Bridging the Translational Gap in Sex-Specific Alzheimer’s Disease Using Human iPSC-Based Neural Cell Models

Alzheimer's disease (AD) exhibits marked sex differences in disease prevalence, progression, and therapeutic responsiveness, with women disproportionately affected by both cognitive decline and neuropathological burden. Although sex hormones such as estrogen, progesterone, and testosterone have demonstrated neuroprotective effects in experimental systems, clinical outcomes of hormone-based interventions remain inconsistent. Emerging evidence further indicates that sex-specific molecular programs extend beyond endocrine signaling alone and include cell type-specific transcriptional architectures established across the lifespan. Recent single-cell transcriptomic studies have suggested that biological sex fundamentally shapes multicellular brain vulnerability. However, prevailing preclinical systems incompletely model human endocrine aging, sex chromosome biology, and patient-specific genetic heterogeneity, thereby limiting translational relevance. Human induced pluripotent stem cell (iPSC)-derived neural systems provide a new platform for mechanistically interrogating sex-specific pathways within human genetic backgrounds. By preserving donor-specific genetic backgrounds and sex chromosome complement, iPSC-derived neurons, astrocytes, microglia, and multicellular systems enable controlled investigation of hormone-responsive phenotypes, APOE-associated mechanisms, and cell type-specific transcriptional programs. However, their developmental immaturity and incomplete representation of systemic aging, vascular, immune, and endocrine physiology limit direct extrapolation to patients. Integration of these cellular systems with human omics datasets, neuropathological observations, and clinical studies may therefore help address specific components of the translational gap in AD.