DOI: 10.1002/alz70856_106501 B I OMARK E R S POSTER PRESENTATION NEUROIMAGING Connectome-based predictions of cognition and sex differences inmidlife individuals at risk for Alzheimer’s Disease Qing Qi1,2 Rory Boyle3,4 Bolin Cao1,5 Graciela Muniz-Terrera6,7 Ivan Koychev8 Paresh Malhotra9,10 John T O’Brien11 Craig Ritchie7,12 Brian Lawlor1,2 Lorina Naci1,2 1Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland 2Trinity College Institute of Neuroscience, School of Psychology, Trinity College Dublin, Dublin, Ireland 3Penn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 4Department of Neurology, University of Pennsylvania Perelman School ofMedicine, Philadelphia, PA, USA 5Trinity College Dublin, Dublin, Ireland 6Department of Social Medicine, Ohio University, Athens, OH, USA 7Edinburgh Dementia Prevention, University of Edinburgh, Edinburgh, United Kingdom 8University of Oxford, Oxford, United Kingdom 9Imperial College London, Department of Brain Sciences, London, London, United Kingdom 10UKDementia Research Institute, Care Research and Technology Centre, London, United Kingdom 11Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom 12Scottish Brain Sciences, Edinburgh, Scotland, United Kingdom Correspondence QingQi, Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland. Email: qiqi@tcd.ie Abstract Background: Females generally show better memory performance, particularly in episodic memory, than males across the lifespan [1-3]. However, two-thirds of Alzheimer’s disease (AD) cases occur in females, who experience more rapid cognitive decline and brain atrophy in the presence of AD-related neuropathology [4]. The functional brain architecture underlying episodic and relational memory in middle- aged individuals—and whether this differs by sex—remains poorly understood. This study aimed to identify the functional brain architecture associated with episodic and relational memory using a data-driven approach, focusing on sex differences. Method:Resting-state functionalMRI data and neuropsychological assessments were obtained from 488 cognitively healthy individuals (316 F/172 M), aged 40-59 years, from the PREVENT-Dementia study. Connectome-based predictive modeling (CPM) was used to identify functional brain networks related to episodic and relational memory across the entire cohort, within female-only and male-only subgroups. Model generalizability was evaluated using data from the Cambridge Center for Ageing and Neuroscience (Cam-CAN) dataset. Result: CPM identified both positive and negative networks significantly associated with episodic and relational memory in the entire cohort (positive: r = 0.16, p < 0.001; negative: r = 0.10, p = 0.017; Figure 1A). These networks were particularly characterized by within-network and between-network connections involving default mode and cingulo-opercular networks in the positive network (Figure 2A). Sex- stratified analyses revealed distinct model performance: both positive and negative networks predicted episodic and relationalmemory in the female-only group (positive: r=0.18,p-corrected=0.002; negative: r=0.11,p-corrected=0.048; Figure1B),whereasonly the negative network predicted episodic and relationalmemory in themale-only group (positive: r = 0.01, p-corrected = 0.836; negative: r = 0.16, p-corrected = 0.048; Figure 1C) This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2025 The Alzheimer’s Association. Alzheimer’s & Dementia published byWiley Periodicals LLC on behalf of Alzheimer’s Association. Alzheimer’s Dement. 2025;21(Suppl. 2):e106501. wileyonlinelibrary.com/journal/alz 1 of 4 https://doi.org/10.1002/alz70856_106501 mailto:qiqi@tcd.ie http://creativecommons.org/licenses/by/4.0/ https://wileyonlinelibrary.com/journal/alz https://doi.org/10.1002/alz70856_106501 2 of 4 BIOMARKERS after Bonferroni correction. These results didn’t generalize to the external Cam-CAN dataset. Conclusion:We identified brain networks underlying episodic and relational memory in middle-aged individuals, revealing sex-specific differences. These findings suggest potential sex-specific mechanisms in memory-related brain networks during midlife, which may contribute to differing trajectories of cognitive decline in aging and Alzheimer’s disease. However, the lack of generalizability to an external dataset underscores the need for further validation in diverse populations. BIOMARKERS 3 of 4 4 of 4 BIOMARKERS Abstract