Exploring sex-specific alterations in early Alzheimer's disease using network MRI analyses

Alzheimers disease (AD) is characterized by the accumulation of amyloid-{beta} plaques and tau neurofibrillary tangles, leading to progressive cognitive decline. Subtle cognitive and neural adaptations mark the preclinical stage of AD, occurring years before mild cognitive impairment and AD diagnosis. Throughout the continuum of AD, women ([~]60% of AD cases) demonstrate faster rates of cognitive decline, greater hippocampal atrophy, and more extensive tau pathology compared to men. This is particularly evident in early AD phases. Therefore, investigating early sex-specific changes is crucial for identifying biomarkers and developing targeted interventions. In the present study, we conducted a longitudinal investigation on the AppNL-F/MAPT double knock-in (dKI) mouse model, to identify sex-specific resting-state functional connectivity (FC) patterns associated with early cognitive deficits. Male and female wild-type and dKI mice were tested for associative and long-term memory deficits, followed by resting-state functional magnetic resonance imaging to examine the default mode network (DMN) connectivity at 2 and 4 months of age. Female dKI mice exhibited earlier and more pronounced memory impairments, with deficits apparent at 2 months, while male deficits emerged at 4 months. FC analyses revealed distinct sex-specific alterations within DMN and between DMN hubs and memory processing nodes. Notably, female dKI mice showed hypersynchrony between the retrosplenial cortex (RSP) and key memory-related regions such as the entorhinal cortex (ENT) and hippocampus (HIP), but also towards subcortical regions overlapping thalamic nuclei, amygdala, and substantia nigra. Meanwhile, male dKI mice exhibited hypoconnectivity along RSP-HIP axis, RSP-reuniens nucleus, and RSP-sensorimotor cortex. Our data particularly highlight sexually dimorphic RSP-ENT and RSP-HIP connectivity. These results underscore the critical role of sex in shaping neural network reorganization and cognitive decline during preclinical AD. These findings position neural network connectivity as a sensitive biomarker of early memory dysfunction and highlight the need for sex-specific investigations and potentially tailored therapeutic strategies in AD.