 
(MIND) Diet Score
Contraindicated
medications 
Elimination/minimization 
 Education on alternatives, including 
nonpharmacologic therapy 
Contra-indicated 
medications for cognition 
(2015 Beers criteria and 
KPWA list)

SMARRT Protocol, Version 1.16 
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Health Education Control Arm 
In this pragmatic pilot trial, our goal is to compare the personalized SMARRT intervention 
to what is currently ‘usual care’ in the healthcare system, while also providing enough 
interaction to maintain retention and blinding. Therefore, participants randomized to the 
Health Education (HE) group will receive mailed materials (typically 1-2 pages) every 3 
months: general information on Alzheimer’s and dementia risk reduction using materials 
from sources such as the Alzheimer’s Association and educational materials commonly 
provided as part of routine care at KPWA. The general information provided will address 
factors that will be targeted in the SMARRT intervention, including physical, mental and 
social engagement; management of cardiovascular risk factors; quitting smoking, healthy 
diet; depression; sleep; and contraindicated medications. HE participants will not be 
provided with personalized information about their Alzheimer’s and dementia risk.  
 
Included in the mailings every 3 months will be a form asking if the HE participant has 
experienced a serious adverse event in the prior 3 months, and if so, a description, date(s), 
whether the participant has recovered, treatment plan if any, and whether we can call the 
participant later to see how they are doing. This approach will allow for more standardized, 
routine collection of SAEs among the control group. 
 
We may contact the primary care providers of Health Education program participants, for 
example if the blood pressure results or cognitive test results at a measurement visit are 
outside of the expected range.   
 
6.2 Handling of Study Interventions  
Interventionists will follow a standard protocol for delivering the SMARRT intervention 
that allows for personalization of the specific action plan. Staff will use a tracking database 
to record information for each participant, including date and time of session, identified 
risk factors, motivational barriers and important values, and the outcome of discussions 
around developing goals. Also documented in the tracking database will be notes about 
participants’ follow-through on recommendations and weekly case review 
recommendations with the clinical support team to supply information about intervention 
adherence. 
6.3 Concomitant Interventions 
6.3.1 Allowed Interventions 
Unless specifically targeted for intervention, participants will remain on medication and 
dosages as prescribed by their primary care provider. 
6.3.2 Prohibited Interventions 
As dementia at baseline is an exclusionary disorder, dementia medications at baseline 
(such as donepezil or memantine) will be prohibited. These medications will be allowed 

SMARRT Protocol, Version 1.16 
20 
if they are newly prescribed during the 24-month follow-up period.  
6.4 Adherence Assessment  
Interventionists will use the tracking database to carefully document each contact with 
participants, including the type (in person, phone) and outcome (risk factor targeted, goal, 
whether the goal was met, comments). This will enable us to determine the total number 
and type of contacts per participant, the number and types of risk factors targeted, and the 
extent to which goals were achieved. Interventionists also will document weekly case 
review recommendations with the clinical support team to supply information about 
intervention adherence. In the control arm, there is no active intervention (only passive 
materials, usual care) so we cannot assess adherence or engagement. 
7 
SAFETY ASSESSMENTS  
7.1 Adverse Events and Serious Adverse Events  
An adverse event (AE) is defined as a not serious condition (e.g., muscle aches from 
physical activity, abnormal lab values) that occurs during the study.  
 
A serious adverse event (SAE) is defined as a serious (defined as death, life-threatening 
event, hospitalization, or significant disability) or unexpected (defined as new or more 
severe than expected) and possibly, probably or definitely study-related (e.g., occur during 
or shortly after study-related activities) condition occurring during the study period. 
 
We expect AEs associated with this intervention to be minimal and consistent with daily 
risks (e.g., anxiety caused by assessments, muscle aches from physical activity); AEs will 
be tracked in the study database. AEs may be detected through reports or contact with 
study participants, from survey data, and from data in the EHR. All participants will be 
prompted to report AEs and SAEs at their measurement visits (approximately 6, 12, and 24 
months). All participants will be asked to respond to an SAE form sent in the mail every 
three months (approximately months 3, 9, 15, and 21) when new health education materials 
are sent. Those in the SMARRT group may also report AEs during check-ins with their 
health coach.  SAEs will be reported immediately to the project PIs and to the IRB and 
DSMB as described below. 
 
Any activities that result in participant distress or serious physical activity-induced injury 
will be reported to the project PIs. The PIs will discuss all such events with co-investigators 
and the IRB and take other action(s) as appropriate (e.g., providing information about 
relevant community services to distressed participant). Summary reports of any such 
adverse events and subsequent actions taken will also be provided to the DSMB and NIA. 
7.2 Reporting Procedures 
Serious Adverse Events (SAEs): SAEs will be reported to NIA and the Data and Safety 
Monitoring Board (DSMB) members by the PIs or their designees by email within 24 hours 
of learning of deaths, and 48 hours of learning of non-deaths. Official reports will be 

SMARRT Protocol, Version 1.16 
21 
submitted within five business days. The DSMB will request additional information as 
needed and will determine whether changes to the study protocol are warranted. 
 
Adverse Events (AEs): AEs will be reported to NIA and the DSMB in aggregate form 
prior to the biannual DSMB meetings.  
7.3 Follow-up for Adverse Events 
Unresolved AEs will be followed until resolved or considered stable. The health coaches 
will follow up during subsequent contact until the AE is resolved for participants in the 
intervention. For those in the HE group, the study nurse will follow-up via phone or EHR 
until the AE is resolved. For occurring SAEs, the MDs will triage for appropriate medical 
care within the KP system. The study nurse will follow-up with the participant and through 
medical records until the condition is stable or resolved.  
7.4 Safety Monitoring 
This study will be monitored by a DSMB, which will act in an advisory capacity to the 
NIA and the Principal Investigators, Dr. Kristine Yaffe and Dr. Eric Larson, to monitor 
participant safety, data quality, and the progress of the study.  
8 
INTERVENTION DISCONTINUATION  
Subjects may withdraw voluntarily from participation in the study at any time and for any 
reason. Participants will continue to be followed, with their permission, even if the study 
intervention is discontinued. Follow-up measurement visits will continue to be scheduled if 
the participant is agreeable. If not, we’ll follow-up via phone calls and/or medical record 
review, as allowed by the participant.   
9 
STATISTICAL CONSIDERATIONS  
9.1 General Design Issues  
The primary outcome will be a global cognitive function composite score. To calculate 
the composite score, each raw test score will be standardized based on the mean/standard 
deviation from all participants at baseline. Then, the resulting z-scores will be averaged 
across tests.  Secondary outcomes will include change in Alzheimer’s risk factors, 
components of the cognitive composite score, and measures of physical performance, 
functional ability, and quality of life. Changes made to the protocol due to Covid-19, i.e., 
switching to telephone data collection, may limit our ability to examine cognitive change 
effectively, as several of the most important cognitive tests cannot be administered via 
telephone. Additionally, the onset of Covid-19 may affect the ability of participants to 
achieve risk factor reduction. In an exploratory outcome we will examine the effect of the 
Covid-19 pandemic on risk factors. Our hypotheses include the following: 
1. We hypothesize that composite cognitive function scores among participants 
randomized to the SMARRT intervention arm will show better scores, relative to 
those in the HE control arm.  We also hypothesize that the component scores will 
be improved by the intervention. 

SMARRT Protocol, Version 1.16 
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2. We hypothesize that participants in the SMARRT intervention will show 
improvements on Alzheimer’s risk factors during the intervention, relative to 
those in the HE control arm. 
3. We hypothesize that additional outcomes including components of the global 
cognitive function composite, physical performance, functional ability, and 
quality of life will be improved by the intervention. We also hypothesize that 
incidence of MCI and Alzheimer’s will be lower among participants in the 
SMARRT arm. 
 
9.2 Sample Size and Randomization 
Because this is a pilot trial, our goal is to estimate effect sizes for a larger trial. Therefore, 
sample size estimates are based primarily on considerations of precision rather than 
power and effect size. For our primary outcome, our sample size of 200 will enable us to 
estimate the effect size with a precision of +/- 0.08 SDs, assuming loss to follow-up of 
10%, and ICC of 0.6, based on data from the FINGER trial (4). This estimate will be used 
in combination with a consensus clinically meaningful effect, based on the literature and 
investigator expertise. For secondary outcomes, we estimate that precision will range 
from +/- 0.06 SDs to +/- 0.08 SDs, depending on the ICC. We anticipate that conversion 
to MCI/AD in this two-year trial will be low (<10%); therefore, this outcome is 
considered exploratory.   
9.2.1 Treatment Assignment Procedures 
Randomization will be implemented using randomly permuted blocks of size two, 
stratified on clinic, age (70-79 vs. 80-89), and race/ethnicity (white vs. non-white), 
This will maximize blinding of outcome assessors and achieve balanced groups that 
accurately reflect the underlying composition of the study population, as a primary 
aim of the study is to lay the groundwork for future large, multisite trials in integrated 
healthcare systems in the US.  The randomization sequences will be generated in 
advance by the study statistician, securely stored electronically, and accessible only to 
intervention staff.  
 
Research staff who enroll study participants and collect outcome data will be unaware 
of the randomization sequence and will be blinded to group assignment. Staff will be 
instructed not to seek information about study group. Outcome assessors will be 
blinded to group assignments. The content of interviewer scripts will be designed to 
deliberately reduce the chance of disclosure, using procedures and language that Dr. 
Rosenberg used in an R21 pilot RCT with blinded assessors. Assessors will document 
if they become unblinded; a different blinded assessor will perform any further 
follow-up assessments. Data analysts will also be blinded as to group assignment by 
using codes for randomization groups. 
 
If unblinding occurs, the following will be recorded: 
o The ID of the unblinded participant 
o The reason for unblinding 
o The study staff person responsible for unblinding 

SMARRT Protocol, Version 1.16 
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o A list of person(s) who have been unblinded 
o Future assessments will be performed by team members who remain blinded.  
9.3 Interim analyses and Stopping Rules 
Because this is a pilot study, no interim analyses are planned. The DSMB may request that 
an interim analysis be performed if there are concerns about participant safety. The interim 
analysis results will be reviewed in closed session and may be presented in blinded or 
unblinded format at the DSMB’s request. If interim analyses are requested, criteria for 
stopping the study will be clearly defined in advance by DSMB.  
9.4 Data Analyses 
We will first assess balance on baseline characteristics of the SMARRT and HE groups 
using graphical and tabular checks for overlap, and statistical comparisons using t-tests, 
Wilcoxon, chi-square, and Fisher’s exact tests as appropriate. All analyses will use intent-
to-treat principles.  
 
Aim 1. To estimate the effect of SMARRT compared to HE on our outcome, repeated 
measures of the composite cognitive function score obtained at 6, 12, and 24 months, we 
will use a linear mixed model (LMM), with fixed effects for the baseline score, time, 
treatment, and the time-by-treatment interaction, as well as random intercepts and slopes. 
Exploratory analyses will be performed within the intervention group to determine 
whether there is evidence that the magnitude of the effect varies based on the number or 
types of risk factors targeted, the extent to which goals are achieved, or the number or 
type of interventionist contacts. These analyses will be restricted to the intervention 
group because among controls, the number and type of risk factors targeted will not be 
assessed, achievement of goals will be undefined, and the number and type of contacts 
will differ systematically by design. Hence these results will be descriptive and will not 
estimate effect modification, mediation or dose-response, respectively. We also will use 
multiple imputation to explore the impact of missing data.  
 
Aim 2. Similar methods will be used to assess the effect of the intervention on continuous 
Alzheimer’s risk factors over two years. Because this is a pilot study, we chose not to 
pre-specify the benchmarks for change/improvement for each risk factor. Instead, we will 
quantify the amount of change achieved for each risk factor.  Generalized linear mixed 
models (GLMMs), also with fixed effects for the baseline value, time, treatment, and the 
time-by-treatment interaction, and random intercepts and slopes, will be used as 
appropriate to assess treatment effects on binary, count, ordinal, and multinomial risk 
factors, including the number of risk factors. 
 
Aim 3. LMMs and GLMMs also will be used to compare the impact of SMARRT vs. HE 
on individual components of the global cognitive score, physical performance, functional 
ability, quality of life. Finally, Cox proportional hazards models will be used to analyze 
intervention effects on time to MCI and Alzheimer’s. 
 
Based on data from prior Alzheimer’s risk reduction trials, differences in intervention 
effect by gender or by race/ethnicity are not expected. Because the study was not 

SMARRT Protocol, Version 1.16 
24 
designed to examine potential differences in intervention effect between gender and 
racial/ethnic subgroups, the recruitment of women and minorities for the proposed project 
is expected to reflect the underlying composition of the aged 70+ population enrolled in 
the KPWHRI health network. As a result, we expect that our study population will not 
include gender and racial/ethnic subgroups large enough for comparisons of the 
intervention effect to have high statistical power for detecting clinically meaningful 
differences. 
10 
DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms 
Outcome assessments will be performed by trained Research Specialists who will be 
blinded to group assignments; if an assessor becomes unblinded, a different assessor will 
perform any further follow-up assessments. Assessors will receive periodic observations 
to ensure fidelity and completeness. Most measures during the outcome assessments will 
be collected using paper forms. The data from these forms will be entered by the 
assessors into a secure, web-based system overseen by UCSF. Questionnaires will be 
administered with the participants answering directly via a tablet computer. The 
participants’ responses will be automatically scored and entered into the web-based 
database.  Telephone assessment forms will be completed via direct entry into the secure 
web-based UCSF database, or onto fillable pdf forms stored separately from PHI on the 
KPWHRI secure file transfer site. 
 
All study forms are described in detail in the Manual of Procedures (MOP). 
10.2 Data Management  
Data will be collected and stored separately for enrollment and intervention activities and 
outcomes activities (secure, web-based data entry system overseen by UCSF; no PHI). 
All data will be collected by KPWHRI staff in KPWA facilities. The following is a list of 
study data management responsibilities which will be undertaken by the clinical site 
(KPWHRI) to ensure protection of participant privacy: 
 
Electronic files and paper forms – Identifiable data (PHI or PII) will be stored in a 
separate file from study data, all in a secure location. Computers are password-protected 
and filing cabinets are kept locked.  
 
Computer security – Computers are password-protected with multiple levels of 
permissions and systems knowledge required to access study data. Users receive security 
training, including annual compliance trainings. The system is routinely backed up in an 
off-site server to prevent loss of data. 
 
Data listings and distribution – No PHI or PII will be included in any published data 
listing. It will not be distributed without proper institutional agreements and IRB 
approval in place. 
 

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25 
Access and storage – Participant records will not be accessible to persons outside of 
KPWHRI and UCSF without the express written consent of the participant. KPWHRI 
offices are locked at all times to protect computer records and paper files locked in filing 
cabinets. Guests must be escorted. Precautions will be maintained during and after the 
study period for as long as the records are retained. 
 
Data disposal – After the appropriate retention period passes, study files will be disposed 
of in an appropriate manner. Computer files will be deleted. Paper files will be placed in 
a locked confidential shred bin. 
 
KPWHRI (Clinical Site) study staff control the data entry into UCSF’s secure web-based 
data entry site, called REDCap. UCSF (Coordinating Center) controls the return of data 
via KPWHRI’s Secure File Transfer site.   
 
The Coordinating Center (UCSF) will receive a limited dataset (outcomes data, including 
cognitive testing and risk factor data) labeled by study ID; no PHI will be entered. This 
data will be stored in UCSF’s secure web-based data entry system, REDCap. Outcomes 
data from REDCap will be transmitted back via KPWHRI’s Secure File Transfer. 
Additionally, UCSF will receive audio recordings of selected cognitive testing batteries 
for the study neuropsychologist to monitor. These recordings, although coded, are 
considered PHI.  
 
10.3 Quality Assurance  
 
10.3.1 
Training 
All study staff will be trained by the same lead person in the same manner. Dr. Kaup 
will train KPWHRI staff in administering neuropsychological tests. Dr. Rosenberg 
will train staff in ActiGraph initialization and download, as well as conducting the 
anthropometric and physical function portions of the measurement visits. Drs. 
Rosenberg, Adams, Ludman, and Balderson will train the interventionists. Each lead 
will also monitor performance and provide feedback to ensure consistency. 
 
Interventionists will have master’s degrees in relevant health-related areas (e.g. public 
health, social work) and will be trained by two licensed clinical psychologists to 
deliver motivational interviewing, problem solving treatment, and general health 
coaching for all health behaviors. They will be trained using didactic techniques, role-
play, and direct observation of at least two initial sessions and two follow-up sessions 
with corrective feedback. The Project Coordinator or Co-Investigators will observe 
new staff members during mock sessions as well as their first three interactions with 
research participants (e.g., screening/consent/baseline visits for enrollment and 
outcomes).  
 
All interviewers, nurses, and other study staff will be trained to identify potentially 
adverse events. These would include subject, family member, or physician 
complaints; threats to withdraw or actual withdrawals from the study; and responses 
to questionnaire items indicating risk of serious consequences. 
 

SMARRT Protocol, Version 1.16 
26 
10.3.2 Metrics 
Data for a random sample of 10% of study participants will be double-entered to 
determine the extent of data entry error and adjust if indicated. 
 
10.3.3 Protocol Deviations 
Any deviations in study protocol will be documented and reported in accordance with 
Kaiser Permanente Washington’s IRB requirements.  
 
10.3.4 Monitoring 
The programmer and project manager, supervised by the PIs, will enact and monitor 
data quality control checks. Data quality control checks will be included to identify 
potential data anomalies such as:  
 Missing data or forms  
 Out-of-range or erroneous data 
 Inconsistent and illogical dates over time  
 Data inconsistency across forms and visits 
 Not completing all fields of a "completed form" or no reason for missing data is 
provided  
 
The data entry forms will include logic and range checks to minimize the possibility 
of missing or invalid entries. Electronic data entry forms will mirror paper case report 
forms. Calculations will be automated whenever possible. Audio will be recorded 
during the cognitive testing battery. The first few sessions and a random selection of 
other visits will be monitored for accuracy and consistency by the study 
neuropsychologist.   
 
Prior to the end of each measurement visit, assessors will review their own forms and 
the participants’ self-report surveys for any incomplete or illegible sections. This will 
allow clarification before the session ends. If incomplete or illegible sections are 
discovered later, those variables will be data entered as missing. 
11 
PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review 
This protocol and the informed consent document (Appendix I) and any subsequent 
modifications will be reviewed and approved by the IRB.   
11.2 Informed Consent Forms 
A signed consent form will be obtained from each participant. The consent form will 
describe the purpose of the study, the procedures to be followed, and the risks and benefits 
of participation. A copy will be given to each participant.  
11.3 Participant Confidentiality  
All KPWHRI employees, including full- and part-time employees of the Survey Research 

SMARRT Protocol, Version 1.16 
27 
Program, sign agreements to maintain confidentiality of data and research information. As 
a condition of employment, all members of the KPWHRI workforce must complete 
training in Health Insurance Portability and Accountability Act (HIPAA) requirements. All 
forms and study procedures are reviewed by KPWA’s IRB for compliance with HIPAA 
and human subjects protections. Any data that will be accessed or disclosed outside KPWA 
will meet HIPAA requirements, through the use of business associate agreements, data use 
agreements, de-identification, and/or accounting of disclosures, as applicable. 
 
All KPWHRI computers require passwords to access the network and the electronic mail 
system. Access to the Institute’s data warehouse also requires special authorization.  
 
KPWHRI policies and procedures ensure controlled access to computers and physical 
space for secure storage of data and confidentiality information. Access to KPWHRI’s 
work areas is restricted by locked doors. Entry requires either a key card or a punch code 
that changes on a regular basis. Key cards or keys are required to enter the building, 
elevator, and KPWHRI floors during off-hours. Visitors must check in with designated 
staff to gain entry. A roster of persons authorized to enter the area is maintained by 
administrative personnel. KPWHRI requires employees to wear employee badges at all 
times and unfamiliar persons are required to state their purpose. 
 
Study documents will be retained for the longest applicable period. Signed consent forms 
that include HIPAA authorizations will be retained six years from the date of creation or 
the date last in effect, whichever is later. Identifiable study data will be retained for 10 
years after the study’s end date. Other study forms will be retained for three years after the 
study’s end date. 
11.4 Study Discontinuation  
The study may be discontinued at any time by the IRB, the NIA, the OHRP, or other 
government agencies as part of their duties to ensure that research participants are 
protected.  
12 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by the policies and procedures of 
UCSF, KPWA, and NIA.   
13 REFERENCES 
1.   
Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimer's 
& Dementia: The Journal of the Alzheimer's Association. 2016;12(4):459-509. 
doi:10.1016/j.jalz.2016.03.001. 
2.   
Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer's 
disease prevalence. Lancet Neurol. 2011; 10(9):819-28. 

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28 
3.   
Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary 
prevention of Alzheimer's disease: an analysis of population-based data. Lancet Neurol. 
2014; 13(8):788-94. 
4.   
Ngandu T, Lehtisalo J, Solomon A, et. al. A 2 year multidomain intervention of 
diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent 
cognitive decline in atrisk elderly people (FINGER): a randomised controlled trial. Lancet. 
2015; 385(9984):2255-63. 
5.   
Larson EB, Yaffe K, Langa KM. New Insights into the Dementia Epidemic. New 
England Journal of Medicine. 2013; 369(24):2275-7.  
6.   
Harrison J, Minassian SL, Jenkins L, et. al. A neuropsychological test battery for 
use in Alzheimer disease clinical trials. Archives of neurology. 2007;64(9):1323-9. 
7.   
Harrison J, Rentz DM, McLaughlin T, et. al. Cognition in MCI and Alzheimer’s 
Disease: Baseline Data from a Longitudinal Study of the NTB. The Clinical 
neuropsychologist. 2014;28(2):252-68. 
14 
SUPPLEMENTS/APPENDICES 
I. 
Informed Consent Form/ HIPAA Authorization