biostudies-literatureLe Borgne JNIA NIH HHSNHLBI NIH HHS2335-2346https://www.ebi.ac.uk/biostudies/studies/S-EPMC12092188biostudies-literatureUnknown30(6)Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10^-⁸) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10^-⁶). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq2Molecular psychiatryX-chromosome-wide association study for Alzheimer's disease.PMC12092188U24 AG021886P30 AG072975RC2 AG036528P30 AG072977U24 AG072122P30 AG066514U01 AG032984R01 AG062634U24 AG041689P01 AG060882R01 HL105756P30 AG066508Hamilton-Nelson KRossi GHyman Bde Mendonca AScheltens PWilliams Jvan der Flier WLeverenz JSchellenberg GDKucukali FBrewer JValladares OPinol-Ripoll GPaulson HMartin EScherbaum NDeCarli CGhidoni RFernandez VReiman EBorroni BPopp JSquassina ANaj ATraykov LSeripa DRoberson EEADB, GR@ACE, DEGESCO, EADI, GERAD, DemGene, FinnGen, ADGC, CHARGESano MCruchaga CLevey ACantwell LMoebus SSoininen HYoung JRiemenschneider MGrunblatt EDeStefano AKukull WAmin NThomassen JQMoreno FHenderson VBullido MJNacmias BKleineidam LRoyo JLLopez OSanchez-Juan PBoland APasquier FSims RCastillo ASchneider ARamirez AAsthana SKunkle BDufouil CCraft SYounkin SGarcia-Gonzalez PVarma Ade Rojas ISchneider JLambert JCLaFerla FGraff CVerhey FKamboh MIVyhnalek MSmall SBush WRuiz ADaniele AGalimberti DReal LMPijnenburg YALKehoe PGDupuis JChui HScarmeas NAhmad SMir PDalmasso CRamakers IWisniewski TCrane PAmouyel PWang LGeorge-Hyslop PSGiedraitis VSpallazzi MAndreassen OAHolstege HMolina-Porcel LDe Jager PBellenguez CPeters OPuerta RLe Borgne JGrabowski TArosio BGrimmer TWang LSJessen FForoud TWiltfang Jvan der Lee SSolfrizzi VTremolizzo LDichgans MHeikkinen SDebette SHaines JCampos-Martin RVassar RRodriguez OGDeleuze JFDamotte VHausner LHeilmann-Heimbach SBoada MStrittmatter SHiltunen MPapenberg GFarrer LGarcia-Alberca JMHort JTripathi KPDeckert JDuzel ESleegers KBis JMehrabian SRiedel-Heller STegos TSaykin AHanon OFrikke-Schmidt RLipton RPericak-Vance MSwerdlow RMecocci PMorris JNicolas GPerez-Tur JParnetti LAlvarez VIngelsson MVan Duijn CKuzma AMayeux RPalmal SMasullo CMcKee AGrenier-Boley BSlifer SPastor PRujescu DVan Eldik LDols-Icardo OSeshadri SAlbert MRodriguez-Rodriguez EGomez LRainero IChoi SHTsolaki Mvan Swieten JBossu PGoate ASanchez-Valle RPetersen RfalseX-chromosome-wide association study for Alzheimer's disease.Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10^-⁸) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10^-⁶). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq22025-01-01T00:00:00Z2025 Jun2026-06-01T10:22:19.337Z2026-04-08T11:22:11.941ZS-EPMC120921883963300610.1038/s41380-024-02838-5