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bioRxiv2026

Sex and APOE Genotype Differentially Shape Microglial Transcriptomic Profiles Across the Hippocampus and Cortex

Female sex and the APOEe4 allele are top risk factors for Alzheimers disease (AD). Microglia play a role in the pathogenesis of AD, yet how sex and APOE genotype affect microglia remain poorly understood. Here, we characterized the transcriptomic and morphological profiles in the hippocampus and cortex of microglia from humanized APOEe3 and APOEe4 mice of males and females. The hAPOEe4 genotype was associated with sex-dependent effects on microglia co-expression modules in both brain regions, involving cellular stress and immunometabolism processes. In females, a hippocampal cell cycle module was supported by reduced microglial proliferation. Cortical modules were enriched for lipid metabolism and immune-related processes whose expression decreased in females but increased in male hAPOEe4. Male, but not female, hAPOEe4 microglia shifted toward an ameboid state in both regions. Together, these findings reveal sex-dependent microglial responses to APOEe4 across brain regions and highlight the need to incorporate sex-specific approaches into AD research.

neuroscience↗

bioRxiv2025

Conjugated GLP-1 and Estradiol Treatment as a Novel Treatment for Age-related Cognitive Decline in Males and Females

Middle age represents a critical window for metabolic and cognitive health, particularly in the context of rising obesity and diabetes rates. Glucagon-like peptide-1 (GLP-1)-based therapies, which regulate blood glucose and body weight, show sex-specific effects, with estradiol potentiating their metabolic benefits. However, research on GLP-1s cognitive and neuroprotective roles has largely been conducted in males. Here, we investigated the effects of GLP-1 conjugated to estradiol (GE2) on metabolism, cognition, cytokine levels and neurogenesis in the dentate gyrus of middle-aged male and female rats fed a standard (SD) or Western (WD) diet. In both sexes, WD increased body weight and plasma leptin levels, regardless of sex. GE2 treatment led to weight loss, enhanced cued and contextual fear memory, reduced cytokine levels in the hippocampus in SD rats, and increased neurogenesis in the dorsal dentate gyrus (DG), regardless of sex. Sex-specific differences were observed in fat distribution, glucose regulation, central cytokine levels, and neuroplasticity after WD and GE2 treatment. In females only, GE2 reduced visceral (gonadal) fat, reduced cytokines in the dorsal hippocampus, and improved basal blood glucose in response to a WD. In males only, GE2 restored neurogenesis in the DG after WD exposure, and reduced cytokine levels in the amygdala. These findings suggest that although WD increased body weight and GE2 improved associative learning in both sexes, both WD and GE2 had differential affects on metabolic hormones, insulin regulation, cytokine levels and neuroplasticity. Our findings underscore the importance of sex-specific approaches in metabolic and neuroprotective therapeutics in middle age.

neuroscience↗