Wang, SelenaWang, YitingXu, Frederick H.Tian, XinyuanFredericks, Carolyn A.Shen, LiZhao, YizeAlzheimer’s Disease Neuroimaging Initiative2025-01-222025-01-222024Wang S, Wang Y, Xu FH, et al. Sex-specific topological structure associated with dementia via latent space estimation. Alzheimers Dement. 2024;20(12):8387-8401. doi:10.1002/alz.14266https://hdl.handle.net/1805/45354Introduction: We investigate sex-specific topological structures associated with typical Alzheimer's disease (AD) dementia using a novel state-of-the-art latent space estimation technique. Methods: This study applies a probabilistic approach for latent space estimation that extends current multiplex network modeling approaches and captures the higher-order dependence in functional connectomes by preserving transitivity and modularity structures. Results: We find sex differences in network topology with females showing more default mode network (DMN)-centered hyperactivity and males showing more limbic system (LS)-centered hyperactivity, while both show DMN-centered hypoactivity. We find that centrality plays an important role in dementia-related dysfunction with stronger association between connectivity changes and regional centrality in females than in males. Discussion: The study contributes to the current literature by providing a more comprehensive picture of dementia-related neurodegeneration linking centrality, network segregation, and DMN-centered changes in functional connectomes, and how these components of neurodegeneration differ between the sexes. Highlights: We find evidence supporting the active role network topology plays in neurodegeneration with an imbalance between the excitatory and inhibitory mechanisms that can lead to whole-brain destabilization in dementia patients. We find sex-based differences in network topology with females showing more default mode network (DMN)-centered hyperactivity, males showing more limbic system (LS)-centered hyperactivity, while both show DMN-centered hypoactivity. We find that brain region centrality plays an important role in dementia-related dysfunction with a stronger association between connectivity changes and regional centrality in females than in males. Females, compared to males, tend to exhibit stronger dementia-related changes in regions that are the central actors of the brain networks. Taken together, this research uniquely contributes to the current literature by providing a more comprehensive picture of dementia-related neurodegeneration linking centrality, network segregation, and DMN-centered changes in functional connectomes, and how these components of neurodegeneration differ between the sexes.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalAlzheimer's diseaseConnectome‐driven degenerationEpicenter progression hypothesisNetwork segregationNetwork topologyNetwork‐based neurodegenerationArticle