Stimulating Neural Activity to Improve Blood Flow and Reduce Amyloid: Path to Clinical Trials
Phase: NA
Conditions: Alzheimer Disease
Sponsor: Emory University

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
1
 
FLICKER: Stimulating neural activity to improve blood flow and reduce 
amyloid: Path to clinical trials 
 
NCT number: NCT03543878 
 
Protocol date: November 4, 2019 
 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
2
FLICKER: Stimulating neural activity to improve blood flow and reduce 
amyloid: Path to clinical trials 
 
Investigators:
 
James J. Lah, MD, PhD 
Department of Neurology 
Emory University School 
of Medicine 
 
 
Co-Investigators: Annabelle Singer, PhD 
Assistant Professor 
Coulter Dept. of 
Biomedical Engineering 
Georgia Tech & Emory 
University 
 
 
Allan I. Levey, MD, PhD 
Department of Neurology 
Emory University School 
of Medicine 
 
 
 
Sponsors:  
Emory University 
With funding provided by 
Cognito Therapeutics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

)/,&.(53URWRFRO
3URWRFROY

'DWH129




%$&.*5281'$1'6,*1,),&$1&(
$O]KHLPHU¶V'LVHDVH$'LVDORRPLQJHSLGHPLFZLWKDQXUJHQWQHHGIRUQHZWKHUDSLHVWR
GHOD\RUSUHYHQWV\PSWRPRQVHWDQGSURJUHVVLRQ7KHUHLVJURZLQJDZDUHQHVVWKDWFOLQLFDO
WULDOVPXVWWDUJHWVWDJHDSSURSULDWHSDWKRSK\VLRORJLFDOPHFKDQLVPVWRHIIHFWLYHO\GHYHORS
GLVHDVHPRGLI\LQJ WUHDWPHQWV  $GYDQFHV LQ $' ELRPDUNHU UHVHDUFK KDYH GHPRQVWUDWHG
FKDQJHV LQDP\ORLG EUDLQ PHWDEROLVPDQGRWKHUSDWKRSK\VLRORJLHV SULRU WR WKH RQVHWRI
PHPRU\ORVVZLWKVRPHPDUNHUVSRVVLEO\FKDQJLQJRQHRUWZRGHFDGHVHDUOLHU7KHEUDLQ
UHJLRQUHVSRQVLEOHIRUVSDWLDOQDYLJDWLRQDQGPHPRULHVRIH[SHULHQFHWKHKLSSRFDPSXVLV
RQH RI WKH DUHDV ILUVW DIIHFWHG LQ $O]KHLPHU¶V GLVHDVH $' DQG RWKHU PHPRU\
GLVRUGHUV5HVHDUFKE\ $ 6LQJHU KDV VKRZQ KRZ FRRUGLQDWHG HOHFWULFDO DFWLYLW\ DFURVV
PDQ\ QHXURQV LQ WKH KLSSRFDPSXV UHSUHVHQWV PHPRULHV RI H[SHULHQFHVDQG WKLV
FRRUGLQDWHGDFWLYLW\IDLOVLQDQLPDOPRGHOVRI$'7KHZRUNDOVRVKRZHGWKDWVWLPXODWLQJ
QHXURQVWRSURGXFHDVSHFLILFFRPSRQHQWRIWKLVDFWLYLW\FDOOHGJDPPDRVFLOODWLRQVUHGXFHV
$'SDWKRORJ\7KHJRDORIWKLVSURSRVDOLVWRWUDQVODWHRXUGLVFRYHU\WKDWVWLPXODWLQJVSHFLILF
SDWWHUQVRIQHXUDODFWLYLW\LVQHXURSURWHFWLYHIURPURGHQWVWRKXPDQVXVLQJDQRQLQYDVLYH
DSSURDFK7KLVILUVWVWXG\ZLOOHVWDEOLVKWKHIHDVLELOLW\DQGWROHUDELOLW\RIXVLQJWKLVQRQLQYDVLYH
PHWKRGWRGULYHJDPPDLQKXPDQV7KLVUHVHDUFKLQFOXGHVSUHFOLQLFDOWHVWLQJWKDWZLOOEHXVHG
WRGHVLJQDQGMXVWLI\DPXOWLVLWHFOLQLFDOWULDOWRWHVWWKLVDSSURDFKDVDWUHDWPHQWIRU$'IRU
ZKLFKWKHUHDUHFXUUHQWO\QRHIIHFWLYHWKHUDSLHV
3UHFOLQLFDO VWXGLHV E\ $ 6LQJHU DQG FROODERUDWRUV UHFHQWO\ UHSRUWHG D SRZHUIXO QHZ
GLVFRYHU\LQ1DWXUHGULYLQJVSHFLILFSDWWHUQVRIQHXUDODFWLYLW\UHFUXLWVWKHEUDLQ¶VLPPXQH
V\VWHPDQGUHGXFHV$'SDWKRORJ\,Q$'PLFHGHILFLWVZHUHIRXQGLQ+]HOHFWULFDO
QHXUDODFWLYLW\WKDWKDVORQJEHHQOLQNHGWRPHPRU\DWWHQWLRQDQGSHUFHSWLRQFDOOHGJDPPD
RVFLOODWLRQV'HILFLWVLQJDPPDRVFLOODWLRQVRFFXUUHGLQSUHV\PSWRPDWLFPLFHVXJJHVWLQJWKDW
WKH\ PD\ FRQWULEXWH WR HDUO\ GLVHDVH SURJUHVVLRQ 6XUSULVLQJO\ VWLPXODWLQJ QHXURQV WR
SURGXFH JDPPD RVFLOODWLRQV ³GULYH JDPPD´ PRELOL]HG WKH LPPXQH V\VWHP WR UHPRYH
DP\ORLG EHWD D SURWHLQ ZKRVH
DJJUHJDWLRQ LV WKRXJKW WR LQLWLDWH
QHXURWR[LF HYHQWV 6SHFLILFDOO\
GULYLQJ
JDPPD
UHFUXLWHG
WKH
SULPDU\LPPXQHFHOOVRIWKHEUDLQ
PLFURJOLDWRLQFUHDVHHQJXOIPHQW
RIEHWDDP\ORLGUHVXOWLQJLQ
UHGXFWLRQLQEHWDDP\ORLG)LJ

,Q WKH DQLPDO VWXGLHV LQYDVLYH
RSWRJHQHWLFVZKLFKUHTXLUHVYLUXVLQIHFWLRQDQGILEHULPSODQWVWRGULYHQHXUDODFWLYLW\ZLWK
OLJKWZHUHXVHGWRGULYHJDPPD
)LJXUH6WLPXODWLQJEUDLQFLUFXLWVWRSURGXFHJDPPDRVFLOODWLRQV
OHIWUHGXFHVDP\ORLGEHWDOHYHOVFHQWHUDQGUHFUXLWVPLFURJOLD
WRWDNHXSDP\ORLGULJKW

)/,&.(53URWRFRO
3URWRFROY

'DWH129




7RWUDQVODWHWKLVGLVFRYHU\WRKXPDQV$6LQJHUDQGFROOHDJXHVGHYHORSHGDPHWKRGWRGULYH
JDPPDQRQLQYDVLYHO\IOLFNHULQJOLJKWVDWJDPPDIUHTXHQF\OLNHDVWUREHOLJKWEXWIDVWHUWR
GULYHJDPPDRVFLOODWLRQVLQYLVXDOEUDLQDUHDV)LJ7KLVVLPSOHQRQLQYDVLYHPDQLSXODWLRQ
FDQEHDSSOLHGWRKXPDQVWRGHWHUPLQHLIWKLVDSSURDFKFDQEHXVHGWKHUDSHXWLFDOO\

%ORRGIORZWKURXJKWKHEUDLQLVFUXFLDOIRUQHXUDOIXQFWLRQDQGFOHDUDQFHRISDWKRJHQV
%ORRGIORZGHFUHDVHVYHU\HDUO\LQ$O]KHLPHU¶VGLVHDVHDQGWKLVGHFUHDVHLVWKRXJKWWROHDG
WRDP\ORLGEXLOGXSDQGIXQFWLRQDOGHILFLWV,QSUHOLPLQDU\VWXGLHVGULYLQJJDPPDOHDGVWR
GLODWLRQRIEORRGYHVVHOVHYHQDIWHUPDQLSXODWLRQRIDFWLYLW\FHDVHV2QHKRXUDIWHUJDPPD
OLJKWIOLFNHUHQGVWKHGLDPHWHURIVPDOOEORRGYHVVHOVLVLQFUHDVHGE\DQGSDWKRJHQLF
SURWHLQVDSSHDUFRORFDOL]HGZLWKWKHVHYHVVHOV)LJ
:HK\SRWKHVL]HWKDWWKLVGLODWLRQRIEORRGYHVVHOV
FRQWULEXWHV WR WKH GHFUHDVH LQ SDWKRJHQLF SURWHLQV
IROORZLQJJDPPDOLJKWIOLFNHUE\LQFUHDVLQJFOHDUDQFH
YLDWKHEORRGVWHDP$FFRUGLQJO\ZHZLOODVVHVVWKH
HIIHFWVRIGULYLQJJDPPDRQEORRGIORZWRUHYHDODQ
HQWLUHO\QHZHIIHFWRIVWLPXODWLQJJDPPDRVFLOODWLRQV
6WLPXODWLQJDFWLYLW\WRLQFUHDVHEORRGIORZPD\UHGXFH
SDWKRJHQLF
SURWHLQV
DQG
FRXOG
KDYH
EURDG
LPSOLFDWLRQVIRUEUDLQKHDOWK

&OLQLFDODQGSUHFOLQLFDOVWXGLHVKDYHGHPRQVWUDWHGWKDWJDPPDDFWLYLW\FDQEHLQFUHDVHGYLD
H[SRVXUHWRVHYHUDOGLIIHUHQWW\SHVRIVHQVRU\VWLPXOL5HFHQWSUHFOLQLFDOILQGLQJVSXEOLVKHG
LQ 1DWXUH KDYH GHPRQVWUDWHG WKDW WKLV LQFUHDVH LQ JDPPD DFWLYLW\ ERWK UHGXFHG WKH
SURGXFWLRQRIEHWDDP\ORLGSODTXHVDQGLQFUHDVHGWKHUDWHRIFOHDUDQFHLQWKHEUDLQVRIPLFH
3UHOLPLQDU\XQSXEOLVKHGGDWDXVLQJFRPELQHGDXGLRDQGYLVXDOVHQVRU\VWLPXODWLRQKDV
GHPRQVWUDWHGLPSURYHPHQWLQFRJQLWLYHEHKDYLRUDOWDVNVLQSUHFOLQLFDOPRXVHPRGHOVRI$'
IROORZLQJWKLVLQWHUYHQWLRQ1RQLQYDVLYHVHQVRU\VWLPXODWLRQSDUDGLJPVWKXVKROGWKHUDSHXWLF
SURPLVHIRUWKRVHLQGLYLGXDOVZLWKPLOGFRJQLWLYHLPSDLUPHQW$O]KHLPHU
VGLVHDVHRUUHODWHG
GLVRUGHUV

7KHVSHFLILFPRGDOLWLHVKDYHEHHQFKRVHQEHFDXVHWKH\KDYHEHHQZLGHO\XVHGLQSUHYLRXV
FOLQLFDOUHVHDUFKIRUDYDULHW\RIJRDOVLQFOXGLQJWKHFKDUDFWHUL]DWLRQDQGXQGHUVWDQGLQJRI
JDPPDEUDLQDFWLYLW\LQ\RXQJHUDQGROGHUDGXOWV)RUH[DPSOHWKHPRVWHIILFLHQWIRUPV
RIYLVXDOVWLPXODWLRQIRUJHQHUDWLQJJDPPDDFWLYLW\LQFOXGLQJSURSHUWLHVVXFKDVIUHTXHQF\
DQGLQWHQVLW\KDYHEHHQLGHQWLILHG)RUDXGLWRU\VWLPXODWLRQWKHWHVWUHWHVWUHOLDELOLW\RI
LWVHIIHFWRQJDPPDEUDLQZDYHDFWLYLW\LVKLJKDQGWKHJDPPDUHVSRQVHLQGXFHGE\DXGLWRU\
FOLFNWUDLQVWLPXOLDW+]KDVEHHQSURSRVHGDVDTXDQWLWDWLYHPHDVXUHRIKHDULQJORVV
LQ ROG DJH DQ LQGLFDWRU IRU QHXURGHYHORSPHQW FRQGLWLRQV VXFK DV VFKL]RSKUHQLDDQG
QHXURGHJHQHUDWLYHFRQGLWLRQVVXFKDV$O]KHLPHU¶VGLVHDVH
)LJXUH  *DPPD OLJKW IOLFNHU IRU  KRXU
LQFUHDVHV EORRG YHVVHO GLDPHWHU LQ YLVXDO
FRUWH[ DQG KLSSRFDPSXV UHODWLYH WR GDUN
FRQWUROV

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
5
 
The urgent and essential next step of this work is to translate these discoveries to humans 
in a clinical investigation. This pilot study in humans will focus on feasibility and safety. Our 
central hypothesis is that driving gamma via sensory flicker will be feasible and tolerable.  
Our secondary hypothesis is driving gamma alters the brain’s immune cells and amyloid beta 
processing. The primary outcomes will be feasibility and tolerability.  Exploratory measures 
will include amyloid and immune signals in the CSF and brain and alterations in cerebral 
blood flow, as seen through arterial spin-labeling (ASL) magnetic resonance imaging (MRI). 
 
2. SPECIFIC AIMS 
 
2.1Aim 1. Assess the safety, and tolerability of gamma flicker and subject compliance.  
We will determine in 10 subjects with a diagnosis of MCI whether flicker exposure for 1 hour 
every day is well tolerated and whether subjects comply with the study procedures.  In 
addition, we will closely monitor the safety of this procedure and document the occurrence 
of any adverse events. 
2.2Aim 2. Assess effects of driving gamma on blood flow in patients with MCI. Blood 
flow decreases very early in Alzheimer’s disease and this decrease is thought to lead to 
amyloid build up and functional deficits.14,15 We will determine if gamma flicker increases 
blood flow in Alzheimer’s patients. We will perform these tests in approximately 10 patients 
with mild cognitive impairment (MCI) in collaboration with Dr.’s Lah and Levey and the Emory 
BHC/ADRC. These pilot studies will support our application for an NIH grant to test gamma 
flicker in Alzheimer’s patients in a clinical trial.   
2.3 Aim 3. Assess effects of driving gamma on amyloid beta levels and inflammation 
markers in patients with MCI. We will assess amyloid beta levels in the brain (florbetapir 
PET), cerebral spinal fluid (Aß42 Luminex assay), the current gold standards in the field, and 
in the retina (Neurovision), a new approach currently being validated at the Emory Brain 
Health Center. We will also assess inflammatory markers in the cerebral spinal fluid (OLink 
inflammatory panel). We will perform these tests in 10 patients with mild cognitive impairment 
(MCI), as determined by clinical or research assessment using local standards at the Emory 
Brain Health Center (BHC)/ Alzheimer’s Disease Research Center (ADRC). 
 
 
3. PRELIMINARY DATA 
 
3.1 Current work in humans– Cognito Therapeutics has licensed the technology from MIT 
to transition this work to humans. The company will provide the flicker devices for 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
6
conducting the study here at Emory. The device is similar to sunglasses and is both 
comfortable and easy to use (Figure 3, redacted). 
 
 
Initial human studies of patients with cognitive impairments have demonstrated that 
sensory stimulation can be safely delivered and is well-tolerated. Three clinical studies 
have been sponsored by Cognito Therapeutics, which have been conducted under IRB 
approval (non-significant risk designation) and with good clinical practice (GCP) using a 
combination of non-invasive sensory stimulation systems in patients with cognitive 
impairments. These studies used three sensory stimulation modalities: visual, auditory, and 
tactile. For the visual and auditory stimulation, the Visual Flicker Unit (COG-VSU001) and 
Auditory Click Unit (COG-ASU001) were utilized, which have similar output light intensity, 
sound volume, repetition rate (40 cycles/second), and duty cycle to the Gamma Sense 
Stimulation System that will be used for this study. For the tactile stimulation, 
transcutaneous electrical nerve stimulation (TENS) was delivered to the palm of the hand 
using the Peripheral Nerve Stimulation Unit (COG-NSU001). Tactile stimulation is not 
included in the clinical investigation described by this protocol.  
 
redacted 
4. EXPERIMENTAL DESIGN AND METHODS 
4.1 Overview: For this 9-week study, 10 subjects with mild cognitive impairment (amnestic 
or multi-domain subtypes) will be randomly assigned to two study arms. Although all 
participants will receive Flicker exposure, half of the participants will receive the exposure 
(driving gamma) during the entire study period (8 weeks of Flicker) while the other half of 
the participants will receive Flicker exposure for half of the study period (2nd 4-
weeks).During the 9-week course of the study, participants will undergo venous blood 
draws and lumbar puncture for biomarker analyses at baseline, midpoint and at 9 weeks. At 
the study week 4 time point, the participants currently undergoing Flicker exposure will 
continue with their sessions while at week 4, those initially randomized to non-exposure will 
initiate Flicker exposure.  The primary goals are to measure safety and FLICKER tolerance 
while verifying the intended response. Secondary objectives include monitoring possible 
effects of Flicker exposure on clinical findings and biomarkers of AD progression, including 
CSF amyloid, tau, and phospho-tau, and volumetric MRI, as well as PET (florbetapir) and 
arterial spin labeling MRI and retinal amyloid changes. 
 
4.2 Sample Size and Power. This is a pilot study designed to assess feasibility and 
tolerability in the patient population. Although the sample size of 10 subjects will allow us to 
make certain claims about tolerability, we do not anticipate generating clinically meaningful, 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
7
broadly applicable results from this data. Thus, our sample size is driven by the need to 
collect pilot data that will position us to develop a clinical trial, if warranted, based on the 
technology described here. 
 
4.3 Flicker tolerance to date. For studies conducted to date by Cognito Therapeutics, a 
total of 17 participants have undergone daily periods of sensory stimulation for up to one 
hour (the study paradigm planned for this work). These subjects include young adults, older 
adults, and older adults with cognitive impairments. These studies have helped establish 
the feasibility of sensory stimulation with regards to safety, comfort, and tolerability of the 
exposure in patients with mild-to-moderate cognitive impairments. No device or exposure-
related adverse events have been reported during this study.  
 
4.4 Future research samples. Per participant consent, blood, cell lines and cerebrospinal 
fluid samples will be stored indefinitely and may be used for future investigation, potential 
development of new biomarkers, and potential treatments for Alzheimer’s disease. 
Samples may also be used to deal with future safety issues for Mild Cognitive Impairment 
or Alzheimer’s disease that are not presently known. These stored samples may also be 
used for genetic (DNA) research. 
5. RESEARCH STUDY PERSONNEL 
5.1 Principal Investigator (PI)for the study is James J. Lah, MD, PhD., Associate 
Professor, Department of Neurology.  The PI will delegate authority for all study 
procedures performed as noted on the Delegation of Authority log. 
 
5.2 Co-Investigators Annabelle Singer, Ph.D. Assistant Professor Coulter Dept. of 
Biomedical Engineering Georgia Tech & Emory University and Allan Levey, MD, PhD 
 
5.3 Research Coordinator Experienced research coordinator(s) will be utilized to 
coordinate the research study. 
 
5.4 Psychometrician Psychometric tools will be administered by research staff certified to 
conduct the specific tests utilized and who are blinded to adverse events/outcomes. 
 
5.5 Blinded clinical rater Clinical rating tools will be administered by research staff who 
are certified to conduct the instruments and who are blinded to adverse 
events/outcomes. 
 
5.6 Statistician. A statistician with expertise in data analysis for clinical studies of this type 
will be engaged to help with data analysis. 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
8
6. SAFETY MONITORING AND ADVERSE EVENT REPORTING 
6.1 Internal Safety Monitoring Subjects will be monitored remotely to determine whether 
they are performing the proper Flicker exposure at home. The study coordinator will call 1 
time during week 1 of the exposure phase to check on the participants. During the first 
week, the study coordinator will also visit the participant at home to observe the session. 
During weeks 2 – 4 of the study, the study coordinator will check-in with participants weekly 
by telephone.  Subjects in the Non-exposure/Flicker group will be monitored in the same 
manner throughout their 4 weeks of Flicker exposure. 
 
Internal monitoring will be performed by the Investigators who will review data from the 
study visits and review all aspects of patient safety.  Serious and unexpected adverse 
events and/or unanticipated problems involving risks to participants or others will be 
reviewed and reported to the Emory IRB, as per the Emory IRB policies and procedures, by 
the research coordinator in collaboration with the investigators. 
 
 
6.2 Emory University Investigational Review Board (IRB) policies and procedures will 
be employed:  
 
Unanticipated Problems involving Risks to Participants or Others (UPs): The PI will 
report to the IRB (using any IRB specified forms, as applicable) any UP in accordance with 
the timetable set forth in the provision below entitled Timetable for Reporting. The PI will 
advise the Emory IRB of: (a) the relationship between the problem and the intervention or 
study protocol; (b) whether or not a protocol change is necessary to reduce risk; and (c) 
whether the information about the problem affects the informed consent process.  
 
Serious Adverse Events: At the time of renewal for the study, the PI will report to the 
Emory IRB a summary of the serious adverse events related to the research that occurred 
in the previous approval period. If adverse events occur at a greater frequency, severity, or 
duration than was previously anticipated, those become unanticipated and are promptly 
reportable.  
 
Protocol Deviations: The PI will report to the Emory IRB any circumstances of which the 
PI becomes aware per which there has been a substantive deviation from the protocol that 
adversely affected at least one of the following: 1) the rights, welfare, or safety of subjects; 
2) the subjects’ willingness to continue participation; or 3) the integrity of the research data. 
Deviations that are reported as protocol modifications undertaken to eliminate apparent 
immediate hazards to Human Subjects do not need to be reported twice. The IRB will 
evaluate reported protocol deviations to determine any action to be taken or other reporting 
requirements that need to be fulfilled.  
 
Protocol Modifications: The PI will request approval of any changes (including, but not 
limited to, any changes in research personnel) that the PI plans to make to a Research 
protocol, which has already been approved by the Emory IRB. Except in cases in which the 
change must be made to eliminate apparent immediate hazards to Human Subjects, the 
Emory IRB must approve of the modification before it can be initiated.  

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
9
 
Non-Compliance: The PI shall notify the IRB of any circumstances of which the PI 
becomes aware of failure to follow Emory IRB Policies &Procedures, federal regulations, or 
other applicable laws. This report shall be made to the IRB as soon as possible after the 
non-compliance occurs. The IRB will work closely with the PI to develop a reasonable 
corrective and preventive action plan that can be implemented by the study team. 
7. PATIENT SELECTION 
7.1 Recruitment Plan. The Emory ADRC has a large clinical practice and clinical research 
registry of subjects interested in participating in research studies. As of December 2017, 
the ADRC registry has an enrollment of 447 participants, among them 110 with MCI. The 
MCI participants include 100 individuals with amnestic MCI (single or multiple domain). 
These ADRC participants have annual research evaluations that include detailed cognitive 
assessments, and all have consented to be contacted for opportunities to participate in 
research studies.  In addition to the existing pool of ADRC participants, the Emory memory 
disorders clinics, staffed by Drs. Levey, Lah, and other specialty-trained health 
professionals provide evaluation and treatment ~2000 patients annually, of whom ~500 are 
new visits (and ~100 MCI). Potential study subjects will be identified from those subjects 
being followed by the Emory Alzheimer's Disease Research Center and by the patients of 
the PIs. Other potential study subjects may be recruited if they contact the Emory ADRC 
specifically to find out about potential research studies that might be appropriate for either 
themselves or a family member. 
7.2 Inclusion Criteria 
1. Subjects must have a subjective memory concern as reported by subject, study 
partner or clinician. 
2. Meets local criteria for diagnosis of MCI.  Subjects with amnestic (single or multi-
domain) will be eligible, as both subtypes of aMCI are at high risk for progression to 
AD. 
3. Montreal Cognitive Assessment (MoCA)score >15.  Exceptions may be made for 
subjects with less than 8 years of education at the discretion of the PI. 
4. Clinical Dementia Rating = 0.5.  Memory Box score must be at least 0.5. 
5. General cognition and functional performance sufficiently preserved such that a 
diagnosis of AD cannot be made by the physician at the time of the screening visit. 
6. Stable on medications for 4 weeks prior to initiation of study sessions.   
7. Geriatric Depression Scale (GDS) ≤ than 6. 
8. Male or female outpatients aged 50-90 (inclusive). 
9. Able to hear without the use of hearing aids. 
10. Study partner who lives with the participant and can provide a reliable assessment of 
the participant’s level of function, is available for all clinic visits, and can serve as a 
supervisor/monitor for the home-based Flicker sessions for the duration of the study. 
11. Visual and auditory acuity adequate for neuropsychological testing. 
12. Good general health with no diseases expected to interfere with the study. 
13. Completed six grades of education or has a good work history (sufficient to exclude 
mental retardation). 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
10 
14. Able to communicate in English with study personnel. 
15. Able to understand the nature of the study and provision of written informed consent 
prior to conduct of any study procedures. 
16. Willing to undergo repeated MRIs and PET scans. No medical contraindications to 
MRI. 
17. Agrees to blood collection for APOE and biomarker testing. 
18. Agrees to lumbar puncture over the course of the study for the collection of 
CSF.CSF levels of Ab42, total Tau, and Tau phosphorylated at threonine 181 
consistent with underlying AD pathology according to established threshold values at 
Emory. 
7.3 Exclusion criteria 
1. Any significant neurologic disease other than MCI and suspected incipient AD, such 
as Parkinson’s disease, multi-infarct dementia, Huntington’s disease, normal 
pressure hydrocephalus, brain tumor, progressive supranuclear palsy, poorly 
controlled seizure disorder, subdural hematoma, multiple sclerosis, or history of 
significant head trauma followed by persistent neurologic deficits or known structural 
brain abnormalities. 
2. Screening/baseline MRI scan with evidence of infection, large vessel infarction or 
other focal structural lesions that could account for the memory deficits.  Subjects 
with multiple lacunes or lacunes in a critical memory structure are excluded.   
3. Contraindication to MRI due to pacemakers, aneurysm clips, artificial heart valves, 
ear implants, metal fragments or foreign objects in the eyes, skin or body, or 
excessive weight. 
4. Presence of clinically significant suicide risk based on the Investigator’s judgment 
informed by a structured clinician interview.  Any suicide attempt within the past 1 
year of the screening visit is exclusionary. 
5. Major depression, bipolar disorder as described in DSM-IV within the past 1 year, or 
history of schizophrenia (DSM-IV). Psychotic features, agitation or behavioral 
problems within the last 3 months which could lead to difficulty complying with the 
protocol. 
6. History of alcohol or substance abuse or dependence within the past 2 years (DSM-
IV criteria). 
7. Known history of epilepsy or migraines, which may be exacerbated by study 
intervention. 
8. History of narrow angle (acute angle) glaucoma. 
9. Current use of warfarin or other blood thinners (exclusionary for lumbar puncture).  
10. Inability to obtain initial CSF sample.  
11. Current use of Namenda (memantine). 
12. Current use of medications that lower seizure threshold, including Wellbutrin, 
Ciprofloxacin, Levofloxacin, Seroquel, Phenergan, and Sumatriptan. 
13. Current use of anti-psychotic medication. 
14. CSF profile inconsistent with underlying Alzheimer’s Disease pathology. 
15. Reasonable likelihood for non-compliance with the protocol or any other reason, in 
the opinion of the investigator, prohibits enrollment of subject into the study. 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
11 
16. Exceptions to these guidelines may be considered on a case-by-case basis at the 
discretion of the protocol director.  
7.4 Patient Numbering 
Patients who have signed the informed consent form to begin screening procedures will 
be assigned a Subject Identification Number at that time. The participant will keep the same 
number throughout the study (a separate randomization number will not be provided). 
7.5 Randomization 
To achieve balanced patient groups, subjects will be randomly assigned on a 1:1 basis in a 
blinded fashion to the 8-week Flicker exposure or the 4-week Flicker exposure, stratified 
based on gender, and age. 
8. STUDY ASSESSMENTS AND PROCEDURES 
The study design and assessment schedule are presented in Table 1.  
 
8.1 Informed Consent. The study will be discussed with the study subject and appropriate 
others (family, study partner) and if they are interested in learning more about the study 
they will be provided with a copy of the informed consent form to review in detail. The 
potential participant will be contacted at a later date to determine if they would like to be 
screened for possible study inclusion. If they are interested, a screening visit will be 
scheduled. Potential subjects are encouraged to discuss participation in this study with their 
family prior to screening for the study.  In addition, they are encouraged to contact the 
office with any questions or concerns.  
At the time of the screening visit, the consent form will be reviewed with the study subject 
and appropriate others, and all questions will be answered. Ample opportunity will be given 
for questions. If they are still interested in participating once all questions are answered to 
participant and study partner satisfaction, the consent is signed. 
This study includes subjects who must score between >15 on the MoCA (Montreal 
Cognitive Assessment) and will therefore be experiencing mild cognitive impairment as a 
result of suspected prodromal Alzheimer's disease. Individuals with mild impairment will 
likely be able to provide informed consent. Capacity for consent will be determined by the 
study subject’s ability to engage in a discussion regarding the study and their ability to 
understand what will be involved in study participation. The individual obtaining consent will 
review and discuss the research project and the consent document with the potential study 
participant and their family/study partner/legally authorized representative and will decide if 
they are able to understand the nature of the research, appreciate the experimental nature 
of the study, and understand the potential risks as well as alternatives to study 
participation. 
In the event that the subject is not competent to provide consent, assent is obtained.  A 
study subject’s legally authorized representative will be present during the initial consenting 
process. Signed consent will be obtained from all participants and their study partners. The 
same process described previously will be employed in obtaining legally authorized 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
12 
representative’s consent, when deemed necessary.  Consent will be obtained prior to 
conducting any screening assessments or procedures. 
Participants under consideration for participation will have a diagnosis of MCI through the 
cognitive clinic or through consensus diagnosis as a participant in another of our research 
studies. Those who do not meet criteria for amnestic MCI will not be considered for 
participation.   
 
8.2 Screening Visits. 
Screening Visit 1a: 
 
• Subjects will sign a written informed consent prior to any study-related 
procedures.  
• Medical history, including review of medications 
• Physical and neurologic exams 
• Vital signs, including: blood pressure, heart rate, respiratory rate, temperature 
• Height and weight 
• Sensory function (see/hear) 
• Cognitive Testing – Montreal Cognitive Assessment (MoCA) 
• Flicker Tolerance Testing 
• EEG 
o Flicker entrainment and exposure titration 
• MR Imaging 
o If imaging is available within 6 months of screening visit 1a (including 
an arterial spin labeling [ASL] sequence), the screening MRI may not 
be performed 
 
Screening visit 1a may take place on more than 1 day (e.g., MRI scan occurs on 
separate day). Subjects cleared for continued participation will undergo the following 
procedures at the second screening (1b). The tasks below may be performed on the 
same day, or may be performed on separate days.  Screening 1b will occur within one 
calendar month of screening 1a. 
 
Screening Visit 1b: 
• Blood work 
o Inflammatory biomarkers 
o Metabolomics 
o Primary Panel for Inflammation, Oxidative, and Nitrosative Stress 
o APOE status (if unknown) 
• Retinal Imaging 
• If the subject has had a clinic or research LP within 6 months prior to visit 1b 
and CSF has been banked, no screening LP will be performed. The banked 
CSF will be used for analysis. In all other cases, an LP will be performed by 
an MD or NP following an overnight (no less than 6-hr) fast.  CSF will be 
assessed for the following: 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
13 
o Aβ42, tau, phospho tau 
o Inflammatory Biomarkers 
• Contact subject on the day after LP to inquire about any adverse events. 
 
8.3 Baseline Visits. The baseline visit will occur within 1 calendar month of Screening visit 
1b.  Patients that continue to meet eligibility requirements will undergo the following at visit  
2a. 
 
Baseline Visit 2a: 
• PET scan (florbetapir) 
 
Baseline Visit 2b: 
• Interim history review 
• Medication review 
• Adverse event review 
• Confirm continued eligibility 
• Vital signs, height & weight 
• Physical and neurologic exams 
• Cognitive testing/Questionnaires – 
o Category Fluency (Animals) 
o Benson 
o Trails A & B 
o Boston Naming Test (30 item) 
o Clinical Dementia Rating (CDR) 
o Neuropsychiatric Inventory (NPI) 
o Activities of Daily Living (FAQ) 
 
• EEG 
o Flicker entrainment with exposure titration 
o EEG evaluation and induced activity 
 
• Eye tracking task 
• Randomization 
o Assigned to Flicker for 1st 4-weeks or 2nd 4-weeks 
• Instructions for at-home Flicker sessions 
o Daily journal 
 
8.4 Study Visits. Study visits at Emory may take place on more than 1 day to 
accommodate all the scheduled procedures (e.g., Visit 1 may be 2 days) 
 
Week 1 (Flicker administration [will start in study week 4 for half of participants and 
procedures will be identical to those followed for the Flicker/Flicker group]) 
• Days 1 -7 
o In-home therapy 
o Telephone call/email contact 
 Assessment of adverse events 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
14 
 Answer any questions 
o Remote adherence monitoring 
 If session has not been completed by 2:00 pm, reminder call is 
placed 
• Day 3, 4 or 5 
o In-home Observation visit  
 
Weeks 2 – 4(Days 15 - 28) 
o In-home therapy  
o Telephone call/email contact 
 Assessment of adverse events 
 Answer any questions 
o Remote adherence monitoring 
 If session has not been completed by 2:00 pm, reminder call is 
placed 
o 
Flicker administration will continue until all assessments have been 
completed. 
Midpoint Visit a: 
• Interim history review 
• Medication review 
• Adverse event review 
• Confirm continued eligibility 
• Vital signs, height & weight 
• Physical and neurologic exams 
• Retinal Imaging 
• PET scan (florbetapir) 
• Cognitive testing/Questionnaires – 
o Clinical Dementia Rating (CDR) 
o Neuropsychiatric Inventory (NPI) 
o Activities of Daily Living (FAQ) 
• EEG –  
o Flicker entrainment with exposure titration 
o EEG evaluation and induced activity 
• Eye tracking task 
• Instructions for at-home Flicker sessions (for those initiating Flicker) 
o Daily journal 
Midpoint Visit b: 
• LP 
• MRI 
 
End-of-study Visit a: 
• Interim history review 
• Medication review 
• Adverse event review 
• Confirm continued eligibility 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
15 
• Vital signs, height & weight 
• Physical and neurologic exams 
• Cognitive testing/Questionnaires – 
o Clinical Dementia Rating (CDR) 
o Neuropsychiatric Inventory (NPI) 
o Activities of Daily Living (FAQ) 
• PET scan (florbetapir) 
• MRI 
• EEG  
o Flicker entrainment with exposure titration 
o EEG evaluation and induced activity 
• Eye tracking task 
• Turn in journal/equipment if Flicker completed during second 4-week period 
 
End of Study Visit b: 
• Retinal Imaging 
• Lumbar puncture 
 
8.5 Assessments: MCI will be assessed using raters blinded to the study design. The 
cognitive battery will consist of: MoCA, CDR-SB and the Geriatric Depression Scale to help 
determine subject eligibility. 
8.6 Safety Measurements: 
a. Vital Signs - Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart 
rate (HR) will be measured while the patient is in sitting position after five minutes 
rest at each office visit. 
b. Physical Exam – A physician will perform a physical exam on all MCI patients at the 
screening visit to evaluate for any significant medical conditions. Subsequent 
physical exams will be performed by an MD or Nurse Practitioner. 
8.6.2 Other Assessments: 
a. Demographic Data - Demographic data (gender, date of birth, marital status, 
ethnicity, race) will be collected for all patients.  
b. Concomitant Medication - All meds taken by subjects as part of their routine health 
care will be documented during the study. 
8.7 Participant Retention 
Subjects who are enrolled in the study will be reimbursed for their time.  Total study 
payment includes reimbursement for undergoing procedures and travel to the clinic for in-
person study visits. Study partners who are required to accompany participants to their 
visits as well as monitor at home Flicker exposure sessions will also be reimbursed for their 
time. 
 
Reimbursement will be made at the completion of the study.  Emory University is required 
to complete form 1099 for any participant payments over $600 in a year.  To comply with 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
16 
this federal mandate the researchers are required to obtain subject’s social security number 
to complete the form. 
 
8.8 Schedule of Assessments  
On the following pages, the schedule of assessments for both treatment groups is 
presented. 
 
 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
17 
Table 1. Schedule of Assessments for the Non-Exposure Phase/Flicker Exposure Phase 
Visit Number 
1a 
1b 
2a 
2b 
3 
4 
5 
6a1 
6b 
7 
8 
9 
10 
11a2 
11b 
Study Week 
Screening4 
Baseline4 
1 
2 
3 
44 
44 
5 
6 
7 
8 
94 
94 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history and medication review 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 X 
 
Physical exam and neurological exam 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 X 
 
Vital signs + height + weight 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Sensory function (see/hear) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
APOE genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for biomarkers 
 
X 
 
 
 
 
 
 
 X 
 
 
 
 
  
  X 
Cognitive assessments 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 X 
 
Retinal imaging 
 
X 
 
 
 
 
 
 
 X 
 
 
 
 
 
  X 
MR imaging 
X5 
 
X5 
 
 
 
 
X3 
 X3 
 
 
 
 
 X 
 
Lumbar puncture 
 
X 
 
 
 
 
 
 
 X 
 
 
 
 
 
  X 
PET Scan 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 X 
 
Eye tracking 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 X 
 
EEG evaluation and induced activity 
X6 
 
 
X 
 
 
 
X 
 
 
 
 
 
 X 
 
Tolerance Testing 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 X 
 
Randomization/Study crossover 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Therapy training 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
In-home observation visit 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
In-home therapy 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Telephone call / email contact 
 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
 
   X 
Remote adherence monitoring 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Assessment of adverse events 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
1Crossover visit (2-day visit) 
 
2End of treatment visit (2-day visit) 
3MRI will occur on either study visit 6a or 6b 
4Study visits may extend over several days, depending on scheduling constraints 
5MRI will be done at visit 1a if not done within the past 2 yrs or at 2a if done within the past 6 months 
6Screening EEG may be repeated if entrainment criteria are not met or data are unreliable in subjects who have met all 
other eligibility criteria. 
 
 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
18 
Table 2.  Schedule of Assessments for the Flicker Exposure/Flicker Exposure Phase 
Visit Number 
1a 
1b 
2a 
2b 
3 
4 
5 
6 
7a1 
7b 
8 
9 
10 
11a2 
11b 
Study Week 
Screening4 
Baseline4 
1 
2 
3 
4 
54 
54 
6 
7 
8 
  94 
  94 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history and medication review 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 X 
 
Physical exam and neurological exam 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 X 
 
Vital signs + height + weight 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Sensory function (see/hear) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
APOE genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for biomarkers 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
  
  X 
Cognitive assessments 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 X 
 
Retinal imaging 
 
X 
 
 
 
 
 
 
 
 X 
 
 
 
 
  X 
MR imaging 
X5 
 
X5 
 
 
 
 
 
X3 
 X3 
 
 
 
 X 
 
Lumbar puncture 
 
X 
 
 
 
 
 
 
 
 X 
 
 
 
 
  X 
PET Scan 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 X 
 
Eye tracking 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 X 
 
EEG evaluation and induced activity 
X6 
 
 
X 
 
 
 
 
X 
 
 
 
 
 X 
 
Tolerance testing 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 X 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Therapy training 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
In-home observation visit 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
In-home therapy 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
   X 
Telephone call / email contact 
 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
Remote adherence monitoring 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assessment of adverse events 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
1Midpoint clinic visit (2-day visit) 
2End of treatment visit (2-day visit) 
3MRI will occur on either study visit 7a or 7b 
4Study visits may extend over several days, depending on scheduling constraints 
5MRI will be done at visit 1a if not done within the past 2 yrs or at 2a if done within the past 6 months 
6Screening EEG may be repeated if entrainment criteria are not met or data are unreliable in subjects who have met all 
other eligibility criteria. 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
19 
9. DATA RECORDING, RETENTION, AND MONITORING 
9.1 Electronic Case Report Forms 
Electronic Case Report Forms will be completed for each patient who signs Informed 
Consent. All clinical information requested in this protocol will be recorded on the eCRFs. If 
an error is made on documents collected (source documents), a single line will be drawn 
through the error and the correct response will be written adjacent to the error; the change 
will be initialed and dated. 
 
9.2 Retention and Availability Of Records 
The Investigator will make study data accessible to Regulatory Agency inspectors upon 
request. A file for each patient will be maintained that includes the signed ICF and the 
Investigator’s copies of all source documentation related to that patient. The Investigator 
will ensure the reliability and availability of source documents from which the information on 
the CRF was derived. 
 
Study documentation will be maintained, including documents created or modified in 
electronic format, for at least 15 years following the completion of the study. ICFs, and 
adequate records for the receipt and disposition of all study drugs will be retained for a 
period of 2 years following the Food and Drug Administration (FDA) or other regulatory 
approval date of the drug or until 2 years after the drug investigational program is 
discontinued, unless a longer period is required by applicable law or regulation.  
10. ASSAY MEASURES AND ANALYSES 
 
10.1Genotyping for apolipoprotein E4 allele status will be performed in the Emory 
Genetics Core facility.  Apolipoprotein E4 allele status will not be disclosed to study 
participants. 
 
10.2 EEG. We will measure electrical brain activity using EEG from the scalp. For the EEG 
recording session, a cap (similar to a swim cap) will be placed on the participant’s head and 
electrodes attached. Gel will be placed on the hair/head so that the electrodes can get a 
good connection to detect electrical charges that come from brain activity. This gel is easily 
removed with hair washing.  
 
During the EEG study session, you will be seated in a chair. You will be asked to rest 
quietly with your eyes open. EEG will be recorded before, during and after use of the 
Flicker device (Figure 3). When the Flicker device is not in place, participants may be 
asked to perform simple movements, to perform a computer/iPad-based task with button 
presses, and/or to complete mood and cognitive assessment questionnaires.  
 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
20 
There are no known risks of EEG. The gel in the hair can be sticky but is easily removed 
with shampooing. The EEG session may last up to 3 hours total time (including electrode 
placement and recording time) and will occur at 3 time points during the study: baseline, 
midpoint, and end-of-study. 
 
EEG evaluation will be performed at Visits 1a and 2b for both groups to determine whether 
it is possible to entrain the gamma waves.  If subjects’ brain waves are unable to become 
entrained, they will be removed from the study.  Screening EEG may be repeated if 
entrainment criteria are not met or data are unreliable in subjects who have met all other 
eligibility criteria. 
 
 
10.3 Lumbar Puncture (LP): Lumbar puncture will be performed by a qualified clinician 
trained to perform the procedure. 20ml of CSF is collected using sterile technique and will 
be assayed for both known and novel biomarkers of disease, including inflammatory 
markers. Lumbar punctures will occur at the three in-person clinic visits (screening, 
midpoint, and end of study). 
 
10.4 CSF and Serum Biomarkers. AD biomarkers including Aß42, tau, and phospho-tau 
levels in the CSF will be assayed at baseline, midpoint, and end of study visits. Specialty 
assays for inflammatory markers will also be conducted via a commercial vendor with 
specialized panels for measuring these markers (OLink, Sweden). Results are not 
disclosed to participants. 
 
10.5 MRI. Brain MRI will be obtained or reviewed at screening to verify eligibility, at 
screening or baseline, at midpoint and end of study.  
  
MRI films performed clinically within the past two years will be reviewed by the investigators 
for eligibility in the study.  If a subject does not have clinical MRI films available, the MRI 
will be performed and reviewed prior to performance of the LP for safety reasons and to 
ensure that the subject meets eligibility criteria. 
  
The 3T MR acquisition sequences will include all, or a subset of, the following 1) Structural 
MRI, 2) FLAIR,3) T2*GRE; 4) arterial spin labeling (ASL), and 5) resting state 
connectivity.  MRI measurements of brain structure have been show to demonstrate brain 
atrophy (which correlates with neuron loss) in MCI and AD and increasing rates of brain 
atrophy as subjects become more impaired.  Therefore, structural MRI is used as a 
measure of the rate of disease progression in AD treatment trials.  Structural MRI 
(MPRAGE//IRSPGR) data will be used both as the rate of change as well as a predictor of 
future change.  Cerebrovascular disease (especially white matter lesions (WMLs) will be 
assessed with FLAIR.  Cerebral blood flow, which closely correlates with cerebral 
hypometabolism as an early biomarker of AD pathogenesis, will be measured by ASL 
imaging.  Finally, resting state fMRI will be used to determine functional connectivity 
changes.  

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
21 
All MRIs will be reviewed by the investigators and the investigator will determine and 
document any clinically significant findings. 
  
10.6 PET Scan. The PET scan includes injection of florbetapir (10 mCi [+/- 10%]) 
administered by intravenous bolus injection. During the 50-minute uptake phase, 
participants will wait in a quiet room. The PET scan will begin at approximately 50 minutes 
post-florbetapir injection. Brain images will be acquired continuously for a period of 20-40 
minutes (scan time based on scan quality and the need for repeat sequences). 
 
10.7 Cognitive testing. Cognitive testing will occur at the baseline visit for each 
participant. A series of pen and paper or computer-based tests are administered to assess 
the current cognitive status (tests listed under Baseline visit 2b). At visit 1a, only the MoCA 
will be administered to determine eligibility. 
 
10.8 Study questionnaires. Interviews will be conducted at each of the three time points in 
the study: baseline, midpoint, and at end-of-study. These questionnaires are conducted 
with the study partner and are meant to assess subjective impressions of the participant’s 
current behaviors and level of function. One questionnaire (the Clinical Dementia Rating 
[CDR]) also asks questions of the participant and helps to offer insight into their current 
beliefs about their cognitive status. 
 
Statistical Analysis 
 
Although this study is meant to assess tolerability and feasibility of Flicker exposure in the 
study population, there is a small chance that we will also obtain preliminary data that 
reflects clinical impact. However, this study is not powered to obtain generalizable results 
and the data will instead be used as pilot data for the preparation of a larger, early-phase 
clinical trial. 
 
11.  OPEN-LABEL EXTENSION 
 
Participants who complete the clinical trial phase of the study will be eligible to participate in 
the open-label extension phase. 
 
Subjects who elect to participate in the open-label phase will be asked to sign a new 
consent form (after the investigator or study coordinator has explained procedures for the 
open-label phase of the trial and after all participant questions have been addressed).  
 
Participants who elect to participate in the extension phase will be required to come to the 
clinic at 6 and 12 months. Flicker administration will continue throughout these visits and be 
terminated only after Visit 15b.  At 6 months (Visit 13), the following procedures will be 
performed: 
• AE review 
• Concomitant medication review 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
22 
• Vital sign collection 
• Physical and neurological exams 
• CDR, NPI and FAQ 
 
At 2 intervals between the clinic visits (Visits 12 and 14), the subjects will be contacted by 
telephone, during which time AEs and concomitant medications will be reviewed. 
 
At Visit 15a and 15b, the following procedures will be performed: 
• AE review 
• Concomitant medication review 
• Vital sign collection 
• Physical and neurological exams 
• Cognitive assessments – those performed in visit 11a 
• MRI 
• Amyloid PET scan (optional) 
• Lumbar puncture (optional) 
• EEG evaluation 
• Tolerance testing 
• Eye tracking 
• Retinal imaging 
• Blood draw 
 
Subjects will be given the option to undergo the PET scan and the LP at Visit 15.  They 
may elect to undergo both procedures or only one; they are required to undergo at least 
one of these procedures. 
 
The EOS visit (Visit 16) will be conducted by telephone call, during which medications and 
AEs will be reviewed. 
 
A schedule of assessments for the open-label phase of the study is found below: 
 
 
 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
23 
Table 3.  Schedule of Assessments for the Extension Phase 
 
 
Visit Number 
11a 
11b 
12 
13 
14 
15a 
15b 
16 
Study Week 
Clinic 
91 
 
Call 
12(+/-2)1 
Clinic 
24(+/-2)1 
Call 
36(+/-2)1 
Clinic 
48(+/-2)1 
Clinic 
48(+/-2)1 
Call 
Follow-up 
52(+/-2)1 
 
 
 
 
 
 
 
 
 
Consent (Confirm) 
X 
 
 
 
 
 
 
 
Medical history and medication review 
X 
 
X 
X 
X 
X 
 
X 
Physical exam and neurological exam 
X 
 
 
X 
 
X 
 
 
Vital signs + height + weight 
X 
 
 
X 
 
X 
 
 
Blood for biomarkers 
 
X 
 
 
 
 
X 
 
Cognitive assessments 
X 
 
 
X 
 
X 
 
 
Retinal imaging 
 
X 
 
 
 
 
X 
 
MR imaging 
X 
 
 
 
 
X 
 
 
Lumbar puncture2 
 
X 
 
 
 
 
X 
 
PET Scan2 
X 
 
 
 
 
X 
 
 
Eye tracking 
X 
 
 
 
 
X 
 
 
EEG evaluation and induced activity 
X 
 
 
 
 
X 
 
 
Tolerance testing 
X 
 
 
 
 
X 
 
 
In-home therapy 
X 
X 
X 
X 
X 
X 
 
 
Telephone call / email contact 
 
 
X 
 
X 
 
 
X 
Remote adherence monitoring 
X 
X 
X 
X 
X 
 
 
 
Assessment of adverse events 
 
 
X 
X 
X 
X 
 
X 
 
1Study visits may extend over several days, depending on scheduling constraints 
2Subject may choose PET scan or lumbar puncture or both 
 
 
 
 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
24 
 
Participants will be asked to report any adverse events that develop during the open-label 
phase of the trial.  
 
The open-label phase of the study will be terminated after 1 year (i.e., 52 weeks) following 
successful completion of the active phase of the study.  The P.I. reserves the right to stop 
the open-label phase of this study at any time. 
 
12.  POST-STUDY PERIOD 
 
Participants will be allowed to retain the device for 1 year following the 1-year study period.  
Participants will not be required to come to Emory during this time to undergo any 
procedures. 
 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
25 
References  
 
1. Selkoe DJ. Alzheimer's disease.Cold Spring Harb Perspect Biol2011;3. 
 
2. Ringman JM, Younkin SG, Pratico D, Seltzer W, Cole GM, Geschwind DH, Rodriguez-
Agudelo Y, Schaffer B, Fein J, Sokolow S, Rosario ER, Gylys KH, Varpetian A, Medina 
LD, Cummings JL. Biochemical markers in persons with preclinical familial Alzheimer 
disease. Neurology 2008;71:85-92. 
 
3. Petrie EC, Cross DJ, Galasko D, Schellenberg GD, Raskind MA, Peskind ER, 
Minoshima S. Preclinical evidence of Alzheimer changes: convergent cerebrospinal fluid 
biomarker and fluorodeoxyglucose positron emission tomography findings. Archives of 
Neurology 2009;66:632-7 
 
4. Jack CR, Jr., Vemuri P, Wiste HJ, Weigand SD, Aisen PS, Trojanowski JQ, Shaw LM, 
Bernstein MA, Petersen RC, Weiner MW, Knopman DS. Evidence for Ordering of 
Alzheimer Disease Biomarkers. Archives of Neurology 2011. 
 
5. Jack CR, Jr., Lowe VJ, Weigand SD, Wiste HJ, Senjem ML, Knopman DS, Shiung MM, 
Gunter JL, Boeve BF, Kemp BJ, Weiner M, Petersen RC. Serial PIB and MRI in normal, 
mild cognitive impairment and Alzheimer's disease: implications for sequence of 
pathological events in Alzheimer's disease. Brain: a journal of neurology 
2009;132:1355-65. 
 
6. Singer AC, Carr MF, Karlsson MP, Frank LM.Hippocampal SWR activity predicts correct 
decisions during the initial learning of an alternation task.Neuron. 2013 Mar 
20;77(6):1163-73. 
 
7. Singer AC, Talei Franzesi G, Kodandaramaiah SB, Flores FJ, Cohen JD, Lee AK, 
Borgers C, Forest CR, Kopell NJ, Boyden ES. Mesoscale-duration activated states gate 
spiking in response to fast rises in membrane voltage in the awake brain. J 
Neurophysiol. 2017 Aug 1;118(2):1270-1291. 
 
8. Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, 
Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden 
ES, Tsai LH. Gamma frequency entrainment attenuates amyloid load and modifies 
microglia.Nature. 2016 Dec 7;540(7632):230-235 
 
9. Allen BD, Singer AC, Boyden ES. Principles of designing interpretable optogenetic 
behavior experiments. Learn Mem. 2015 Mar 18;22(4):232-8. 
 
10. Cardin JA, Carlén M, Meletis K, Knoblich U, Zhang F, Deisseroth K, Tsai LH, Moore CI. 
Driving fast-spiking cells induces gamma rhythm and controls sensory 
responses.Nature. 2009 Jun 4;459(7247):663-7 
 

 
 
FLICKER Protocol 
Protocol: v07 
 
 
Date: 04NOV2019 
 
 
 
26 
11. Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends 
Neurosci. 2005 Apr;28(4):202-8. Review. 
 
12. Alsop, D.C., Detre, J.A., Grossman, M. Assessment of cerebral blood flow in 
Alzheimer's disease by spin-labeled magnetic resonance imaging. Ann Neurol. 2000 
Jan;47(1):93-100. 
 
13. Girouard&Iadecola, J. Applied Physiology 2006 Girouard H, Iadecola C. Neurovascular 
coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl 
Physiol (1985). 2006 Jan;100(1):328-35. Review. 
 
14. Yoshikawa et al., American Jour. Neuroradiology 2003 
 
15. Binnewijzend MA, Kuijer JP, Benedictus MR, van der Flier WM, Wink AM, Wattjes MP, 
van Berckel BN, Scheltens P, Barkhof F. Cerebral blood flow measured with 3D 
pseudocontinuous arterial spin-labeling MR imaging in Alzheimer disease and mild 
cognitive impairment: a marker for disease severity. Radiology. 2013 Apr;267:221-30. 
 
16. Rieder, M. K., Rahm, B., Williams, J. D. & Kaiser, J. Human gamma-band activity and 
behavior. Int. J. Psychophysiol.79, 39–48 (2011). 
 
17. Thut, G., Schyns, P. G. & Gross, J. Entrainment of Perceptually Relevant Brain 
Oscillations by Non-Invasive Rhythmic Stimulation of the Human Brain. Front. 
Psychol.2, (2011). 
 
18. Schadow, J. et al. Stimulus intensity affects early sensory processing: Visual contrast 
modulates evoked gamma-band activity in human EEG. Int. J. Psychophysiol.66, 28–36 
(2007). 
 
19. Schadow, J. et al. Stimulus intensity affects early sensory processing: Sound intensity 
modulates auditory evoked gamma-band activity in human EEG. Int. J. 
Psychophysiol.65, 152–161 (2007). 
 
20. Lenz, D., Fischer, S., Schadow, J., Bogerts, B. & Herrmann, C. S. Altered evoked 
gamma-band responses as a neurophysiological marker of schizophrenia? Int. J. 
Psychophysiol.79, 25–31 (2011). 
 
21. Thuné, H., Recasens, M. & Uhlhaas, P. J. The 40-Hz Auditory Steady-State Response 
in Patients With Schizophrenia: A Meta-analysis. JAMA Psychiatry73, 1145 (2016). 
 
22. Basar-Eroglu, C., Mathes, B., Brand, A. & Schmiedt-Fehr, C. Occipital gamma response 
to auditory stimulation in patients with schizophrenia. Int. J. Psychophysiol.79, 3–8 
(2011). 
 
23. De Lucia, M. & Tzovara, A. Decoding auditory EEG responses in healthy and clinical 
populations: A comparative study. J. Neurosci. Methods250, 106–113 (2015).