biostudies-literatureUnknownThomassen JQNIH HHSAmong the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E gene (<i>APOE</i>) ε2/ε3/ε4 polymorphism remains the longstanding benchmark for genetic disease risk with a consistently large effect across studies^1-10. Despite this massive signal, the exact mechanisms for how ε4 increases and for how ε2 decreases dementia risk is not well-understood. Importantly, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in s4 carriers^11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASmedRxiv : the preprint server for health sciences2025.05.07.25327065https://www.ebi.ac.uk/biostudies/studies/S-EPMC12083631biostudies-literature&lt;i&gt;APOE&lt;/i&gt; stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease.PMC12083631OT2 OD027852OT2 OD027060OT2 OD032100Rossi Gde Mendonca AJonson CWilliams JTesi NGim JAarsland DKucukali FPinol-Ripoll GStordal EMartiskainen HScherbaum NGhidoni RJerez PABorroni BPopp JSquassina ASeripa DScheffler KMoebus SPorcel LMBillingsley KFladby TGrunblatt Evan der Flier WMLeinonen VLipponen AAmin NThomassen JQCao HMoreno FBullido MJNacmias BRoyo JLFu AKYFernandez MVSanchez-Juan PUlms BSims RYoon DSchneider AHeilmann-Hemibach SRamirez ADufouil CSelbæk GIkeuchi Tde Rojas IRongve ALambert JCGraff CHolmans PAKim YRuiz ADaniele AIp NYLee KHGalimberti DPijnenburg YALReal LMKehoe PGKikuchi MScarmeas NMir PMakarious MSanchez-Garcia FAmouyel PHampton LGiedraitis VSpallazzi MAndreassen OAHolstege HBellenguez CPeters OArosio BGrimmer TSandau NJessen FCarracedo ACookson MWiltfang JSolfrizzi VTremolizzo Lvan der Lee SDichgans MGarcia-Ribas GHeikkinen SDebette SGarcia PBoada MHausner LMok KYHiltunen MFratiglioni LGarcia-Alberca JMHort JNalls MDeckert JDuzel ETripathi KPSleegers KEscott-Price VCastillo-Morales AKuznetsov NMehrabian SRiedel-Heller SSaez MEMiyashita AHanon OFrikke-Schmidt RBlauwendraat CJensen Kvan Duijn CMecocci PDjurovic SNicolas GParnetti LPerez-Tur JAlvarez VIngelsson MMasullo CSingleton ABBergh SGrenier-Boley BPastor PRujescu DDols-Icardo ORodriguez-Rodriguez ERainero ILuo JBossu PSaltvedt ISanchez-Valle Rfalse&lt;i&gt;APOE&lt;/i&gt; stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease.Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E gene (<i>APOE</i>) ε2/ε3/ε4 polymorphism remains the longstanding benchmark for genetic disease risk with a consistently large effect across studies^1-10. Despite this massive signal, the exact mechanisms for how ε4 increases and for how ε2 decreases dementia risk is not well-understood. Importantly, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in s4 carriers^11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWAS2025-01-01T00:00:00Z2025 May2026-04-08T19:09:12.752Z2026-04-08T11:58:25.326ZS-EPMC120836314038539110.1101/2025.05.07.25327065