Feasibility Trial Assessing Adherence and Response to a Ketogenic Dietary Intervention for Individuals at High Risk for Alzheimer's Disease
Phase: NA
Conditions: Adherence, Treatment, Retention, Cognitive Impairment, Mild
Sponsor: Florida State University

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PROTOCOL TITLE: Feasibility Trial Assessing Adherence and Response 
to a Ketogenic Dietary Intervention for Individuals at High Risk for 
Alzheimer’s Disease 
 
PRINCIPAL INVESTIGATOR: 
Julia Sheffler 
Behavioral Sciences and Social Medicine 
Center for Translational Behavioral Science 
850-644-4199 
Julia.sheffler@med.fsu.edu 
 
NCT: NCT04968041  
REVISION HISTORY 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent 
Change? 
1 
10/28/19 
Removal of fMRI Procedures 
Y 
2 
2/4/20 
Addition of follow-up assessment & clarify 
some procedures in Consent 
Y 
3 
3/27/20 
Adaptation of contingency plan in response to 
recent COVID-19 restrictions 
Y 
 
 
 
 
 
 
 
 
 
 
 

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1.0 
Study Summary 
 
Study Title 
Feasibility Trial Assessing Adherence and Response to a 
Ketogenic Dietary Intervention for Individuals at High Risk 
for Alzheimer’s Disease 
Study Design 
Intervention with pre- and post-assessments 
Primary Objective 
Assess ways to promote adherence & acceptability of 
ketogenic diet for individuals at high risk for Alzheimer’s 
Secondary 
Objective(s) 
Assess neuropsychological, health, and functional outcomes 
in response to a 6-week ketogenic diet.  
Research 
Intervention(s)  
6-week group diet intervention 
Study Population 
Older adults aged, 60-75 (approximately) 
Sample Size 
N=10 
Study Duration for 
individual 
participants 
6-week intervention, and a maximum of 2 pre-intervention 
assessment meetings, 2 follow-up intervention assessments, 
and 1-month follow-up assessment.  
Study Specific 
Abbreviations/ 
Definitions  
EEG = electroencephalogram; APOE = apolipoprotien E; 
MNCD = Mild Neurocognitive Disorder; AD = Alzheimer’s 
Disease 
 
 

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2.0 
Objectives* 
There is significant and growing evidence that adherence to a ketogenic diet may 
be an effective behavioral intervention for AD. While previous studies have 
identified the basic mechanisms and interactions of a ketogenic diet with ApoE and 
lipid and glucose metabolism, feasibility testing in diverse human samples remains in 
the earliest phases of translational science. The current project will translate these 
findings into a new behavioral intervention to prevent AD using the NIH ORBIT model 
for early phase translational behavioral studies.  This model includes Phase 1a: Define 
the Intervention, Phase 1b: Refine the Intervention, Phase 2a: Proof of Concept, and 
Phase 2b: Pilot Study.22 Phase 1a of this model (Defining the intervention) is underway.  
We have already recruited over 500 participants for the initial phase to identify a 
sample meeting our study criteria. Additionally, we have teamed with a community 
nurse practitioner to modify an existing ketogenic group intervention for application in 
research with older individuals. The current study builds on both the basic science 
and existing feasibility trials to implement an intervention that would take into 
account genetics, neurophysiological correlates, and other psychosocial factors in a 
diverse, high risk older adult population. Especially important to the current 
application is the inclusion of neurophysiological assessment to identify neural 
correlates and improve assessment of intervention effects.  
Measurement of Intervention effect and Identification of Neural Correlates 
The existing literature suggests a link between the ApoE genotype and risk for AD—
and further implicates a ketogenic diet in ameliorating this risk.  One of the primary 
goals of the current study is to extend this work to neural measures linked to both ApoE 
genotype and ad in a diverse population. To this end, the current proposal involves the 
use of neuropsychological testing, electroencephalogram (EEG) to assess 
neurophysiological risk for ad and potential changes in neural measures post-
intervention.  
Aim 1:  Refine. Use a team science approach to optimize and develop a protocol to 
promote adherence to a 6-week ketogenic diet intervention in high risk older 
adults. We expect that the use of a team science and patient-driven approach will 
enhance adherence (80%) and retention (100%) in the Proof of Concept stage. 
Aim 2: Proof of Concept.  Assess the feasibility, acceptability, and preliminary 
effects of implementing a ketogenic dietary intervention for older adults at high 
risk for AD.  Participants, aged 60-75 (N=50), will complete in-person 
neuropsychological assessments to assess for MNCD status, and saliva samples will be 
collected to assess for ApoE genotype. We will recruit 10 participants (5/10 ApoE €4+) 
who meet criteria for MNCD to complete a feasibility study assessing adherence to a 
ketogenic diet. Hypothesis 1: We expect that interdisciplinary collaboration and a 
patient-centered approach will increase acceptability to a ketogenic diet, as 
evidenced by an 80% dietary adherence rate. Hypothesis 2: We expect 
preliminary evidence that adherence to the ketogenic diet will improve cognitive 
performance on memory tasks, and the diet may have a greater impact on 
cognitive scores for ApoE €4+ participants.  
Aim 3: Examine the intervention effect on neural correlates of AD and ApoE €4. 
Participants selected for the intervention (N=10) will complete pre- and post-

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intervention EEG assessments to identify treatment effects. Hypothesis 1: Ketogenic 
Diet will reduce P300 latency and increase P300 amplitude Hypothesis 2: The 
impact of the ketogenic diet on P300 latency and amplitude will be larger among 
ApoE €4+ carriers.   
 
COVID-19 Update: Pre- intervention assessments have mostly been completed. Post-
intervention EEG assessments have been suspended; however, if COVID-19 restrictions 
are lifted in time, post-intervention EEG, vitals, and blood-draw assessments will be 
completed according to original protocol. For the 1 participant who did not complete the 
pre-assessments, we will collect cognitive data over the phone and will not include EEG 
data.  
Aim 4: We will examine whether variability in the p300 relates to cognitive 
measures, and if it better differentiates ApoE genotype and the impact of a 
ketogenic diet than cognitive measures. In conjunction with the in-person 
neuropsychological assessments and genotyping (n=50), we are proposing to add an 
EEG assessment at this phase to assess neural risk factors for ad. For this portion, we 
are interested in adding an additional 25 low-risk participants to the sample as a 
comparison group in order to identify and confirm neural correlates of MNCD and 
ApoE €4 status. Hypothesis 1: MNCD will have increased latency and reduced 
amplitude p300 relative to healthy controls. Hypothesis 2: among MNCD, ApoE 
€4 genotype will be associated with increased latency and reduced amplitude p300.  
 
COVID-19 Update: All phase 2 in-person and EEG assessments were completed prior to 
recent restrictions and are not subject to change. 
 
1.0 
 Background* 
 
AD is the sixth leading cause of death in the United States,1 and minority older 
adults are disproportionately affected by such neurocognitive disorders.2 For 
example, the Alzheimer’s Association3 reports that African Americans are twice as 
likely to develop AD, while Hispanic Americans are approximately one and a half times 
more likely compared to Caucasians. Existing research demonstrates that genetic risks 
such as the apolipoprotein E (ApoE) €4 allele may be a significant contributor to this 
discrepancy, due to higher rates in certain minority groups.4 In addition to increased 
genetic risk, minority individuals may also be more likely to experience sociocultural 
risk factors, such as reduced access and poorer quality of health care,5 lower quality of 
education,6 and increased chronic environmental and psychosocial stressors.7 Combined, 
the literature demonstrates that aging African Americans and other minority groups may 
be at the greatest risk for being diagnosed with a neurocognitive disorder, but have been 
disproportionately neglected in research.8 Despite this underrepresentation, basic 
science, as well as large epidemiological studies over the past several decades have 
illuminated a wide range of risk and resiliency factors for late-life cognitive decline for 
both minority and Caucasian populations.  
For example, it is well accepted that carriers of an ApoE €4 allele, compared to 
carriers of €2 and €3 alleles, are at the greatest risk for developing AD;9 yet, having 
an ApoE €4 allele is not sufficient to develop AD. The expression of this genetic risk is 

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influenced by a wide range of environmental risk factors, ranging from stressful life 
events to diet and exercise.10-11 A ketogenic diet, in particular, holds promise for 
addressing deficiencies linked to the ApoE €4 allele.9,12-13   
ApoE is involved in lipid metabolism, and the ApoE €4 allele is not as efficient as other 
variants; thus, researchers have indicated that genotype should be taken into account 
when applying a dietary intervention for AD.9 In addition to lipid metabolism, glucose 
metabolism may be another contributor to neurodegeneration due to decreasing 
metabolic efficiency with age.14 For example, researchers have demonstrated that a high-
glycemic diet (e.g., high sugar/carbohydrate) is associated with accumulation of amyloid 
plaques in cognitively normal adults.15 A diet high in healthy fats and low in 
carbohydrates (i.e., ketogenic) induces the creation of ketone bodies, which can be 
processed by the brain in place of glucose. Further, ketone supplements, specifically, 
appear to improve cognitive functioning, even when a normal diet is maintained.16-17 
The effect, however, is weakened in individuals with an ApoE €4 allele;17-18 ketone 
supplements do not account for the potential benefits of healthy fats and reduced 
carbohydrate intake on APOE functioning – an effect only diet change may produce. 
The ketogenic diet shows promise in addressing problems in lipid metabolism and 
may circumvent inefficient glucose metabolism, which indicates diet as a potent 
therapeutic intervention for cognitive functioning.10-11 The ketogenic diet has already 
proven a powerful therapeutic tool in pharmacoresistant epilepsy and is being studied for 
its effect on tumor growth in cancer.19 
Less attention has been given to the potential therapeutic effects of a ketogenic diet in 
individuals with mild neurocognitive disorder (MNCD) and AD. A small feasibility 
study demonstrated that the ketogenic diet can successfully improve cognitive scores in 
older adults with mild AD (N=10 completers) across a 3-month span, although all four 
patients with moderate AD dropped out before completing the trial.15 Additionally, 
ketone supplements to a normal diet have shown small, but positive effects in improving 
cognitive functioning scores in individuals with AD without an ApoE €4 allele.16 These 
findings demonstrate that ketosis is generally beneficial and such a trial is feasible; 
however, implementation may be challenging in patients who are already diagnosed 
with AD. Further, given the evidence of an interaction between ApoE and ketone 
bodies9,20,21, feasibility studies and future clinical trials should experimentally assess the 
cognitive effects and neural correlates associated with a ketogenic diet in humans.   
In sum, there is significant and growing evidence that adherence to a ketogenic diet 
may be an effective behavioral intervention for AD. While previous studies have 
identified the basic mechanisms and interactions of a ketogenic diet with ApoE and lipid 
and glucose metabolism, feasibility testing in diverse human samples remains in the 
earliest phases of translational science. The current project will translate these findings 
into a new behavioral intervention to prevent AD using the NIH ORBIT model for early 
phase translational behavioral studies.  This model includes Phase 1a: Define the 
Intervention, Phase 1b: Refine the Intervention, Phase 2a: Proof of Concept, and Phase 
2b: Pilot Study.22 Phase 1a of this model (Defining the intervention) is underway.  We 
have already recruited over 300 participants for the initial phase to identify a sample 
meeting our study criteria. Additionally, we have teamed with a community clinic to 
modify an existing ketogenic group intervention for application in research with older 
individuals. The current study builds on both the basic science and existing 

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feasibility trials to implement an intervention that would take into account genetics, 
neurophysiological correlates, and other psychosocial factors in a diverse, high risk 
older adult population. Especially important to the current application is the 
inclusion of neurophysiological assessment to identify neural correlates and 
improve assessment of intervention effects.  
Measurement of Intervention effect and Identification of Neural Correlates 
The existing literature suggests a link between the APOE genotype and risk for AD—
and further implicates a ketogenic diet in ameliorating this risk.  One of the primary 
goals of the current study is to extend this work to neural measures linked to both APOE 
genotype and AD in a diverse population. To this end, a key component of the current 
proposal involves the use of electroencephalogram (EEG) to assess neurophysiological 
risk for AD and potential changes in neural measures post-intervention. This is a 
significant addition insofar as neural measures derived from EEG are ideally suited to 
assess neurocognitive risk factors linked to APOE and MNCD – and are an appropriate 
target for assessing the impact of a ketogenic diet. Further, EEG assessments may not be 
prone to the biases inherent in many neuropsychological tests, making it ideal for 
assessing more diverse populations.  
In previous EEG studies, AD has been associated with reduced amplitude of the P300 
event-related brain potential23-24, as well as delayed latency of the P300.23-25  The P300 
is one of the most robust and commonly studied event-related brain potentials (ERPs). It 
is typically elicited in either auditory or visual oddball tasks, in which participants must 
count or respond to an infrequently presented ‘target’ stimulus and ignore a more 
frequently presented ‘standard’ stimulus.  The P300 is evident as a parietally-maximal 
positive deflection that peaks a few hundred milliseconds after stimulus onset.  A shorter 
latency of the P300 has been associated with faster decision-making and quicker 
information processing26, whereas a larger P300 amplitude has been associated with 
better cognitive abilities (i.e., attention, memory).  The P300 effects seen in AD reflect 
delayed information processing and reduced cognitive abilities – and appear irrespective 
of task modality.23  
Importantly, the ApoE genotype has also been associated with deficits in the P300:  
ApoE €4 carriers are characterized by reduced amplitude of the P300 event-related 
brain potential27-28, as well as delayed latency of the P300.28-30 Other studies have found 
that positive familial risk for AD is related to delayed latency of the P300.29,31 
Collectively, these data strongly suggest that abnormalities of the P300 may be a risk 
factor for AD, and may further mediate the association between ApoE €4 and AD risk.  
One primary aim of the current grant application is to replicate these associations in our 
sample—to demonstrate that the ApoE €4 genotype is associated with a reduced 
amplitude and delayed latency of the P300.  Our second aim is to collect pilot data to 
determine whether a ketogenic diet would ‘normalize’ P300 abnormalities – and if it 
would do so more among ApoE €4 gene carriers.  Our working hypothesis is that a 
reduced and prolonged P300 will be characteristic of ApoE €4, and that a ketogenic diet 
will normalize these deficits.  If confirmed, these data would provide mechanistic data 
that P300 abnormalities could be a novel target for a ketogenic diet intervention to 
reduce risk for AD.  
 

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2.0 
Study Endpoints* 
Proof of Concept.  Assess the feasibility, acceptability, and preliminary effects of 
implementing a ketogenic dietary intervention for older adults at high risk for AD.  
Hypothesis 1: We expect that interdisciplinary collaboration and a patient-centered 
approach will increase acceptability to a ketogenic diet, as evidenced by an 80% dietary 
adherence rate. Hypothesis 2: We expect preliminary evidence that adherence to the 
ketogenic diet will improve cognitive performance on memory tasks, and the diet may 
have a greater impact on cognitive scores (i.e., RBANS) for ApoE €4+ participants.  
Examine the intervention effect on neural correlates of AD and ApoE €4. Hypothesis 1: 
Ketogenic Diet will reduce P300 latency and increase P300 amplitude Hypothesis 2: 
The impact of the ketogenic diet on P300 latency and amplitude will be larger among 
ApoE €4+ carriers.   
We will examine whether variability in the p300 relates to cognitive measures, and if it 
better differentiates ApoE genotype and the impact of a ketogenic diet than cognitive 
measures. Hypothesis 1: MNCD will have increased latency and reduced amplitude p300 
relative to healthy controls. Hypothesis 2: among MNCD, ApoE €4 genotype will be 
associated with increased latency and reduced amplitude p300. 
3.0 Study Intervention 
As previously described, we are assessing the feasibility of implementing a 6-
week ketogenic dietary intervention. Our primary outcomes involve the 
assessment of adherence and acceptability of the diet, and our secondary 
outcomes involve assessing neuropsychological changes and neural correlates 
of ketosis.  
The dietary intervention will consist of weekly group meetings for 6-weeks, which will 
take place in the CTBScience conference room. Our consultant, Patrice Bullock, MSN, 
FNP-C, who specializes in functional medicine and the impact of diet on health, will 
lead the group meetings via video conference. The meetings will be co-led by the PI, 
Julia Sheffler, Ph.D., who will assist with collection of in-person assessments, 
distribution of group materials, and group facilitation. 
 
In the first week of the intervention, there will be 2 meetings. Prior to the first meeting, 
participants will provide a blood sample to assess their metabolic profile. The first 
meeting will be a 1.5 hour informational session to provide participants with materials 
(i.e., informational handouts, recipes, food logs, ketosis test strips). The second meeting 
of the first week will consist of a 1-hour video conference designed to answer 
remaining follow-up questions, assess issues that might arise early in the diet, and 
provide additional support. The remaining 5-weeks will consist of 1-hour, weekly 
group meetings in the CTBScience conference room. Participants will be asked to 
return their ketosis logs, and complete weekly assessments (i.e., Health profile screener, 
weight and vitals assessment, food and ketosis log, and self-evaluation of their 
adherence and obstacles to adherence). These 1-hour meetings will provide additional 
information about adhering to a ketogenic diet, identifying barriers and solutions to 
adherence, and providing group support and accountability. These meetings will 
provide time for participants to ask questions and to discuss any adverse reactions to 
the diet. These meetings will also provide the researchers an opportunity to complete 

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brief health assessments in order to identify any physical adverse reactions. These will 
be reported to the FNP-C to determine if additional assessments may be required. 
Adverse responses to the diet will be identified by the FNP-C and the consulting M.D., 
Dr. Paul Katz.  Participants will be compensated $50 each week for their time and for 
the purchase of any additional groceries required for dietary adherence. Thus, 
participants will be compensated $300 for their total time spent in the intervention.   
As described below in the Procedures section, there will be pre-assessment and 
post-assessment appointments around the intervention to provide additional data 
on neuropsychological and neurophysiological outcomes associated with the 
diet. Participants will be compensated an additional $75 for the pre-assessments 
(RBANS, EEG, & blood draw) and $75 for a post-assessment (RBANS, blood 
draw, and EEG), and $50 for completing the 1-month follow-up.  
 
COVID-19 Updates: The dietary intervention will consist of weekly group virtual 
meetings, which will take place via HIPAA-compliant Zoom. The meetings will be led 
by PI, Julia Sheffler, Ph.D. and a nurse practitioner who will still be mailing 
informational handouts and ketone test strips to the participants prior to the meetings, so 
participants may request clarification if needed. Blood sample collection, weight, and 
vital assessments are suspended in accordance with the recent restrictions. However, if 
these restrictions are lifted in time, we will proceed with these final blood sample, 
weight, and vital assessments in-person, but on an individual one-on-one basis. We may 
request that participants provide their most recent standard bloodwork from their primary 
care physician at the start of the intervention; however, this will remain optional. Weekly 
food logs and paper assessments will be mailed to the participants in addition to weekly 
compensation checks. If COVID-19 restrictions are not lifted prior to the end of the 
intervention, post-intervention neuropsychological assessments will be completed via 
telephone, while paper pre- and post-intervention assessments will be adapted into 
Qualtrics or telephone interviews.  
 
4.0 
Procedures Involved* 
Screening call: 
Participants who completed the previous phase of the study and indicated that 
they would like to be contacted for future studies will be first screened based on 
APOE e4 status. Participants who meet all eligibility criteria based on the 
survey, genetic testing, and neuropsychological testing (i.e., meet criteria for 
MNCD, 5/10 APOE e4+, 5/10 APOE e4-, no exclusionary health conditions or 
significant dietary restrictions based on nurse practitioner’s discretion, and 
interest in completing a dietary intervention). The call screening script is 
attached. 
Pre-intervention Assessments: 
All participants will complete two pre-intervention assessment appointments. 
These appointments will be scheduled within 2 weeks of the first intervention 
group meeting. This appointment will include: consenting, brief 
neuropsychological testing (The Repeatable Battery for the Assessment of 

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Neuropsychological Status - RBANS), and the emotion battery of NIH toolbox. 
The total meeting should last approximately 1 hour. These meetings will be 
completed by a clinical psychologist or a Ph.D. level clinical psychology 
graduate student.  
The second visit will involve completing an EEG, which will involve picture 
and audio memory tasks. Each appointment will last approximately 1-hour. 
Participants will be compensated $75 total for both appointments. 
COVID-19 Updates: If in-person restrictions are lifted by the end of the six-
week intervention, post-intervention EEG and follow-up assessments will be 
completed on an individual basis, while we continue to take necessary safety 
and hygiene precautions outlined in the original protocol. Neuropsychological 
assessments will be completed via telephone using a battery of pre-standardized 
assessments. Otherwise, the EEG post-intervention assessments will not be 
completed, and all assessments will be completed via HIPAA-compliant Zoom 
or telephone. 
Given that all participants have already enrolled in the trial, we will also 
complete individuals calls to these participants to explain the changes in the 
protocol and to obtain verbal consent to continue in the study. We will test each 
participants capability to use the video conferencing software prior to the first 
group meeting.  
Intervention: 
Week 1: Participants will be asked to come to the center approximately 1 hour 
prior to the group meeting to complete pre-intervention health assessments. 
These assessments will include a blood draw for comprehensive metabolic 
profiles (completed by a certified phlebotomist), a weight and body composition 
assessment, basic vitals (blood pressure and heart rate), and a health profile 
screener (see attached). Participants will also be given a food diary and ketone 
test strips for recording level of ketosis and net carbohydrate intake throughout 
the intervention trial. Of note, weight, vitals, and the health profile screener 
will be administered at each weekly meeting to monitor participant well-
being.  
The first group meeting will consist of a 1.5 hour informational session to 
provide participants with materials and to introduce them to the diet and diet 
plan in detail. The meetings will be led by a certified Nurse Practitioner via 
video conference. The PI, Julia Sheffler, will be present in-person as well to 
help facilitate the group. Participants will be given an opportunity to ask 
questions and complete and to provide feedback about the session. Participants 
will be encouraged to track their diet until the next session, and to slowly begin 
reducing their carbohydrate intake. Participants will be compensated $50 for 
their time and to purchase any additional groceries. 
A second group meeting will be scheduled later in the same week in order to 
give participants an opportunity to attempt reducing carbohydrate and increase 
healthy fat intake across multiple days. This meeting will be offered to provide 

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additional assistance and for participants to ask questions or voice concerns 
after attempting the diet on their own. This meeting will be semi-structured, 
with the goal of providing support.  
Week 2-4: After the first week, the following meetings will consist of 1-hour 
weekly group meetings. These will be designed to answer questions, provide 
additional dietary information, and to provide general support for increasing 
adherence. In week 4, participants will be reminded of the upcoming post-
assessments and will begin scheduling appointments. Participants will be 
reminded that they should be in ketosis when completing the post-intervention 
assessments. Each week, participants will be compensated $50, and will be 
asked to record ketone level on a daily basis.  
Week 5-6: The group meetings will continue as usual in the final weeks; 
however, during this time, participants will be scheduled to complete post-
intervention neuropsychological testing. Testing will be completed during the 
active intervention in order to assess individuals who are actively in ketosis. In 
the final session, participants will be asked to come early or stay late to 
complete a follow-up blood draw (by a certified phlebotomist). The final 
session will conclude with qualitative feedback about the intervention program 
in order to inform future studies.  
Follow-up intervention Assessments: All participants actively engaged in the 
intervention by week 4 will complete 2 follow-up appointments during the final 
2 weeks of the intervention. The first visit will repeat the brief 
neuropsychological test (RBANS) and the NIH toolbox. The second visit will 
involve completing a follow-up EEG, which will involve picture and audio 
memory tasks. Each appointment will last approximately 1-hour. Participants 
will be compensated $75 total for both appointments.  
1-Month Follow-up Assessment: All participants will be contacted 1 month 
after completing the final group meeting to repeat the brief neuropsychological 
test (RBANS) and the NIH toolbox, as well as to respond to brief semi-
structured questions about their experiences since ending the intervention. 
Participants will be compensated $50 for completing this appointment. 
COVID-19 Updates: If COVID-19 restrictions are not lifted, the dietary 
intervention will consist of virtual group meetings, which will take place via 
HIPAA-compliant Zoom. The meetings will be led by PI, Julia Sheffler, Ph.D. 
and a registered nurse practitioner, who will mail informational handouts and 
ketone test strips to the participants prior to beginning the intervention. Online 
assessments will be sent using email prior to each meeting, so participants may 
request clarification if needed. Blood sample collection, weight, and vital 
assessments are suspended in accordance with the recent restrictions; however, 
if these restrictions are lifted, we may proceed with these assessments in-person 
on an individual, one-one-one basis, with additional safety precautions and 
sanitation taken. We will request that participants provide their most recent 
standard bloodwork from their primary care physician; however, this will 
remain optional. 

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Week 1: Prior to the first meeting, participants will be mailed the ketone test 
strips, informational handouts and food diaries to monitor carbohydrate intake 
over the course of the intervention. They will complete a 1.5-hour virtual group 
meeting, which will act as the initial informational session. A second meeting 
will be scheduled with participants within this first 7-day period to give 
participants the opportunity to begin reducing carbohydrate intake and to ask 
follow-up questions. This meeting will retain the original goals of providing 
support and giving the participant the opportunity to ask questions after 
attempting the diet on their own. 
Week 2-4: After the first week, subsequent meetings will be 1-hour long and 
will retain the original goals of providing support and answering dietary 
questions. Participants will still be asked to record ketone levels on a daily 
basis. 
Week 5-6: These final one-on-one HIPAA-compliant Zoom meetings will 
collect qualitative feedback as previously mentioned and will omit the blood-
drawings. 
The follow-up intervention assessments and 1-month follow ups will continue 
as planned, but will continue with online and telephone-based assessments 
rather than in-person. 
If COVID-19 restrictions are lifted prior to the end of the program, post- and 
follow-up intervention assessments and 1-month follow ups will be conducted 
as individual, one-on-one in-person assessments. 
5.0 
Data and Specimen Banking* 
Blood samples will be collected in a phlebotomy lab at the Center for 
Translational Behavioral Science. Samples will be labeled and identified only 
by an ID number. These samples will be used to assess comprehensive 
metabolic profiles (CMPs) of participants. Samples will be stored temporarily in 
the phlebotomy lab and then will be transported via medical transport cooler to 
the lab on FSU campus for analysis. If immediate analysis is not possible, 
samples will be stored in a –80 F freezer at the Translational Science Laboratory 
at the College of Medicine in a locked suite until analysis is possible. Once 
results of the CMPs are returned, these will be coded and stored with other 
participant data (described below).   
Specimens will not be released to participants or entities outside the study. If the 
Nurse Practitioner on the study identifies concerning findings in regards to the 
participants’ comprehensive metabolic profiles or other health data, she will 
notify the study team’s M.D. consultant for a clinical decision on 
recommendations. If necessary, participants will be notified that follow-up with 
a physician may be indicated, and they will be given the option to sign a release 
of information (see attached) to have this information shared with their 
physician for follow-up. Findings will be faxed directly to their physician. 
 

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6.0 
Sharing of Results with Subjects* 
Participants will not receive diagnostic feedback about their performance on the 
RBANS, NIH toolbox, or EEG results. If participants request information about 
their performance on the memory tasks, the researchers will provide general 
feedback about whether the participant performed the same, better, or worse at 
follow-up compared to baseline. Participants will be told that fluctuations in 
performance are normal and are not necessarily indicative of a problem.  
If the Nurse Practitioner identifies concerning findings in regards to the 
participants’ comprehensive metabolic profiles or other health data. Participants 
will be notified that follow-up with a physician may be indicated, and they will 
be given the option to sign a release of information (see attached) to have this 
information shared with their physician for follow-up. Findings will be faxed 
directly to their physician. 
7.0 
Study Timelines* 
 
Recruitment will not begin until Fall 2019. Participation in the full study participation 
in the full study will require a maximum of 15-weeks for participation from the first in-
person appointment to the last.  
 
8.0 
Subject Population* 
Participants will include individuals between the ages of 60 and 75 years; 
however, we will allow participants over the age of 75 if they completed the 
initial screening survey when they were 75. That is, some individuals may have 
had a birthday since initial screening, and we will still include these individuals 
if they meet other study criteria. The sample will be randomly selected from 
participants who complete a previous screening study who expressed interest in 
participating in a dietary intervention. Inclusion criteria for the intervention are: 
meet criteria for a MNCD, no self-reported dietary restrictions or health 
conditions/medications that might interact with a ketogenic diet, and interest in 
completing a dietary intervention to improve cognitive functioning. In addition 
to the total sample inclusion criteria, half the sample will also be selected based 
on their ApoE €4 status. We are specifically interested in targeting older adults 
who are at high risk for developing AD, but have not progressed to a 
diagnosable major neurocognitive disorder. 
We will not include any of the following as participants in the current study: 
• 
Adults unable to consent 
• 
Individuals who are not yet adults (infants, children, teenagers) 
• 
Pregnant women 
• 
Prisoners 
9.0 
Vulnerable Populations* 

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We will not include any participants who are unable to provide consent. Of 
note, a mild neurocognitive disorder is characterized by slight decline in 
cognitive functioning, which require compensatory strategies to retain 
independence. Individuals with MNCD are able to live and function 
independently and are able to provide consent to participate. The PI is a trained 
clinical psychology with a specialty in geropsychology and while rule out 
individuals who do not have capacity to consent via previous screening studies.  
10.0 Local Number of Subjects 
Our goal is to recruit 10 participants to complete the intervention, as this is a small 
feasibility study.  
 
11.0 Recruitment Methods 
Participants will be recruited from a previous screening study (IRB approved: 
STUDY00000213), where they provided consent to be contacted for future 
research studies. Participants will be called by one of the key personnel and will 
provide verbal consent to complete a brief screening (see attached script).  
Participants who qualify based on this telephone screener will be scheduled for 
the initial assessment appointment.  
Participants will be excluded from the study if they identify an unstable chronic 
medical condition, such as kidney/renal disease or failure, congestive heart 
failure, heart disease, heart rhythm irregularities, severe lipid dysfunction or 
deficiencies, unstable gallbladder disease, Chron’s disease, ulcerative colitis or 
other serious GI disorder, including history of ostomy, Type 1 and Type 2 
diabetes requiring insulin, chronic auto-immune disorders, active psychosis or 
serious unstable psychiatric conditions, or any other significant surgery or 
chronic health condition that may interfere with their ability to alter their diet, as 
determined by a certified nurse practitioner. Further, participants who report 
using the following medications will be excluded: insulin, diuretics, 
antipsychotics, MAOIs, narcotics, immunosuppressant medications, or others at 
the nurse practitioner’s discretion.  
12.0 Withdrawal of Subjects* 
Participants will be withdrawn from the study based on the investigator’s 
discretion. The consultant leading the intervention is a registered Nurse 
Practitioner who will assist in monitoring the participants’ vitals each week. 
Participants who experience significant adverse responses to the diet (as 
determined by a nurse practitioner or MD) will be withdrawn from the 
intervention. If a participant is withdrawn due to health, they will be provided 
partial compensation and provided the option of completing follow-up 
assessment appointments.   
13.0 Risks to Subjects* 
Intervention Risks: We are only recruiting healthy individuals with no unstable 
chronic medical conditions for this diet (e.g., gallbladder problems, Type 1 
diabetes). Thus, primary risks associated with changing diet may include, 

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Revised: December 1, 2018 
gastrointestinal upset (i.e., bloating, diarrhea, gas, and constipation), change in 
weight, headache, and fatigue. Participants will be closely monitored by a nurse 
practitioner on a weekly basis to assess any adverse response to the diet. If a 
significant adverse response is reported or identified, the team will consult the 
MD consultant on the team for a clinical decision.  
EEG Risks: There is a small possibility of mild skin irritation (redness) where 
the electrode contacts the skin. This is rare and usually temporary.  
14.0 Potential Benefits to Subjects* 
A goal of the current study is to assess whether a ketogenic diet may be 
beneficial for memory in older adults. Previous research has demonstrated that a 
low-carbohydrate diet has multiple benefits on cognitive functioning and other 
health factors in older individuals. Thus, participants will be provided with a 
supportive environment for making this diet change. Participants may 
experience improvements in their cognitive status and will be closely monitored 
by health professionals.  
15.0 Data Management* and Confidentiality 
In regards to the data analytic plan, we will complete descriptive analyses of the 
sample and correlational analyses of outcomes. Regression, ANOVA, and t-
tests may be used.  
Physical copies of tests and measures will be stored in locked cabinets in a 
secured suite in Research Building B at Innovation Park. Data from these 
physical copies will be coded and transferred to electronic spreadsheets, which 
will be password protected and stored in encrypted locations. All identifiable 
participant data will be stored separately in a password protected document. 
Data will be connected to an ID number rather than participant information.  
Data will be entered by a research assistant and checked by the PI for 
consistency.  
If data or specimens require transport from one study location to another (I.e., 
innovation park to college of medicine), these will be transported only by study 
key personnel directly from location to another.  
16.0 Provisions to Monitor the Data to Ensure the Safety of Subjects* 
Weight and basic vitals assessments and the health profile screener will be 
administered at each weekly meeting to monitor participant well-being. These 
will be reviewed by the Nurse Practitioner on the study at each weekly session. 
She will determine if additional follow-up or referral is warranted. If the Nurse 
Practitioner identifies a potential adverse response, she will notify the M.D. 
consultant for further review and a clinical decision on course of action. The 
IRB will be notified in the case of any adverse event.  
COVID-19 Updates: Although we may not be able to conduct the weight and 
basic vitals assessments if COVID-19 restrictions are not lifted by the end of the 
study, we will be asking participants to disclose any discomfort or adverse 

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experiences they might be having throughout the duration of the study. We will 
also ask participants to self-monitor weight and health information and to self-
report these each week through the online questionnaires. These will still be 
reviewed by the Nurse Practitioner following the original protocol. We will also 
introduce the option for participants to provide their most recent standard 
bloodwork from their primary care physician to attain some indication of their 
baseline health status. 
17.0 Provisions to Protect the Privacy Interests of Subjects 
Research records will be kept confidential to the extent allowed by law. Research 
records will be numerically coded to remove any identifying information. Only the 
researchers in this project and the research sponsor will have access to this data. 
Anonymized information derived from the research records may be used more broadly 
for publications and product development efforts, and as a result will not necessarily be 
kept confidential. The research team will not request to access existing patient records 
covered by HIPPA or other entities. All information collected during the study will be 
at the participants’ discretion.  
 
If a participant reports feeling discomfort at completing a task or item, they will be 
given the option to skip the item or task. Participants will be reminded that their 
participation is voluntary and there is no penalty for leaving the study.  
  
18.0 Compensation for Research-Related Injury 
Engaging in a monitored low-carbohydrate diet should pose no more risk to 
participants than encountered in daily life. Similarly, risks for the EEG portion 
of the study are minimal and clearly laid out in the consents and in other 
sections of this protocol. We state the following about compensation: 
“Medical Treatment: FSU, its agents, or its employees do not routinely 
compensate for or provide free care for human subjects in the event that any 
injury results from participation in a research project. If you become ill or 
injured as a direct result of participating in this study, contact your regular 
medical provider. If you have insurance, your insurance company may or may 
not pay for these costs. If you do not have insurance, or if your insurance 
company refuses to pay, you will be billed. Funds to compensate for pain, 
expenses, lost wages and other damages caused by injury are not routinely 
available.” 
 
19.0 Economic Burden to Subjects 
Participants will be required to supply their own transportation to and from 
appointments. No other economic burden to participants is expected. 
 
20.0 Consent Process 
We will follow the “SOP: Written Documentation of Consent (HRP-091).” 
Participants will receive a separate consent form for the intervention portion of 

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Revised: December 1, 2018 
the study. This consent is attached. The consent process will take place in a 
research office at the Center for Translational Behavioral Science and will be 
completed by the PI or a trained research assistant.  
Participants are being selected for the current study based on results of 
neuropsychological testing from a previous, related study. Thus, the cognitive 
status of participants as cognitively capable of providing consent will be 
determined by a clinical psychologist (the study PI). If there is concern during 
the study that a participant no longer has capacity to provide consent to 
participate, a brief cognitive assessment will be completed (I.e., the Montreal 
Cognitive Assessment & judgment questions) to assess whether their cognitive 
status has precipitously declined. If a participant is identified as no longer 
having capacity to participate, they will be removed from the study and 
provided with community referrals.   
 
COVID-19 Updates: Participants will be re-consented and provided with 
updated information regarding study procedures as they adjust to follow recent 
restrictions. They will be given the option to reconsider their participation given 
these changes now, as well as throughout the study’s completion. However, 
participants will be made aware that if COVID-19 restrictions are lifted before 
the end of the study, they will be asked to come in for in-person follow-up 
assessments. The study team will take the greatest care to ensure the safety of 
our participants. Even if restrictions are lifted, we will continue to screen all 
researchers who may have contact with participants, we will limit any 
physical contact with participants unless we obtain PPE, and we will take 
additional safety and cleaning measures for all surfaces and participant 
areas.  
 
21.0 Process to Document Consent in Writing 
We will follow the “SOP: Written Documentation of Consent (HRP-091).” 
Participants will receive a separate consent form for the intervention portion of 
the study. This consent is attached. 
 
22.0 Setting 
Participants will be recruited from a previous study via phone contact. Only 
participants who expressed interest in being contacted will be recruited. 
The majority of participant interactions will occur at the Center for 
Translational Behavioral Science at Innovation Park Campus.  
COVID-19 Updates: If Covid-19 restrictions are not lifted before the end of the 
intervention, all participant interactions will occur via telephone and HIPAA-
compliant Zoom to maintain social distancing practices. 
 

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23.0 Resources Available 
We are proposing to recruit a total of 10 participants, with at least 5 being 
APOE 4+. Participants will be selected from eligible participants from a 
previous, related study who express interest in completing the dietary 
intervention. As part of an initial screening/recruitment study, we have surveyed 
over 500 participants. The next screening study will recruit a subsample of these 
individuals for neuropsychological testing and APOE sequencing. The current 
study will further select from this subsample. 
The current PI will devote up to %50 time to conducting the current research 
study. The Center for Translational Behavioral Science is currently being 
equipped with a phlebotomy room, which will be used for health assessments 
and blood draws. We will also have a conference room equipped with video 
conferencing to complete the intervention. Participant rooms in the center will 
be used for completing assessments in a quiet environment. Our center will be 
sharing a space with Dr. Greg Hajcak’s EEG lab, where the follow-up EEGs 
will occur.  
Our team consists of multiple clinical psychologists, a nurse practitioner, 
Geriatrician M.D., geneticist, research methodologist, and a Ph.D. level 
registered dietician. These study personnel will be available for consultation in 
the case of any adverse event. 
Our team has met multiple times to develop the current grant and after award to 
plan the project. A copy of this protocol will be shared with all key personnel.