Abstract Alzheimer?sdisease(AD),thefourthleadingcauseofdeathindevelopedcountriesandoneof themostcommonformsofdementias,isknowntohaveastronggeneticcomponent.Late- onsetAD(LOAD),whichconstitutes>99%ofADcases,hasbeenestimatedtobeupto80% heritable.TheAPOEalleleisthemostprominentgeneticriskfactorforLOAD,accountingforup to30%ofLOADheritability,andappearstomodulateADriskinanisoform-dependentmanner: APOE4isthemajorrisk-conferringgenotypewhileAPOE2isprotectiveofdiseaseand positivelyassociatedwithcognitivelongevity.However,themechanismbywhichAPOEvariants modulateriskfororprotectionfromADandtheirinteractionwithothergeneticriskfactorsin mediatingLOADisstillpoorlyunderstood.Functionalperturbationtostudyhowmultiplegenetic hitscancollaboratetodevelopageneticriskprofileofLOADwouldbehighlyvaluablefor identifyingandprioritizingpotentialtherapeuticpathways.Todothis,wewillfirstdevelopanin vitroco-culturesystemforstudyingAPOE2andAPOE4variantsinisogenichumanEScell- derivedneuronsandastrocytes.Tounderstandthedifferentialcontributionofthesetwo isoformstoneuronaldeath,wewillemploygenome-scaleCRISPR-Cas9screensforthe systematicgeneticinterrogationoftheAPOEinteractome.Theseexperimentswillbethefirst geneticscreenlookingattheroleofAPOE2andAPOE4inahumanmodelof neurodegeneration,acentralphenotypeofAlzheimer?sdisease.Weaimtoidentifykeygenes andpathwaysthatmediatethesystems-levelcellularandfunctionaldifferencescausedby APOEallelesthatcanprotectfromordriveneuronalatrophy.Thiswillhelpprovideinsightinto theunderlyingmechanismsofAPOE-mediatedneurodegenerationandhasthepotentialto providenoveltargetsfortherapeuticintervention.