Sex-aware Cross-tissue Regulatory Transformer Identified Sexually Dimorphic Alzheimer's Disease Risk Loci and Causal Cellular Circuit
- 1Cornell University
Abstract
Sex differences in Alzheimers disease susceptibility remain poorly understood at the level of gene regulation. Here we analyzed 449,335 individuals of European ancestry and identified 24 variants with genotype-by-sex interactions at genome-wide significance. We developed STAGE-AD, a sex-conditioned Transformer integrating association statistics with cross-tissue molecular quantitative trait loci, functional annotations, epigenomic profiles, single-cell annotations and neuropathology characteristics. Statistical-genetic analyses in independent cohorts supported 236 genes at 106 prioritized loci. Female-biased loci implicated lipid-responsive microglia and reactive astrocytes, whereas male-biased loci implicated vascular endothelium and oligodendrocytes. Corresponding genetic modules were associated with tau pathology and episodic memory decline, and with white matter injury and executive decline, respectively. Integration of molecular and neuropathological evidence prioritized 11 candidate regulatory chains linking variants to cellular contexts and disease phenotypes, which were validated in NPAD cohort. These findings delineate sex-differentiated regulatory contexts within a largely shared genetic architecture of Alzheimers disease and nominate mechanisms for experimental investigation.
Related
- Sexually Dimorphic Glutamatergic Control of R-Spondin 1 and R-Spondin 3 Neurons in Hypothalamic Reproductive and Metabolic Nuclei
- Sex-stratified autosomal association analysis reveals dimorphic genetic risk factors in non-systemic juvenile idiopathic arthritis.
- Sex-dimorphic immune trajectories across the canine lifespan and early-life signatures of geroprotective interventions
- Resurgence of Sexually Transmitted Hepatitis C Virus Infection in Men Who Have Sex With Men Living With HIV
- Sexually transmitted infection testing among U.S. adolescents in relation to U.S. Preventive Services Task Force screening guidelines
BibTeX
@misc{cheng2026sexaware,
title = {{Sex-aware Cross-tissue Regulatory Transformer Identified Sexually Dimorphic Alzheimer's Disease Risk Loci and Causal Cellular Circuit}},
author = {Z. Cheng and S. Judaprawira and J. Perez and A. Goldstein},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.26362488},
url = {https://www.medrxiv.org/content/10.64898/2026.09.08.26362488v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Sex-aware Cross-tissue Regulatory Transformer Identified Sexually Dimorphic Alzheimer's Disease Risk Loci and Causal Cellular Circuit
AU - Z. Cheng
AU - S. Judaprawira
AU - J. Perez
AU - A. Goldstein
PY - 2026
DA - 2026/09/08
PB - medRxiv
DO - 10.64898/2026.09.08.26362488
UR - https://www.medrxiv.org/content/10.64898/2026.09.08.26362488v1
AB - Sex differences in Alzheimers disease susceptibility remain poorly understood at the level of gene regulation. Here we analyzed 449,335 individuals of European ancestry and identified 24 variants with genotype-by-sex interactions at genome-wide significance. We developed STAGE-AD, a sex-conditioned Transformer integrating association statistics with cross-tissue molecular quantitative trait loci, functional annotations, epigenomic profiles, single-cell annotations and neuropathology characteristics. Statistical-genetic analyses in independent cohorts supported 236 genes at 106 prioritized loci. Female-biased loci implicated lipid-responsive microglia and reactive astrocytes, whereas male-biased loci implicated vascular endothelium and oligodendrocytes. Corresponding genetic modules were associated with tau pathology and episodic memory decline, and with white matter injury and executive decline, respectively. Integration of molecular and neuropathological evidence prioritized 11 candidate regulatory chains linking variants to cellular contexts and disease phenotypes, which were validated in NPAD cohort. These findings delineate sex-differentiated regulatory contexts within a largely shared genetic architecture of Alzheimers disease and nominate mechanisms for experimental investigation.
ER -