Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To finally 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 four X-chromosome-wide significant loci (P ≤ 1.7 × 10−6). Two signals locate in the FRMPD4 and DMD genes, while the two others are more than 300 kb away from the closest protein coding genes NLGN4X and GRIA3. Overall, this XWAS found no common genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

The authors have declared no competing interest.

EADB: This study was supported by grants from the Fondation pour la Recherche sur Alzheimer (convention 2022-A-01 and cluster grant), and the JPco-fuND-2 'Multinational research projects on Personalized Medicine for Neurodegenerative Diseases' PREADAPT project (ANR-19-JPW2-0004). We thank the many study participants, researchers and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille and the staff at CEA-CNRGH for their help with sample preparation and genotyping and excellent technical assistance. We thank Antonio Pardinas for his help. We thank the Netherlands Brain Bank. This research was conducted using the UKBB resource (application number 61054). This work was funded by a grant (EADB) from the EU Joint Programme - Neurodegenerative Disease Research. Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government's LABEX DISTALZ program (Development of Innovative Strategies for a Transdisciplinary Approach to ALZheimer's disease). This work was also supported by the Research Council of Finland grants 338182 and 334802, the Sigrid Jusélius Foundation, and the Strategic Neuroscience Funding of the University of Eastern Finland. Full consortium acknowledgements and funding are in the Supplementary Note.

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Summary statistics will be made available upon publication through the European Bioinformatics Institute GWAS Catalog (https://www.ebi.ac.uk/gwas/).