ResearchProposal

Abstract
Thisresearchprojectwilllookatthepathologyofalzheimer'sdiseaseandcurrent
advancementsinmedicineseekingtocurethedisease.Specificquestionsofinterestinclude:
Whatisthecauseofalzheimer'sdisease?
Whatcircumstancescanleadtoalzheimer'sdisease?
Whatmethodsaredoctorsandscientistsutilizingtotreatalzheimer'sdisease?
Whatresearchandadvancementsarebeingmadetocurealzheimer's
disease?
Alzheimer'sDisease,alsoknownasAD,isaneurodegenerativediseasethatslowlyerodes
thebraincausingindividualstolosememory,linguisticability,andothercognitivefunction.
ADisresponsibleforalargemajorityofdementia.Itisalsooneofthecostliestdiseasesto
treatandlivewithintheUnitedStatesandotherdevelopingcountries.Thediseaseaffects
6%ofindividualsovertheageof65
(WorldHealthOrganization,2015)
,accountingforover
35millionpeopleworldwide
(Burns,2009)
.Alzheimer'sstartsasbasicmemorylossandmost
commonlyassociatedwithageing.Thediseasethenprogressestothesecondphasewhich
involvesconfusion,forgettingmajoreventssuchasappointments,andabsentmindedness.
Themiddlephaseinvolvesspeechproblems,repetitioninconversation,andaninabilityto
learnandremembernewthings.Latestagealzheimer'sinvolvescompleteattitudechanges,a
debilitatinglackofcognitivefunction,andlossofselfawareness.Thediseasewilleventually
degradethebrainsabilitytocontrolbasicbodilyfunctionswhichleadstodeath.Currently
therearenoknownwaystotreatorcureADandotherformsofdementia.Theonlymedical

progressthathasbeenmadeismakingliveseasierforpatientswithAD.Clinicaltrialsare
currentlyinprogresstotreatpatientswithAD.
ExperimentalQuestion
Currently,researchersstudyingalzheimer'sarelookingatmanydifferentphasesofthe
disease,differenttypesofdrugs,andthecausesofthedisease.Thereisrelativelylittle
knownabouttheoriginsofthediseaseorthecausesofthediseaseamongindividuals.Some
neuroscientistsbelievethatthediseaseishereditaryandcausedbygenetics,othersbelieve
thatitcanoccurduetoenvironmentalfactorssuchasdietandlifedecisions,othersbelieve
thatthediseaseistoosporadictobeclassifiedassuchandthatthediseaseisaresultof
dysfunctionofpartsofthecellofstructuresinthebrain.Thisresearchisattemptingtoanswer
atleastpartofthatquestion.
ResearchQuestion:
IsAlzheimerstheresultofgeneticmutationoftheamyloidprecursor
proteins?
Background
Thetheoryofgeneticmutationessentiallystatesthatageneticmutationoccursinindividuals
thatallowsaspecifictypeofproteincalledamyloidbetatodevelopinthebrainandharmand
eventuallykillneuronsleadingtocognitivedegeneration.Whiletheresearchisstill
inconclusive,thereisageneralconsensusthatamyloidproteinshaveanaffectonthe
developmentofAD.Thereisdisputethattheprevalenceofamyloidproteinsinthebrainarea
resultofageneticmutationasopposedtoabyproductofthetruecauseofAD.Onefactor
thatstronglysupportsthecaseforgeneticmutationistheprevalenceofamyloidproteinsthat
latertranslatetoADinpatientswithdownsyndrome.Downsyndromeiscausedbyanextra
geneinthepatient'sgeneticcode,thesamegenethatestablishestheprecursorforamyloid
proteins.Inotherwords,patientswithdownsyndromearefarmorelikelytobediagnosedwith

ADbecauseofageneticmutationcausingamyloidprecursors.Morepromisingsignshave
beendiscoveredinpatientstakingdrugstoreduceandcontrolamyloidproteins.Thebiotech
firmBiogensuccessfullyimprovedcognitivefunctionamongearlystagealzheimer'spatients
usingaspecificantibody.Otherresearchisbeingdonetoanalyzeandexperimentwith
amyloidproteinsandthegeneticmutationitmayspurfrom.Ifthishypothesisisproved
correct,doctorswillbeabletoidentifyADbeforeitbeginstoshowsymptomsanddevelopa
drugtoremovetheproteinsfromthebrain.
ModelOrganism
ThemodelorganismthatIwilluseinthisresearchstudyismice.Duetotherelativelysimple
neurologicalstructureofc.elegansandtheundocumentedimpactofamyloidproteinsinthat
organism,miceisthenextbestoptionforresearchingneurologicaldegeneration,alsoknown
asAD.Micehavebeenusedtoresearchamyloidproteinprevalencebefore.Whilelookingat
amyloidproteinsinmicebrainsatStanfordUniversityin2013,researcherslookedathowthe
proteinsaffectedsynapsesandeventuallyneuralcognition.Theresearchshowedthatmice
thatareaffectedbymemorylosssimilartoalzheimer'shaveamyloidproteinclusterswithin
theirbrainsataveryearlyage.Thatspecificstudyamongothersareproofthatmicecanbe
usedasaneffectivemodelorganismwhenlookingatamyloidrelatedmemoryloss.During
thebeginningsofamyloidresearch,asuitableanimalmodelwasdifficulttofindbecauseofa
lackofgeneticmutationallowingfortheprecursorofamyloidproteins.Progresswasmadein
the1990sthatdiscoveredtransgenic,orartificiallymutatedgenesinmice,couldallowfor
amyloidproteinproductionandleadtoalzheimer'sinthemice.Thecorrelationhowever
betweenthemutationhasnotyetbeendiscovered.Tryingtodiscoverthatconnectionispart
ofthisresearchstudy.
ExperimentalTechnique

Thisresearchstudywillbelookingatthespecificeffectsthatamyloidproteinshaveinthe
brainandwhatcausesthemtooccur.Tobeginwewillmeasuretheeffectthatartificially
producedamyloidproteinshaveonthebraintoensurethatamyloidproteinshaveaneural
degenerativeeffectonthemodelorganismsweareusing.Wewillinjectorartificiallyplace
amyloidproteinsintothebrainandthenusingelectrophysiology,wewillidentifyneural
degenerationandchangesatthecellularlevel.Thisimagingtechniquewillbepairedwith
moretraditionalbrainimagingsuchasPETandMRItolookatneuraldegenerationwithinthe
brainasawhole.Oncethefirstphaseofresearch(artificialamyloidproteineffects),hasbeen
completedwecanmoveontothesecondphasewhichwilllookatthegeneticoriginof
amyloidproteinsandthecorrelationbetweengeneticmutationandtheprevalenceofamyloid
proteinprecursors.Toconducttheresearchwewillneedtousetransgenicmicetoartificialize
amyloidproteinproductionandseetheresultsthatitcouldhaveinmicethatotherwisewould
notshowsymptomsofAD.Inotherwordswewilltakeaperfectlyhealthymouseand
geneticallymutateitsoffspringtoseehowthatmutationcouldcauseAD.Discoveringthat
mutationwillhelpusfindoutspecificallyifgeneticscausesADandhowwecanfixthe
mutation.
SocietalandEthicalImpacts
Thisresearchisrelativelystandardprocedureanddoesnotpushthelimitsofscientific
explorationtoofar.Thereisanethicalconcernwithusingmiceastestsubjectsespecially
giventhefactthatmostofthemareexpectedtodieduringthestudy.Themicearegoingto
beartificiallygivenamyloidprecursorstoseewhattheaffectofthoseproteinsareinthebrain.
Ifourhypothesisiscorrect,themicewillbediagnosedwithADandlaterdie.Orcomplications
willarisewiththeartificialimplantationthatwilleventuallykillthem.Eitherwaythemicewill
die.Whilemanyanimalrightsactivistsareconcernedbythis,itisimperativetorememberthat

thisresearchispavingthewayforacuretoadiseasethatkillsnearly500,000peopleeach
year(AlzheimersAssociation,2015).Anotherconcernwiththisresearchisthededicationof
resourcestothisstudywhenthedataisinconclusivethatthisisthecorrectpathtotakein
researchingAD.ManywithinthescientificcommunitybelievethatthecauseofADisthings
otherthangenetics.Anadditionalethicalconcernthatisprevalentinthisstudyisthe
manipulationofneuralactivityinanartificialcapacity.Byimplantingamyloidproteinsintothe
brainsofmiceinanattempttospurADcouldbeseentosomeasadangerousweaponif
proventobeeffective.Theconcernisthatsomeonecouldusethistechniquetodestroythe
memoryofanotherindividualiftheywish.Allthataside,giventherelativelyproceduralnature
ofthisstudy,manyofthesocietalandethicalimpactsofstudiesrelatedtothisonehave
alreadybeenacceptedbythescientificcommunityandthepublicatlarge.
References
http://www.who.int/mediacentre/factsheets/fs362/en/
http://www.bmj.com/content/338/bmj.b158
http://www.fiercebiotech.com/story/biogenbarrelstowardalzheimersphaseiiiafterpromising
earlysignal/20141202
http://www.utsandiego.com/news/2015/mar/01/paulaisenalzheimers/all/?print
https://www.alz.org/national/documents/Imaging_consensus_report.pdf
http://med.stanford.edu/news/allnews/2013/09/scientistsrevealhowbetaamyloidmaycaus
ealzheimers.html
http://www.ncbi.nlm.nih.gov/pubmed/7845465
http://www.alz.org/alzheimers_disease_facts_and_figures.asp
http://www.ncbi.nlm.nih.gov/pubmed/25763997