Sex differences in locus coeruleus structure and function across the adult lifespan: effects of APOE, Alzheimer’s disease pathology, and estrogen levels

The prevalence of Alzheimer’s disease (AD) is sex-dependent, with females at higher risk than males. While the locus coeruleus (LC) plays a critical role in early AD-related tauopathy, sex differences in LC structure and function remain poorly characterized in vivo in humans despite evidence from animal models. Here, we investigated sex differences in LC structural integrity and activity during an emotional arousal task, as well as the modifying effects of APOE genotype, plasma biomarkers of AD-related pathology, and estrogen levels across the adult lifespan. One hundred and one cognitively unimpaired participants aged 30-85 years were included. LC MRI signal intensity and LC activity were measured at 7T MRI, using dedicated LC MRI sequences, and functional MRI during an emotional arousal task, respectively. Blood samples were collected to measure levels of estradiol, estrone, AD-related plasma biomarkers (p-tau 217 , p-tau 181 , p-tau 231 , GFAP, NfL), and to determine APOE genotype. No overall sex differences were observed in LC MRI signal intensity or activity. Among APOE ε4 non-carriers, females exhibited higher LC MRI signal intensity than males, whereas this sex difference was absent in ε4 carriers. In addition, female ε4 carriers displayed lower LC MRI signal intensity than female ε4 non-carriers. In females, a higher estrone-to-estradiol ratio was associated with lower LC MRI signal intensity among participants older than approximately 56 years in our sample. Finally, females exhibited greater LC activity in response to emotional stimuli in the context of elevated p-tau 217 and GFAP levels compared to males. Our findings provide in vivo evidence that, in females, age-related estradiol decline and APOE carriership are associated with compromised LC structure, whereas greater LC activity is associated with higher AD plasma biomarker levels, supporting the LC as a target for sex-specific AD prevention strategies.