Tri-AD: Hippocampal cell-type-specific responses to age, sex and APOE genotype

Li, Y.; Pereda Serras, C.; Yao, L.; Liang, Z.; Almonte-Loya, A.; Blumenfeld, J.; Suan, K.; Yoon, S. Y.; Grone, B.; Ding, L.; Ma, Y.; Sun, S.; Oskotsky, B.; Oskotsky, T.; Condello, C.; Huang, Y.; Sirota, M.

doi:10.64898/2025.12.03.691944

bioRxiv · 10.64898/2025.12.03.691944

Tri-AD: Hippocampal cell-type-specific responses to age, sex and APOE genotype

Li, Y.·Pereda Serras, C.·Yao, L.·Liang, Z.·Almonte-Loya, A.·Blumenfeld, J.·Suan, K.·Yoon, S. Y.·Grone, B.·Ding, L.·Ma, Y.·Sun, S.·Oskotsky, B.·Oskotsky, T.·Condello, C.·Huang, Y.·Sirota, M.

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Abstract

Alzheimers disease (AD) risk is strongly shaped by age, sex, and the apolipoprotein E {varepsilon}4 (APOE4) allele--the strongest genetic risk factor for late-onset AD. While each factor has been studied independently, their combined impact on cellular and molecular processes remains unclear. Here, we used single-nucleus RNA sequencing (snRNA-seq) to profile hippocampal cell states in a sex-balanced cohort of human APOE4/4 and APOE3/3 knock-in mice across 6, 12, and 18 months of age. We identify sex as the major driver of variation in cell-type abundance and find that oligodendrocytes exhibit pronounced male-biased transcriptional sensitivity to APOE4. Differential expression and cell-cell communication analyses further reveal sex-divergent temporal trajectories in inhibitory neurons, with females showing early APOE4-associated suppression of synaptic pathways and males displaying a delayed but convergent decline. Together, these findings clarify how age, sex, and APOE genotype jointly regulate cell-type-specific gene expression and intercellular communication in the aging hippocampus, providing an innovative and publicly accessible database for aging and AD research and related precision medicine.

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Li, Y., Pereda Serras, C., Yao, L., Liang, Z., Almonte-Loya, A., Blumenfeld, J., Suan, K., Yoon, S. Y., Grone, B., Ding, L., Ma, Y., Sun, S., Oskotsky, B., Oskotsky, T., Condello, C., Huang, Y., Sirota, M.. 2025-12-08. Tri-AD: Hippocampal cell-type-specific responses to age, sex and APOE genotype. https://doi.org/10.64898/2025.12.03.691944

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