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 Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

1st Department of Neurology Aiginition Hospital National and Kapodistrian University of Athens Medical School Athens Greece

1st Department of Neurology Medical school Aristotle University of Thessaloniki Thessaloniki Makedonia Greece

Aging Research Center Department of Neurobiology Care Sciences and Society Karolinska Institutet and Stockholm University Stockholm Sweden

Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam The Netherlands

Alzheimer Research Center and Memory Clinic Andalusian Institute for Neuroscience Málaga Spain

Alzheimer's Centre Reina Sofia CIEN Foundation ISCIII Madrid Spain

Alzheimer's Disease and Other Cognitive Disorders Unit Neurology Service Hospital Clínic of Barcelona Fundació Recerca Clinic Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer and University of Barcelona Barcelona Spain

Alzheimer's Disease and Other Cognitive Disorders Unit Service of Neurology Hospital Clínic of Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer University of Barcelona Barcelona Spain

Arizona Alzheimer's Consortium Phoenix AZ USA

Banner Alzheimer's Institute Phoenix AZ USA

Boston University and the NHLBI's Framingham Heart Study Boston MA USA

Center for Cognitive Disorders Department of Psychiatry and Psychotherapy Technical University of Munich School of Medicine and Health Klinikum rechts der Isar Munich Germany

Center for Cognitive Neurology and Departments of Neurology New York University School of Medicine New York NY USA

Centre for Memory Disturbances Lab of Clinical Neurochemistry Section of Neurology University of Perugia Perugia Italy

Centro de Biología Molecular Severo Ochoa Madrid Spain

Charité Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Institute of Psychiatry and Psychotherapy Hindenburgdamm 30 12203 Berlin Germany

CHU de Bordeaux Pole Santé Publique Bordeaux France

CIBERNED Network Center for Biomedical Research in Neurodegenerative Diseases National Institute of Health Carlos 3 Madrid Spain

Cleveland Clinic Lou Ruvo Center for Brain Health Cleveland Clinic Cleveland OH USA

Clinic of Neurology UH Alexandrovska Medical University Sofia Sofia Bulgaria

Cluster of Excellence Cellular Stress Responses in Aging associated Diseases University of Cologne Cologne Germany

Cognitive and Behavioural Neurology Department of Continuity of Care and Frailty ASST Spedali Civili Brescia Brescia Italy

Cognitive Neurology and Alzheimer's Disease Center Northwestern University Feinberg School of Medicine Chicago IL USA

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Disease University of Cologne Cologne Germany

Complex Genetics of Alzheimer's Disease Group VIB Center for Molecular Neurology VIB Antwerp Belgium

Department for Neurodegenerative Diseases and Geriatric Psychiatry University Hospital Bonn Venusberg Campus 1 53127 Bonn Germany

Department of Biomedical Sciences Section of Neuroscience and Clinical Pharmacology University of Cagliari Cagliari Italy

Department of Biomedical Sciences University of Antwerp Antwerp Belgium

Department of Biomedical Surgical and Dental Sciences University of Milan Milan Italy

Department of Biostatistics Boston University Boston MA USA

Department of Biostatistics Boston University School of Public Health Boston MA USA

Department of Child and Adolescent Psychiatry and Psychotherapy University Hospital of Psychiatry Zurich University of Zurich Zurich Switzerland

Department of Clinical and Experimental Sciences University of Brescia Brescia Italy

Department of Clinical Biochemistry Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Clinical Genetics VU University Medical Centre Amsterdam The Netherlands

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Clinical Sciences and Community Health University of Milan 20122 Milan Italy

Department of Complex Trait Genetics Center for Neurogenomics and Cognitive Research Amsterdam Neuroscience Vrije University Amsterdam The Netherlands

Department of Epidemiology and Biostatistics Case Western Reserve University Cleveland OH USA

Department of Epidemiology and Population Health Stanford University Stanford CA USA

Department of Epidemiology Biostatistics and Occupational Health McGill University Montreal QC Canada

Department of Epidemiology Boston University Boston MA USA

Department of Epidemiology Erasmus MC Rotterdam The Netherlands

Department of Epidemiology University of Washington Seattle WA USA

Department of Geriatric Psychiatry Central Institute for Mental Health Mannheim Faculty Mannheim University of Heidelberg Heidelberg Germany

Department of Geriatric Psychiatry University Hospital of Psychiatry Zürich Zürich Switzerland

Department of Hematology and Stem Cell Transplant Vito Fazzi Hospital Lecce Italy

Department of Human Genetics University of Pittsburgh Pittsburgh PA USA

Department of Medical and Molecular Genetics Indiana University Indianapolis IN USA

Department of Medicine and Surgery Unit of Neurology University Hospital of Parma Parma Italy

Department of Medicine Boston University Boston MA USA

Department of Medicine Cardiovascular Health Research Unit University of Washington Seattle WA USA

Department of Medicine Tanz Centre for Research in Neurodegenerative Disease Temerty Faculty of Medicine University of Toronto and University Health Network Toronto ON USA

Department of Medicine University of Washington Seattle WA USA

Department of Medicine University of Wisconsin Madison WI USA

Department of Neurobiology and Behavior University of California Irvine Irvine CA USA

Department of Neurological Sciences Rush University Medical Center Chicago IL USA

Department of Neurology Albert Einstein College of Medicine New York NY USA

Department of Neurology and Neurological Sciences Stanford University Stanford CA USA

Department of Neurology Bordeaux University Hospital Bordeaux France

Department of Neurology Boston University Boston MA USA

Department of Neurology Boston University School of Medicine Boston MA USA

Department of Neurology Columbia University New York NY USA

Department of Neurology Emory University Atlanta GA USA

Department of Neurology Erasmus MC Rotterdam The Netherlands

Department of Neurology Hospital Universitario Donostia San Sebastian Spain

Department of Neurology Johns Hopkins University Baltimore MD USA

Department of Neurology Massachusetts General Hospital Harvard Medical School Boston MA USA

Department of Neurology Mayo Clinic Rochester MN USA

Department of Neurology Northwestern University Feinberg School of Medicine Chicago IL USA

Department of Neurology University of Alabama at Birmingham Birmingham AL USA

Department of Neurology University of California Davis Sacramento CA USA

Department of Neurology University of Southern California Los Angeles CA USA

Department of Neurology University of Washington Seattle WA USA

Department of Neurology Washington University St Louis MO USA

Department of Neuroscience Mayo Clinic Jacksonville FL USA

Department of Neuroscience Mount Sinai School of Medicine New York NY USA

Department of Neuroscience Psychology Drug Research and Child Health University of Florence Florence Italy

Department of Neuroscience Rita Levi Montalcini University of Torino Torino Italy

Department of Neuroscience Università Cattolica del Sacro Cuore Rome Italy

Department of Neurosciences University of California San Diego La Jolla CA USA

Department of Old Age Psychiatry and Cognitive Disorders University Hospital Bonn University of Bonn Bonn Germany

Department of Ophthalmology Boston University Boston MA USA

Department of Pathology and Immunology Washington University St Louis MO USA

Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

Department of Pathology Boston University Boston MA USA

Department of Pathology Rush University Medical Center Chicago IL USA

Department of Population and Quantitative Health Sciences and Cleveland Institute for Computational Biology Case Western Reserve University Cleveland OH USA

Department of Psychiatry and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases San Antonio TX USA

Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration Washington University School of Medicine St Louis MO USA

Department of Psychiatry and Psychotherapy Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Department of Psychiatry and Psychotherapy LVR Klinikum Essen University of Duisburg Essen Germany Medical Faculty Duisburg Germany

Department of Psychiatry and Psychotherapy University Medical Center Goettingen Goettingen Germany

Department of Psychiatry Mount Sinai School of Medicine New York NY USA

Department of Psychiatry New York University New York NY USA

Department of Psychiatry Psychosomatics and Psychotherapy Center of Mental Health University Hospital of Würzburg Würzburg Germany

Department of Psychiatry University of Arizona Phoenix AZ USA

Department of Public Health and Caring Sciences Geriatrics Uppsala University Uppsala Sweden

Department of Public Health Sciences University of Miami Miller School of Medicine Miami FL USA

Department of Radiology Indiana University Indianapolis IN USA

Department of Radiology University of Washington Seattle WA USA

Depatamento de Especialidades Quirúrgicas Bioquímica e Inmunología Facultad de Medicina Universidad de Málaga Málaga Spain

Division of Clinical Geriatrics Department of Neurobiology Care Sciences and Society Karolinska Institutet Stockholm Sweden

Division of Neurogenetics and Molecular Psychiatry Department of Psychiatry and Psychotherapy University of Cologne Medical Faculty Cologne Germany

Division of Psychological Medicine and Clinical Neuroscience School of Medicine Cardiff University Wales UK

Dr John T Macdonald Foundation Department of Human Genetics University of Miami Miami FL USA

Estudios en Neurociencias y Sistemas Complejos CONICET HEC UNAJ Buenos Aires Argentina

Faculty of Medicine University of Lisbon Lisbon Portugal

Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Fundació Docència i Recerca MútuaTerrassa Terrassa Barcelona Spain

Geriatric Research Education and Clinical Center University of Wisconsin Madison WI USA

Geriatric Unit Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico 20122 Milan Italy

German Center for Neurodegenerative Diseases Berlin Germany

German Center for Neurodegenerative Diseases Bonn Germany

German Center for Neurodegenerative Diseases Goettingen Germany

German Center for Neurodegenerative Diseases Magdeburg Germany

German Center for Neurodegenerative Diseases Munich Germany

Gerontology and Geriatric Medicine Center on Diabetes Obesity and Metabolism Wake Forest School of Medicine Winston Salem NC USA

Gertrude H Sergievsky Center Columbia University New York NY USA

Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases San Antonio TX USA

Inserm Bordeaux Population Health Research Center UMR 1219 Univ Bordeaux ISPED CIC 1401 EC Univ Bordeaux Bordeaux France

Institut de Recerca Biomedica de Lleida Lleida Spain

Institute for Regenerative Medicine University of Zürich Zurich Switzerland

Institute for Stroke and Dementia Research University Hospital LMU Munich Munich Germany

Institute for Urban Public Health University Hospital of University Duisburg Essen Essen Germany

Institute of Biomedicine University of Eastern Finland Kuopio Finland

Institute of Clinical Medicine Neurology University of Eastern Finland Kuopio Finland

Institute of Clinical Medicine University of Oslo Oslo Norway

Institute of Cognitive Neurology and Dementia Research Otto von Guericke University Magdeburg Germany

Institute of Gerontology and Geriatrics Department of Medicine and Surgery University of Perugia Perugia Italy

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany

Institute of Neurology Catholic University of the Sacred Heart Rome Italy

Institute of Social Medicine Occupational Health and Public Health University of Leipzig 04103 Leipzig Germany

Instituto de Investigacion Sanitaria 'Hospital la Paz' Madrid Spain

Instituto de Investigación Sanitaria del Principado de Asturias Oviedo Spain

Interdisciplinary Department of Medicine Geriatric Medicine and Memory Unit University of Bari A Moro Bari Italy

IRCCS Fondazione Don Carlo Gnocchi Florence Italy

Klinik für Psychiatrie und Psychotherapie Saarbrücken Germany

Krembil Brain Institute University Health Network Toronto ON Canada

Laboratorio de Genética Hospital Universitario Central de Asturias Oviedo Spain

Laboratory of Experimental Neuropsychobiology IRCCS Santa Lucia Foundation Rome Italy

Laboratory of Genetics Immunology and Human Pathology Faculty of Science of Tunis University of Tunis El Manar 2092 Tunis Tunisia

Maastricht University Department of Psychiatry and Neuropsychologie Alzheimer Center Limburg Maastricht The Netherlands

Martin Luther University Halle Wittenberg University Clinic and Outpatient Clinic for Psychiatry Psychotherapy and Psychosomatics Halle Germany

Medical Science Department iBiMED Aveiro Portugal

Memory Clinic Department of Neurology Charles University 2nd Faculty of Medicine and Motol University Hospital Praha Czech Republic

Memory Disorders Unit Department of Neurology Hospital Universitari Mutua de Terrassa Terrassa Barcelona Spain

Michigan Alzheimer's Disease Center Department of Neurology University of Michigan Ann Arbor MI USA

Molecular Markers Laboratory IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli Brescia 25125 Italy

Munich Cluster for Systems Neurology Munich Germany

Neurodegenerative Diseases Unit Fondazione IRCCS Ca' Granda Ospedale Policlinico Milan Italy

Neurogenomics Division Translational Genomics Research Institute Phoenix AZ USA

Neurological Tissue Bank Biobank Hospital Clinic FRCB IDIBAPS Barcelona Spain

Neurology Service Marqués de Valdecilla University Hospital Santander Spain

Neurology Unit IRCCS Fondazione Policlinico Universitario A Gemelli Rome Italy

Neurology Unit San Gerardo Hospital Monza and University of Milano Bicocca Milan Italy

Neuroscience Center Zurich University of Zurich and ETH Zurich Zurich Switzerland

Neurosciences Area Instituto Biodonostia San Sebastian Spain

NORMENT Centre Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Nuffield Department of Population Health Oxford University Oxford UK

Old Age Psychiatry Department of Psychiatry Lausanne University Hospital Lausanne Switzerland

Penn Neurodegeneration Genomics Center Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

Program in Cellular Neuroscience Neurodegeneration and Repair Yale University New Haven CT USA

Program in Medical and Population Genetics Broad Institute Cambridge MA USA

Program in Translational Neuro Psychiatric Genomics Institute for the Neurosciences Department of Neurology and Psychiatry Brigham and Women's Hospital and Harvard Medical School Boston MA USA

Research Center and Memory Clinic ACE Alzheimer Center Barcelona Universitat Internacional de Catalunya Barcelona Spain

Rush Alzheimer's Disease Center Rush University Medical Center Chicago IL USA

Sanders Brown Center on Aging and University of Kentucky Alzheimer's Disease Research Center Department of Neuroscience University of Kentucky Lexington KY USA

Sant Pau Memory Unit Institut de Recerca Sant Pau Department of Neurology Hospital de la Santa Creu i Sant Pau Barcelona Spain

Tanz Centre for Research in Neurodegenerative Diseases Departments of Medicine and Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada

Taub Institute for Research in Alzheimer's Disease and the Aging Brain The Gertrude H Sergievsky Center Depatment of Neurology Columbia University New York NY USA

Taub Institute for Research on Alzheimer's Disease and the Aging Brain Department of Neurology Columbia University Irving Medical Center 630 West 168th Street New York NY 10032 USA

Taub Institute on Alzheimer's Disease and the Aging Brain Department of Neurology Columbia University New York NY USA

The John P Hussman Institute for Human Genomics University of Miami Miami FL USA

Translational Health Sciences Bristol Medical School University of Bristol Bristol UK

UK Dementia Research Institute Cardiff University Cardiff UK

Unidad Clínica de Enfermedades Infecciosas y Microbiología Hospital Universitario de Valme Sevilla Spain

Unidad de Trastornos del Movimiento Servicio de Neurología y Neurofisiología Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío CSIC Universidad de Sevilla Seville Spain

Unidad Mixta de Neurologia Genètica Instituto de Investigación Sanitaria La Fe Valencia Spain

Unit for Hereditary Dementias Theme Aging Karolinska University Hospital Solna 171 64 Stockholm Sweden

Unitat de Genètica Molecular Institut de Biomedicina de València CSIC Valencia Spain

Unitat Trastorns Cognitius Hospital Universitari Santa Maria de Lleida Lleida Spain

Univ Lille Inserm 1171 CHU Clinical and Research Memory Research Centre of Distalz Lille France

Univ Lille Inserm CHU Lille Institut Pasteur de Lille LabEx DISTALZ U1167 RID AGE Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement Lille France

Univ Rouen Normandie Normandie Univ Inserm U1245 and CHU Rouen Department of Genetics and CNRMAJ F 76000 Rouen France

Universidad Autónoma de Madrid Madrid Spain

Université de Paris EA 4468 APHP Hôpital Broca Paris France

Université Paris Saclay CEA Centre National de Recherche en Génomique Humaine 91057 Evry France

University Bordeaux Inserm Bordeaux Population Health Research Center Bordeaux France

University of Kansas Alzheimer's Disease Center University of Kansas Medical Center Kansas City KS USA

University of Miami Miller School of Medicine Miami FL USA

University of Pittsburgh Alzheimer's Disease Research Center Pittsburgh PA USA

Wisconsin Alzheimer's Disease Research Center Madison WI USA

Zurich Center for Integrative Human Physiology University of Zurich Zurich Switzerland

See more in PubMed

Lambert JC, Ramirez A, Grenier-Boley B, Bellenguez C. Step by step: towards a better understanding of the genetic architecture of Alzheimer’s disease. Mol Psychiatry. 2023;28:2716–27. PubMed PMC

Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet. 2022;54:412–36. PubMed PMC

Holstege H, Hulsman M, Charbonnier C, Grenier-Boley B, Quenez O, Grozeva D, et al. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease. Nat Genet. 2022;54:1786–94 PubMed PMC

Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019;51:414–30. PubMed PMC

Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat Genet. 2021;53:1276–82. PubMed PMC

Sims R, Van Der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet. 2017;49:1373–84. PubMed PMC

Carrel L, Brown CJ. When the lyon(Ized chromosome) roars: ongoing expression from an inactive X chromosome. Philos Trans R Soc B Biol Sci. 2017;372:20160355. PubMed PMC

Lyon MF. Gene action in the X-chromosom (Mus musculus L.). Nature. 1961;190:372–3. PubMed

Amos-Landgraf JM, Cottle A, Plenge RM, Friez M, Schwartz CE, Longshore J, et al. X chromosome-inactivation patterns of 1,005 phenotypically unaffected females. Am J Hum Genet. 2006;79:493–9. PubMed PMC

Shvetsova E, Sofronova A, Monajemi R, Gagalova K, Draisma HHM, White SJ, et al. Skewed X-inactivation is common in the general female population. Eur J Hum Genet. 2019;27:455–65. PubMed PMC

Zito A, Davies MN, Tsai PC, Roberts S, Andres-Ejarque R, Nardone S, et al. Heritability of skewed X-inactivation in female twins is tissue-specific and associated with age. Nat Commun. 2019;10:1–11. PubMed PMC

Busque L, Mio R, Mattioli J, Brais E, Biais N, Lalonde Y, et al. Nonrandom X-inactivation patterns in normal females: Lyonization ratios vary with age. Blood. 1996;88:59–65. PubMed

Tukiainen T, Villani AC, Yen A, Rivas MA, Marshall JL, Satija R, et al. Landscape of X chromosome inactivation across human tissues. Nature. 2017;550:244–8. PubMed PMC

Sun L, Wang Z, Lu T, Manolio TA, Paterson AD. eXclusionarY: 10 years later, where are the sex chromosomes in GWASs? Am J Hum Genet. 2023;110:903–12. PubMed PMC

Chen B, Craiu RV, Strug LJ, Sun L. The X factor: a robust and powerful approach to X-chromosome-inclusive whole-genome association studies. Genet Epidemiol. 2021;45:694–709. PubMed PMC

Smith SM, Douaud G, Chen W, Hanayik T, Alfaro-Almagro F, Sharp K, et al. An expanded set of genome-wide association studies of brain imaging phenotypes in UK Biobank. Nat Neurosci. 2021;24:737–45. PubMed PMC

Mallard TT, Liu S, Seidlitz J, Ma Z, Moraczewski D, Thomas A, et al. X-chromosome influences on neuroanatomical variation in humans. Nat Neurosci. 2021;24:1216–24. PubMed

Neri G, Schwartz CE, Lubs HA, Stevenson RE. XLID update 2017. Am J Med Genet A. 2018;176:1375. PubMed PMC

Hickman RA, O’Shea SA, Mehler MF, Chung WK. Neurogenetic disorders across the lifespan: from aberrant development to degeneration. Nat Rev Neurol. 2022;18:117–24. PubMed PMC

Ferretti MT, Santuccione Chadha A. The missing X factor in Alzheimer disease. Nat Rev Neurol. 2021;17:727–8. PubMed

Alzheimer Europe. Dementia in Europe yearbook 2019: estimating the prevalence of dementia in Europe. Alzheimer Europe; 2019. pp. 108.

Nichols E, Steinmetz JD, Vollset SE, Fukutaki K, Chalek J, Abd-Allah F, et al. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022;7:e105–25. PubMed PMC

Corrada MM, Brookmeyer R, Paganini-Hill A, Berlau D, Kawas CH. Dementia incidence continues to increase with age in the oldest old the 90+ study. Ann Neurol. 2010;67:114–21. PubMed PMC

Gilsanz P, Corrada MM, Kawas CH, Mayeda ER, Glymour MM, Quesenberry CP, et al. Incidence of dementia after age 90 in a multiracial cohort. Alzheimers Dement. 2019;15:497–505. PubMed PMC

Mayeda ER, Glymour MM, Quesenberry CP, Whitmer RA. Inequalities in dementia incidence between six racial and ethnic groups over 14 years. Physiol Behav. 2016;176:100–6. PubMed PMC

Matthews FE, Stephan BCM, Robinson L, Jagger C, Barnes LE, Arthur A, et al. A two decade dementia incidence comparison from the Cognitive Function and Ageing Studies I and II. Nat Commun. 2016;7:11398. PubMed PMC

Wolters FJ, Chibnik LB, Waziry R, Anderson R, Berr C, Beiser A, et al. Twenty-seven-year time trends in dementia incidence in Europe and the United States: the Alzheimer Cohorts Consortium. Neurology. 2020;95:E519–31. PubMed PMC

Shaw C, Hayes-Larson E, Glymour MM, Dufouil C, Hohman TJ, Whitmer RA, et al. Evaluation of selective survival and sex/gender differences in dementia incidence using a simulation model. JAMA Netw Open. 2021;4:e211001. PubMed PMC

Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, Bennett DA. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry. 2005;62:685–91. PubMed

Liesinger AM, Graff-Radford NR, Duara R, Carter RE, Hanna Al-Shaikh FS, Koga S, et al. Sex and age interact to determine clinicopathologic differences in Alzheimer’s disease. Acta Neuropathol. 2018;136:873–85. PubMed PMC

Oveisgharan S, Arvanitakis Z, Yu L, Farfel J, Schneider JA, Bennett DA. Sex differences in Alzheimer’s disease and common neuropathologies of aging. Acta Neuropathol. 2018;136:887–900. PubMed PMC

Buckley RF, Mormino EC, Rabin JS, Hohman TJ, Landau S, Hanseeuw BJ, et al. Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults. JAMA Neurol. 2019;76:542–51. PubMed PMC

Wisch JK, Meeker KL, Gordon BA, Flores S, Dincer A, Grant EA, et al. Sex-related differences in tau positron emission tomography (PET) and the effects of hormone therapy (HT). Alzheimer Dis Assoc Disord. 2021;35:164–8. PubMed PMC

Pereira JB, Harrison TM, La Joie R, Baker SL, Jagust WJ. Spatial patterns of tau deposition are associated with amyloid, ApoE, sex, and cognitive decline in older adults. Eur J Nucl Med Mol Imaging. 2020;47:2155–64. PubMed PMC

Edwards L, La Joie R, Iaccarino L, Strom A, Baker SL, Casaletto KB, et al. Multimodal neuroimaging of sex differences in cognitively impaired patients on the Alzheimer’s continuum: greater tau-PET retention in females. Neurobiol Aging. 2021;105:86–98. PubMed PMC

Filon JR, Intorcia AJ, Sue LI, Vazquez Arreola E, Wilson J, Davis KJ, et al. Gender differences in Alzheimer disease: brain atrophy, histopathology burden, and cognition. J Neuropathol Exp Neurol. 2016;75:748–54. PubMed PMC

Babapour Mofrad R, Tijms BM, Scheltens P, Barkhof F, Van Der Flier WM, Sikkes SAM, et al. Sex differences in CSF biomarkers vary by Alzheimer disease stage and APOE ϵ4 genotype. Neurology. 2020;95:e2378–88. PubMed

Hohman TJ, Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B, et al. Sex-specific association of apolipoprotein E with cerebrospinal fluid levels of tau. JAMA Neurol. 2018;75:989–98. PubMed PMC

Levine DA, Gross AL, Briceño EM, Tilton N, Giordani BJ, Sussman JB, et al. Sex differences in cognitive decline among US adults. JAMA Netw Open. 2021;4:1–13. PubMed PMC

Bloomberg M, Dugravot A, Dumurgier J, Kivimaki M, Fayosse A, Steptoe A, et al. Sex differences and the role of education in cognitive ageing: analysis of two UK-based prospective cohort studies. Lancet Public Health. 2021;6:e106–15. PubMed PMC

Lipnicki DM, Crawford JD, Dutta R, Thalamuthu A, Kochan NA, Andrews G, et al. Age-related cognitive decline and associations with sex, education and apolipoprotein E genotype across ethnocultural groups and geographic regions: a collaborative cohort study. PLoS Med. 2017;14:1–21. PubMed PMC

Ferretti MT, Iulita MF, Cavedo E, Chiesa PA, Dimech AS, Chadha AS, et al. Sex differences in Alzheimer disease—the gateway to precision medicine. Nat Rev Neurol. 2018;14:457–69. PubMed

Arenaza-Urquijo EM, Boyle R, Casaletto K, Anstey KJ, Vila-Castelar C, Colverson A, et al. Sex and gender differences in cognitive resilience to aging and Alzheimer’s disease. Alzheimers Dement. 2024;20:5695–719. PubMed PMC

Ferretti MT, Martinkova J, Biskup E, Benke T, Gialdini G, Nedelska Z, et al. Sex and gender differences in Alzheimer’s disease: current challenges and implications for clinical practice: position paper of the Dementia and Cognitive Disorders Panel of the European Academy of Neurology. Eur J Neurol. 2020;27:928–43. PubMed

Tifratene K, Robert P, Metelkina A, Pradier C, Dartigues JF. Progression of mild cognitive impairment to dementia due to AD in clinical settings. Neurology. 2015;85:331–8. PubMed

Lin KA, Choudhury KR, Rathakrishnan BG, Marks DM, Petrella JR, Doraiswamy PM. Marked gender differences in progression of mild cognitive impairment over 8 years. Alzheimers Dement Transl Res Clin Interv. 2015;1:103–10. PubMed PMC

Davis EJ, Broestl L, Williams G, Garay BI, Lobach I, Devidze N, et al. A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease. Sci Transl Med. 2020;12:eaaz5677. PubMed PMC

Zheng X, Wang S, Huang J, Li C, Shang H. Predictors for survival in patients with Alzheimer’s disease: a large comprehensive meta-analysis. Transl Psychiatry. 2024;14:1–9. PubMed PMC

Davis EJ, Solsberg CW, White CC, Miñones-Moyano E, Sirota M, Chibnik L, et al. Sex-specific association of the X chromosome with cognitive change and tau pathology in aging and Alzheimer disease. JAMA Neurol. 2021;78:1249–54. PubMed PMC

Yan Y, Wang X, Chaput D, Pieper AA, Woo JA, Kang DE, et al. X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women increases tauopathy vulnerability in women. Cell. 2022;185:3913–30.e19. PubMed PMC

Liu JZ, Erlich Y, Pickrell JK. Case-control association mapping by proxy using family history of disease. Nat Genet. 2017;49:325–31. PubMed

Jansen IE, van der Lee SJ, Gomez-Fonseca D, de Rojas I, Dalmasso MC, Grenier-Boley B, et al. Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers. Acta Neuropathol. 2022;144:821–42. PubMed PMC

Luck T, Riedel-Heller SG, Kaduszkiewicz H, Bickel H, Jessen F, Pentzek M, et al. Mild cognitive impairment in general practice: age-specific prevalence and correlate results from the German study on ageing, cognition and dementia in primary care patients (AgeCoDe). Dement Geriatr Cogn Disord. 2007;24:307–16. PubMed

Grande G, Vetrano DL, Fratiglioni L, Marseglia A, Vanacore N, Laukka EJ, et al. Disability trajectories and mortality in older adults with different cognitive and physical profiles. Aging Clin Exp Res. 2020;32:1007–16. PubMed PMC

Artero S, Ancelin ML, Portet F, Dupuy A, Berr C, Dartigues JF, et al. Risk profiles for mild cognitive impairment and progression to dementia are gender specific. J Neurol Neurosurg Psychiatry. 2008;79:979–84. PubMed

Kurki MI, Karjalainen J, Palta P, Sipilä TP, Kristiansson K. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023:613;508–18. PubMed PMC

Taliun D, Harris DN, Kessler MD, Carlson J, Szpiech ZA, Torres R, et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature. 2021;590:290–9. PubMed PMC

Auton A, Abecasis GR, Altshuler DM, Durbin RM, Bentley DR, Chakravarti A, et al. A global reference for human genetic variation. Nature. 2015;526:68–74. PubMed PMC

Loh PR, Danecek P, Palamara PF, Fuchsberger C, Reshef YA, Finucane HK, et al. Reference-based phasing using the Haplotype Reference Consortium panel. Nat Genet. 2016;48:1443–8. PubMed PMC

Walter K, Min JL, Huang J, Crooks L, Memari Y, McCarthy S, et al. The UK10K project identifies rare variants in health and disease. Nature. 2015;526:82–89. PubMed PMC

Clayton DG. Sex chromosomes and genetic association studies. Genome Med. 2009;1:1–7. PubMed PMC

Clayton DG. Testing for association on the X chromosome. Biostatistics. 2008;9:593–600. PubMed PMC

Ghosh A, Hartge P, Kraft P, Joshi AD, Ziegler RG, Chanock SJ, et al. Leveraging family history in population-based case-control association studies. Genet Epidemiol. 2014;38:114–22. PubMed PMC

Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–1. PubMed PMC

Magi R, Lindgren CM, Morris AP. Meta-analysis of sex-specific genome-wide association studies. Genet Epidemiol. 2010;34:846–53. PubMed PMC

Satizabal CL, Adams HH, Hibar DP, White CC. Genetic architecture of subcortical brain structures in 38,851 individuals. Physiol Behav. 2019;176:139–48. PubMed PMC

Aulchenko YS, Ripke S, Isaacs A, van Duijn CM. GenABEL: an R library for genome-wide association analysis. Bioinformatics. 2007;23:1294–6. PubMed

Marchini J, Howie B, Myers S, McVean G, Donnelly P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet. 2007;39:906–13. PubMed

Philipps V, Amieva H, Andrieu S, Dufouil C, Berr C, Dartigues JF, et al. Normalized mini-mental state examination for assessing cognitive change in population-based brain aging studies. Neuroepidemiology. 2014;43:15–25. PubMed

Kleineidam L, Chouraki V, Próchnicki T, van der Lee SJ, Madrid-Márquez L, Wagner-Thelen H, et al. PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment. Acta Neuropathol. 2020;139:1025–44. PubMed PMC

Wingo AP, Liu Y, Gerasimov ES, Vattathil SM, Liu J, Cutler DJ, et al. Sex differences in brain protein expression and disease. Nat Med. 2023;29:2224–32. PubMed PMC

Lukacsovich D, O’Shea D, Huang H, Zhang W, Youn JI, Chen XS, et al. MIAMI-AD (methylation in aging and methylation in AD): an integrative knowledgebase that facilitates explorations of DNA methylation across sex, aging, and Alzheimer’s disease. MedRxiv. 2023. PubMed PMC

de Leeuw CA, Mooij JM, Heskes T, Posthuma D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015;11:1–19. PubMed PMC

Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371:64–74. PubMed

Group WW. Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Organ. 1989;67:601–11. PubMed PMC

Lee HW, Jeonghoon C, Hyewon S, Karam K, Jinhee Y, Moonseok N, et al. Preso, a novel PSD-95-interacting FERM and PDZ domain protein that regulates dendritic spine morphogenesis. J Neurosci. 2008;28:14546–56. PubMed PMC

Piard J, Hu JH, Campeau PM, Rzońca S, Van Esch H, Vincent E, et al. FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis. Hum Mol Genet. 2018;27:589–600. PubMed PMC

Okbay A, Wu Y, Wang N, Jayashankar H, Bennett M, Nehzati SM, et al. Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals. Nat Genet. 2022;54:437–49. PubMed PMC

Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet. 2019;51:404–13. PubMed PMC

Smith ER, Cayrou C, Huang R, Lane WS, Côté J, Lucchesi JC. A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16. Mol Cell Biol. 2005;25:9175–88. PubMed PMC

Hayward GC, Caceres D, Copeland EN, Baranowski BJ, Mohammad A, Whitley KC, et al. Characterization of Alzheimer’s disease-like neuropathology in Duchenne’s muscular dystrophy using the DBA/2J mdx mouse model. FEBS Open Bio. 2022;12:154–62. PubMed PMC

Wang K-W, Yuan Y-X, Zhu B, Zhang Y, Wei Y-F, Meng F-S, et al. X chromosome-wide association study of quantitative biomarkers from the Alzheimer’s Disease Neuroimaging Initiative study. Front Aging Neurosci. 2023;15:1–15. PubMed PMC

Begum G, Yuan H, Kahle KT, Li L, Wang S, Shi Y, et al. Inhibition of WNK3 kinase signaling reduces brain damage and accelerates neurological recovery after stroke. Stroke. 2015;46:1956–65. PubMed PMC

Wu D, Lai N, Deng R, Liang T, Pan P, Yuan G, et al. Activated WNK3 induced by intracerebral hemorrhage deteriorates brain injury maybe via WNK3/SPAK/NKCC1 pathway. Exp Neurol. 2020;332:113386. PubMed

Zhu J, Lin X, Chen C, Tan H, Gao Y, Li D, et al. WNK3 promotes neuronal survival after traumatic brain injury in rats. Neuroscience. 2021;477:76–88. PubMed

Naqvi S, Sleyp Y, Hoskens H, Indencleef K, Spence JP, Bruffaerts R, et al. Shared heritability of human face and brain shape. Nat Genet. 2021;53:830–9. PubMed PMC

Sha Z, Schijven D, Fisher SE, Francks C. Genetic architecture of the white matter connectome of the human brain. Sci Adv. 2023;9:eadd2870. PubMed PMC

Belloy ME, Guen YL, Stewart I, Herz J, Sherva R, Zhang R, et al. The role of X chromosome in Alzheimer′s disease genetics. JAMA Neurol. 2024;11:2024.04.22.24306094. PubMed PMC

Gorlov IP, Amos CI. Why does the X chromosome lag behind autosomes in GWAS findings? PLoS Genet. 2023;19:1–19. PubMed PMC

Seto M, Hohman TJ, Mormino EC, Papp KV, Rentz READM, Johnson KA, et al. Parental history of memory impairment and β-amyloid in cognitively unimpaired older adults. JAMA Neurol. 2024;81:798–804. PubMed PMC

Dubal DB, Elser HC. β-Amyloid in cognitively unimpaired individuals-blame mom? JAMA Neurol. 2024;81:795–7. PubMed