Citations 1
An APOE *4-Informed Genomic Atlas of the X Chromosome in Alzheimer’s Disease
Cook, Noah , Zeng, Youjie , Yang, Chenyu , Jiang, Zhiwen , Wang, Ting‐Chen , Guen, Yann Le , Cody, Karly Alex , Johnson, Matthew, Zhang, Rui, Merritt, Victoria C. , Hauger, Richard L. , Program, the VA Million Veteran, FinnGen, Koran, Mary Ellen, Mormino, Elizabeth C. , Gordon, Brian , DeCasien, Alex, Andrews, Shea J. , Logue, Mark, Greicius, Michael D. , Le Guen, Yann , Cody, Karly A , Koran, Mary Ellen , Gordon, Brian A , Andrews, Shea , Dumitrescu, Logan , Archer, Derek , Seto, Mabel , Pottier, Cyril , Cruchaga, Carlos , Sherva, Richard , Logue, Mark W. , Napolioni, Valerio , Belloy, Michael E , Cook, Noah , Zeng, Youjie , Yang, Chenyu , Zhang, Rui, Merritt, Victoria C. , Hauger, Richard L. , Koran, Mary Ellen I. , Mormino, Elizabeth C. , DeCasien, Alex R. , Dumitrescu, Logan , Archer, Derek B. , Hohman, Timothy J. , Belloy, Michaël E.
No container title available | May 6, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract The genetic contributions of the X chromosome to Alzheimer’s disease (AD) remain poorly understood yet are expected to importantly shape sex differences in AD. We therefore performed large-scale X-chromosome-wide association studies (N=1,240,451), evaluating differential risk due to sex, APOE *4, and escape from X-chromosome inactivation, finding most X-linked loci appear relevant to female-biased AD etiology. In evaluating genetic pleiotropy with hormonal, lipid, and brain imaging traits, we discovered X-linked AD loci converged on white matter traits, particularly in the anterior corona radiata and splenium of the corpus callosum. Through brain-centric functional genomics analyses, we then nominated candidate causal genes, including 5 that appeared highly robust. Notably, we found the escape gene RBBP7 decreases AD risk in APOE *4 carriers likely through higher expression in excitatory neurons to counter tau-related neurodegeneration. Altogether, we provide an atlas of sex and APOE *4-informed candidate X-linked AD risk loci, genes, and mechanisms that will guide future studies.