Supplementary Material for: Locus Coeruleus sexual dimorphism and its impact on cognitive impairment and cortical atrophy in Alzheimer’s Disease

Introduction: Experimental data suggest sexual dimorphism in the Locus Coeruleus (LC), with females exhibiting higher neuronal count and noradrenergic activity. In Alzheimer’s Disease (AD), progressive LC dysfunction may contribute early to pathogenesis, and female sex is a key risk factor for AD. This study aimed to investigate if such sex differences exist in humans and whether they influence the relationship between LC degeneration and AD features, such as cortical atrophy and cognitive decline. Methods: Fifty-three healthy controls (HC), 70 Mild Cognitive Impaired (MCI) subjects, and 29 Alzheimer’s Disease Demented (ADD) patients underwent high-field brain MRI with LC-sensitive sequences following detailed neuropsychological and neurological assessments. LC integrity was measured using the LC Contrast Ratio (LCCR) parameter based on a previously published template approach. Results: Within the HC and MCI groups, females showed higher LCCR values than males. A significant sex effect was observed in the relationship between LC integrity and cortical volume in the frontotemporal cortices, with males showing a stronger association. Conclusion: LC structure and function may differ between sexes, influencing AD pathophysiology through distinct mechanisms. While this sexual dimorphism may have a minor role, it should be considered in clinical investigations and drug development research.