Botanical Mixture Stabilizes Cognitive Function in Patients with Mild and Moderate Alzheimer’s Disease

Abstract

Context: Currently, there is no treatment that can stop the progression of Alzheimer’s disease. We have used transgenic Drosophila melanogaster models and machine learning to develop an eight component botanical mixture (Geneaire™ ReBuilder™) that targets multiple genetic pathways involved in brain aging and dementia that are homologous between Drosophila and humans.

Objective: To test the effects of ReBuilder on the cognitive function of subjects diagnosed with mild or moderate Alzheimer’s disease.

Methods: We recruited 50 subjects with mild to moderate AD to participate in a double-blind, placebo-controlled clinical study. During the 12-month pilot study, the subjects were evaluated quarterly on the Mini Mental State Exam (MMSE), Alzheimer’s Disease Cooperative Study’s Activities of Daily Living (ADCS-ADL), and the Clinical Dementia Rating Sum of Boxes (CDR-SB).

Results: The addition of ReBuilder to subjects’ existing Namenda and Exelon regimens stabilized cognitive decline in patients with mild AD and slowed cognitive decline in patients with moderate AD.

Conclusions: These results were observed in both sexes and in all ages tested. Importantly, no adverse side effects attributable to ReBuilder were reported. The results of this clinical pilot warrant further study of ReBuilder in AD.

Full text

2018
Vol. 3 No. 3: 14
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Research Article
Journal of Clinical Medicine and Therapeutics
© Copyright iMedPub | This article is available from: http://imedpub.com/clinical-medicine-and-therapeutics\
Matsagas K1*, Villeponteau
B2, Shankle WR3,4, Cruise
RJ1, Morales S1, Goertzel B1,
Simmon VF1, Benford G5 and
Rizza C1
1. Genescient Corporaon, Fountain
Valley, California, United States of
America
2. Centagen Inc., Boulder, Colorado,
UnitedStatesofAmerica
3. ShankleClinic,HoagHospital,Newport
Beach, California, United States of
America
4. Department of Cognive Sciences,
UniversityofCaliforniaatIrvine,Irvine,
California,UnitedStatesofAmerica
5. DepartmentofPhysicsandAstronomy,
UniversityofCaliforniaatIrvine,Irvine,
California,UnitedStatesofAmerica
*Corresponding author: Kennedy
Matsagas
 kmatsagas@genescient.com
GenescientCorporaon,FountainValley,
California,UnitedStatesofAmerica.
Tel: 55622098912
Citaon: MatsagasK,VilleponteauB,
ShankleWR,CruiseRJ,MoralesS, et 
al.(2018)BotanicalMixtureStabilizes
CogniveFunconinPaentswithMildand
ModerateAlzheimer’sDisease.JClinMed
Ther.Vol.3No.3:06
Introducon
Alzheimer’sDisease(AD)isthe6thleadingcauseofdeathinthe
UnitedStates[1].Today,morethan5millionAmericansareliving
withAlzheimer’sdisease(AD), and 1 in3 seniors’ dies with AD
oranotherformofdemena[2].By2050,thenumberofpeople
expectedtobelivingwith AD will riseto14million and costan
esmated$1.1trilliondollars[2].DeathsofthosewithADwere
about 600,000 in 2010 and are projectedto rise to 1.6 million
by 2050, which is expected to be some 43% of all older adult
deaths[3].Beta-amyloid(Abeta)plaquesandhyperphosphylated
Tau(pTau)neurobrillarytangleshavebeenthedominantfocus
of research on AD pathophysiology since the disease was rst
recognizedby Alois Alzheimer in 1906 [4,5]. Whileplaquesand
tanglesare diagnoscforAD [5-7], the cause(s) of theirsoluble
precursors that kill neurons has not been determined. The
majorityofADpaentsarediagnosedaer60yearsofage.Many
studiespointtoagingrelatedprocesseslikeinammaon[8-14],
Received: July20,2018; Accepted: August08,2018;Published: August17,2018
Botanical Mixture Stabilizes Cognive
Funcon in Paents with Mild and Moderate
Alzheimer’s Disease
Abstract
Context: Currently,thereisnotreatmentthatcanstoptheprogressionofAlzheimer’s
disease. We have used transgenic Drosophila melanogaster models and machine
learningtodevelop an eight componentbotanicalmixture(Geneaire™ReBuilder™)
thattargetsmulplegenecpathwaysinvolvedinbrainaginganddemenathatare
homologousbetweenDrosophila andhumans.
Objecve: To test the eects of ReBuilder on the cognive funcon of subjects
diagnosedwithmildormoderateAlzheimer’sdisease.
Methods: We recruited 50 subjects with mild to moderate AD to parcipate in a
double-blind, placebo-controlled clinical study. During the 12-month pilot study,
the subjects were evaluated quarterly on the Mini Mental State Exam (MMSE),
Alzheimer’sDiseaseCooperaveStudy’sAcviesofDailyLiving(ADCS-ADL),andthe
ClinicalDemenaRangSumofBoxes(CDR-SB).
Results: TheaddionofReBuildertosubjects’exisngNamendaandExelonregimens
stabilizedcognivedecline inpaentswith mildADandslowed cognivedeclinein
paentswithmoderateAD.
Conclusions: These results were observed in both sexes and in all ages tested.
Importantly, no adverse side eects aributable to ReBuilder were reported. The
resultsofthisclinicalpilotwarrantfurtherstudyofReBuilderinAD.
Keywords: Alzheimer's disease; Demena; Aging; Neurology; APOE; Genecs;
Cognion
neuralvascular damage[15-21],neuralstress[9,22-32], altered
cell metabolism [33-37], cellular autophagy [38-45], microglial
dysfuncon[46-48],mitochondrialdysfuncon[49-52],astrocyte
funcon [53-59] and dietary factors[60-65] as potenal causal
factors in the decline of brain funcon over the decades that
precedean actual AD diagnosis. AD is a mulfacetedpathology
involving many biochemical pathways and thus a mulfaceted
therapeucapproachmayprovebenecial.
Drosophila melanogaster, the common fruit y, has been
extensively studied and is a highly tractable genec model

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organism for understanding molecular mechanisms of human
diseases. Many basic biological, physiological,and neurological
properesareconservedbetweenmammalsandD. melanogaster,
andnearly75%ofhumandisease-causinggenesarebelievedto
haveafunconal homologinthey[66,67].Thereforeweused
genec and machine learning approaches on age-related data
bases for humans and ies to idenfy many homologousCNS-
specicgenecandbiochemicalpathwaysinvolvedinlongevity.
Wetargetedgenesknowntobe important in AD and screened
botanical products known to interact with the pathways we
idenedusing transgenicDrosophila models [68]. The resultis
ReBuilder,a7-componentbotanicalsupplementthatiseecve
in reducing neural dysfuncon in our Drosophila model of AD.
For this human pilot study, we added an eighth component,
bioperine,toimproveabsorponofReBuilder.
Materials and Methods
Fiy human subjects of mixed gender between the agesof 60
and90wererecruitedandenrolledinthisdouble-blind,placebo-
controlled, IRB-approved pilot clinical study. The subjects had
beenonstablemaximumtolerateddosesofMemanneand/or
Rivasgmineforatleast2months,and nothing waschangedin
their standard therapyfor the duraon of our pilot study. The
subjectswererandomlyassignedtoeithertheacveorplacebo
arm of the study. The subjects were evaluated approximately
everythreemonths(quarterly)fromOctober2013toDecember
2015.Thesubjectswerereferredto Genescient Corporaonby
William R. Shankle, MD, and evaluatedin the oce of Crisna
Rizza,MDinFountainValley,CA.
At the inial enrollment oce visit, we administered the Mini
Mental State Examinaon (MMSE) and the Clinical Demena
Rang Sum of Boxes (CDR-SB) to each subject. Each subject’s
caregiver was interviewed using the Alzheimer’s disease
Cooperave Study’s Acvies of Daily Living (ADCS-ADL)
Inventory to assess the subject’s current self-care capabilies.
Aer this inial visit, the subjects were instructed to begin
takingonecapsuleofReBuilderinthemorningandonecapsule
intheeveningdaily.Each subject had acaregiverwhoensured
compliance in taking all their medicaons. The subjects and
theircaregiversreturnedtoouroceapproximatelyeverythree
monthstohavetheaforemenonedtestsrepeated.ReBuilderis
currentlydistributedbyGeneaire.
ThecomponentsoftheReBuildertreatmentusedin theclinical
studyandtheirknownacvesand targetsaregiveninTable 1.
TheformulaonisprotectedbyUSPatent9744204.
Ethics
The subjects signed informed consent forms upon enrollment.
ThisstudyprotocolwasapprovedbytheInstuteofRegenerave
and Cellular Medicine Instuonal Review Board (approval
number:ICSS-2013-007).Thisstudyisregisteredon the Clinical
TrailswebsiteoftheUnitedStatesgovernment(NCT03611439).
Stascs
Throughout the 12-month period, the subjects’ scores on the
MMSE,ADCS-ADL,andCDR-SBwererecordedandcomparedto
theirinialbaselinescores.Thesubjects’ mean test scoresand
changesintheirmeantestscorewereploedinrelaontotheir
average baseline scores and presented with 95% condence
intervals.Onlythesubjectsforwhomwehaddatafortheinial
visitandall4subsequentquarterswereincludedintheanalysis
presentedhere.
Tomaximizethenumberofsubjectsthatwouldbeassignedthe
acvebotanicalcompound,43subjectsweregivenReBuilderand
only7paentswereassignedtothe placebo arm of thestudy.
Tomakeupforthesmallnumberofsubjectsintheplaceboarm
(only 5 completed the trial), we compared the data from our
acvesubjectstopreviouslypublisheddatafrom471ADsubjects
ofmatched demographicsandADsymptomsfromthestudyby
Bernicketal.Thesubjectsinthispreviouslypublishedstudywere
treatedandtestedinthesamemannerasourplaceboarm.Our5
placebosubjectsexperiencedsimilarlossofcognivefunconas
measuredbyMMSE, ADCS-ADL,andCDR-SBasthe471placebo
subjects in the Bernick study. Moreover,with the large clinical
study from Bernick et al. we wereable to match all the acve
subjects in our pilot with large numbers of age and condion
matchedsurrogateplacebocontrols.
Results
Thirty out of the 43 subjects receiving ReBuilder successfully
completed our 12-month pilot study. Of those 30, 17 were
categorized as “mild” in disease severity based on an inial
scoreatenrollmentof21to30pointsoutofapossible30points
on the Mini Mental Status Exam (MMSE), a widely used test
for demena. The remaining 13 subjects were categorized as
“moderate”in diseaseseveritybased on an inial MMSEscore
Component Known Acve (s) Targets References
Astragalus membranaceus (extract) AstrogalosidesI-VIIFlavenoids,
HDTICs
Telomerase,Mitochondria,ptau,mTOR,TNF-α,
ERK,AMPK [69-75]
BerberineHCL Berberine(98%) Acetylcholinesterase,AMPK,α-adrenergic
receptors,β-Amyloid [76-81]
Vaccinium uliginosum or
Pterocarpus marsupium(extracts) ResveratrolAnalogs PPARα,PGE2,AMPK,phosphodiesterase,
Mitochondria [82-86]
L-Theanine L-Theanine(98%) NMDAreceptors,EAATs,GABAreceptors,eNOS,
mitochondria [87-93]
Genistein Genistein(98%) ERα,AMPK,p450c21,PRPF8 [94-96]
LithiumOrotate Lithium NCS-1/Frequenin,Abeta,NMDA,GSK3B,ptau [97-105]
SeleniumGlycinate Selenium PRPF8,ERCC1,Selenoproteins [106-108]
Table 1 Composion,knownacves,andtargetsoftreatment(USPatent9744204).

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of11to20points.
During the course of the 12-month pilot study, the mild and
moderate subjects taking ReBuilder maintained MMSE scores
close to their inial baseline scores. The ReBuilder  
  
subjects

did

not 
experience 
the 
rate 
of 
decline 
seen

in

the

subjects

from

the

Bernick 
study 
[109], 
which 
we 
used 
as

our

benchmark

control

for

the 
expected 
rate 
of 
decline 
during 
the

same

study

(Figure 1A).
Lookingatthe 17 mild subjects who completedthepilot,there
appearstobeapronouncedpreservaonofthebaselineMMSE
scoresaer12monthsoftreatment(Figure 1B).
Looking at the 13 subjects with moderate AD who received
ReBuilder and completed the pilot study, there is also a
pronouncedpreservaonofbaselineMMSEscore.Themoderate
AD subjects taking ReBuilder, as with the mild AD subjects,
connuedtoscoremuchclosertotheirbaselinethanthesubjects
intheBernickstudy(Figure 1C).
The trend of baseline score maintenance in subjects taking
ReBuilder connues if we separate the subjects by gender.
Generally,Alzheimer’sdiseaseaectsmorewomenthanmendue
towomenhavinglongeraveragelifespans,andpossiblybecause
ofhormonaldierencesbetweenthegenders.Inourpilotstudy,
we had nearly equal numbers of each gender, with 16 women
and14men.Bothgenderssawposiveeectswhen ReBuilder
wasaddedtotheirstandardtherapy(Figures 1D and 1E).
The E4 variant of the Apolipoprotein E (APOE) gene puts an
individualatanincreasedriskofdevelopingAlzheimer’sdisease.
Theriskincreaseispresentinanindividualwithonecopyofthe
E4allele,andgreaterslliftheindividualhas2copies.TheAPOE4
genevariantisassociatedwithan increasednumberof amyloid
protein plaques in the brain ssue of aected individuals and
earlieronsetofADsymptoms[110].Inourpilotstudy,wehad14
subjectstakingReBuilderwhocarriedatleastoneE4allele.While
ittook 6monthsforthesesubjectstoseean eectfromtaking
ReBuilder,theoverallchangesintheirMMSEscoreswereposive
byQ4(Figure 1F).
The Alzheimer’s Disease Cooperave Study Acvies of Daily
Living (ADCS-ADL) is a quesonnaire widely used to assess the
Figure 1A Mean MMSE Scores for All Subjects. Average MMSE
scores for ReBuilder study subjects and the Bernick
groupoverthecourseof12months.
Figure 1B Mean MMSE Scores for Mild Subjects. Average
MMSEscores formild subjects intheReBuilderstudy
comparedtotheBernickgroupover12months.
Figure 1C Mean Mini Mental State Exam (MMSE) Scores
for Moderate Subjects.  Average MMSE score for
moderatesubjectsintheReBuilderstudycomparedto
theBernickgroup.
Figure 1D Mean Mini Mental State Exam (MMSE) Scores for
Female Subjects.  Female subjects taking ReBuilder
duringour pilot studywereable tomaintaina MMSE
scorecloser tothebaseline than thoseintheBernick
study.
competence of paents with Alzheimer’sDisease (AD) in basic
and instrumental acvies of daily living (ADL). The ADCS-ADL
scorescompetence in dailyacvieson a 78-point scale.Slight
scorechangesinthis assessment can indicate that a subjectis,

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orisnot,abletochooseappropriateclothingorprepareasimple
meal.
Onaverage,oursubjects takingReBuildergained2.34pointson
this measure aer 12 months of treatment.The control group
isexpectedtohavelost6.67points duringthesameamountof
me(Figure 2A).
The17mildsubjects whocompletedthepilotappeartodisplay
animprovement,onaverage,ofADCS-ADLscoresaer12months
oftreatment(Figure 2B).
TheADCS-ADLscoresofthe13subjectswithmoderateADwho
completed the pilot study did not see an overallimprovement
compared to their mean baseline scores aer 12 months of
treatment.However,themean point loss of 1.69 sllfallsquite
short of the projected point loss of 6.67 based on the Bernick
study(Figure 2C).
When the subjects in our pilot study are separatedby gender,
the overall improvement in acvies of daily living remains.
The subjects taking ReBuilder achieve and maintaina clinically
meaningful improvement in the ADCS-ADL assessment that is
Figure 1E MeanMiniMentalStateExam(MMSE)ScoresforMale
Subjects.  Male subjects taking ReBuilder during our
pilot study took 6 months to see an improvementin
theirMMSEscore.BYQ4themenreboundedbackto
theirbaselinescore.
Figure 1F Mean Mini Mental State Exam (MMSE) Scores for
APOE4Subjects.AverageMMSEscoresoftheReBuilder
subjects eventually rebounded to baseline bythe end
of12months.
Figure 2A Mean Alzheimer’s Disease Cooperave Study Acvies
of Daily Living (ADCS-ADL) Scores for All Subjects.  The
mean score for all subjects taking ReBuilder rises above
their inial baseline average score and maintains that
improvementfortheduraonofthepilotstudy.
Figure 2B Mean Alzheimer’s Disease Cooperave Study Acvies
ofDaily Living (ADCS-ADL) Scores forMildSubjects.On
average,theMildADsubjectstakingReBuilderimproved
inAcviesofDaily Livingandremainedabovebaseline
fortheduraonofthestudy.
Figure 2C Mean Alzheimer’s Disease Cooperave Study Acvies
ofDailyLiving(ADCS-ADL)ScoresforModerateSubjects.
Moderate subjects taking ReBuilder remained close to
theirbaselinescorefortheduraonofthestudy.

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above their average baseline scores, and far above the score
projectedbased on the Bernick study attheendof12months,
regardlessofgender(Figures 2D and 2E).
Separang out the subjects with the APOE4 genec variant, a
clinicallymeaningful improvementintheADCS-ADLassessment
issllobservedattheendof12months(Figure 2F).
The Clinical Demena Rang (CDR-SB) is used to quanfy the
severity of symptoms of demena. This measure assesses a
subject’s cognive and funconal performance in six areas:
memory,orientaon, judgment & problem solving, community
aairs,homeandhobbies,andpersonalcare. Scoresineachof
thesearecombinedtoobtainacompositescore,with ahigher
scoreindicanggreaterseverityofdemenasymptoms.
Overall, the subjects taking ReBuilder in our pilot study
maintainedaCDR-SBscoreclosetotheirbaseline.Thissuggests
that the subjects’ severity of demena symptoms did not
increaseasexpectedoverthe12-monthpilotstudyandthatthey
experiencedbeerstabilityintheirsymptoms(Figure 3A).
For our mild subjects, the mean CDR-SB scores stayed above
baselineforthelaerporonofthe pilot, possibly indicang a
reduconindemenasymptoms(Figure 3B).
Formoderatesubjects,theseverityoftheirdemenasymptoms
doesincreasebytheendofthepilotstudy,butnottothesame
degree that is seen in the Bernick group over the same me
period(Figure 3C).
When the subjects taking ReBuilder are separated by gender,
wesllseea reduconindemenaseverityasindicatedbythe
averageCDR-SBscores(Figures 3D and 3E).
Looking at the subjects with the APOE4 genec variant [110],
we also see a reducon in demena symptoms. This suggests
that ReBuilder can improvethe symptoms of those genecally
predisposedtoAlzheimer’sdisease(Figure 3F).
On the whole, the above results show that subjects taking
ReBuilderduring our12-monthpilotat leastslowedintheir AD
progressionasindicatedbytheMMSE,ADCS-ADL,andCDR-SB.In
somemeasures,thesubjectsappeartostabilizeandevenreduce
theirADsymptoms.Noadversesideeectssuchaschangesin
mood,sleeping habits,balanceissues,or digesvedisturbances
wereobservedinthesubjectstreatedwithReBuilder.
Figure 2D MeanAlzheimer’sDiseaseCooperaveStudyAcvies
ofDailyLiving(ADCS-ADL)ScoresforFemaleSubjects.
FemalesubjectstakingReBuildermaintainedscoresabove
theirbaselinefortheduraonofthestudy.
Figure 2E MeanAlzheimer’sDisease CooperaveStudyAcviesof
Daily Living (ADCS-ADL) Scores for Male Subjects.  Male
subjects taking ReBuilder maintained ADL scores above
theirbaselinefortheduraonofthestudy.
Figure 2F Mean Alzheimer’s Disease Cooperave Study Acvies
of Daily Living (ADCS-ADL) Scores for APOE4 Subjects.
Subjects genecally predisposed to Alzheimer’s taking
ReBuildermaintainedADLscoresclosetotheirbaselinefor
theduraonofthestudy.
Figure 3A Mean Clinical Demena Rang Sum of Boxes (CDR-SB)
ScoresforAllSubjects.Onaverage,CDR-SBscoresstayed
veryclosetobaselineforsubjectstakingReBuilder.Note
thatthescorescaleontheY-axisisinvertedtoshowthat
a decreasing CDR-SB score indicates improvement of
symptoms.

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Figure 3B Mean Clinical Demena Rang Sum of Boxes (CDR-SB)
Scores forMild Subjects. Mild sub jectstaking ReBuilder
sawareducedCDR-SBscorebytheendofthepilotstudy.
NotethatthescorescaleontheY-axisisinvertedtoshow
thatadecreasingCDR-SBscoreindicatesimprovementof
symptoms.
Figure 3C Mean Clinical Demena Rang Sum of Boxes (CDR-SB)
Scores for Moderate Subjects. Moderate AD subjects
taking ReBuilder had symptoms close to baseline unl
thelastquarterofthestudy.Notethatthescorescaleon
theY-axisisinvertedto show that a decreasingCDR-SB
scoreindicatesimprovementofsymptoms.
Figure 3D Mean Clinical Demena Rang Sum of Boxes (CDR-
SB) Scores for Female Subjects. Female Subjects taking
ReBuilder saw a reducon in demena severity on
the CDR-SB. Note that the score scale on the Y-axis is
invertedtoshowthatadecreasingCDR-SBscoreindicates
improvementofsymptoms.
Figure 3E Mean Clinical Demena Rang Sum of Boxes(CDR-SB)
ScoresforMaleSubjects.MalesubjectstakingReBuilder
reducedtheirdemenarangontheCDR-SB.Notethat
the score scale on the Y-axis is inverted to show that
a decreasing CDR-SB score indicates improvement of
symptoms.2015.
Discussion
The subjects with mild and moderate AD in our pilot study
experienced clinically meaningful stabilizaon in their disease
progressionovera12 monthperiodcomparedwith thedecline
expectedbasedontheBernick study[109].Theresultsformild
andmoderateAD subjects occurredregardlessof the subjects’
age,gender,orgenecstatuswithrespecttotheAPOE4genec
variant[111-114]. Thebenet of reduced mental decline byall
measures was greaterin paents diagnosed with mild AD and
less pronounced in moderate AD subjects. This suggests that
treatmentwithReBuilderisbenecialregardlessofage,gender,
APOE4 status, or disease severity when added to standard AD
treatment.
Thoughnoquantavebiomarkerstudiesweredoneduringthis
pilotstudy,theposiveeectsseenincognivefunconsuggest
that there are biological changes taking place that should be
invesgatedfurther.ReBuilderiscomposedenrelyofbotanical
substancesthataregenerallyregardedassafe(GRAS)bytheFDA,
andnodeleterioussideeectswere reportedorobservedthat
wereaributedtoReBuilderinthispilotstudy.Therefore,thereis
thepotenalforReBuildertonotonly  usedas asupplemental
AD treatment, but also prophylaccally as a part of a normal
individual’sdailydietarysupplementregimen.
While we cannot make denive claims on the success of
ReBuilderdue tothesmall number of subjects inthispilot, we
cansaythattheimprovementincognivefunconthatwehave
seeninsubjectstakingReBuilderwarrantsfurtherstudyinalarger
ADcohortwithbiomarkerassessment.Infutureclinical studies,
advancedimaging technologies[33,115-120]shouldbeusedto
verifythatReBuilderhas eectson structuraloutcomessuchas
amyloidplaques,Tautangles,andneuronallossprevenonwith
me.
be

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Figure 3F Mean Clinical Demena Rang Sum of Boxes (CDR-SB)
ScoresforAPOE4Subjects.SubjectstakingReBuilderwho
areposive fortheAPOE4 genevariantsaw a reducon
in demena symptoms, on average, as measured by
the CDR-SB.  Note that the score scale on the Y-axis is
invertedtoshowthatadecreasingCDR-SBscoreindicates
improvementofsymptoms.
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11
2018
Vol. 3 No. 3: 14
Journal of Clinical Medicine and Therapeutics
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