Simultaneous WF-Ca2+ and BOLD-fMRI reveals modality-specific and sex-based differences in prodromal Alzheimer’s disease

Motivation: This work lays a foundation for studying sex-specific network dysfunction in prodromal AD with multiple contrasts. Goal(s): Sex-, mode-, time-, and group- (AD vs. control) based differences in connectivity were quantified. Approach: Male and female wild-type (WT) and AD mice were imaged at 4 and 6 months-of-age (M), paralleling young adulthood in humans. Results: Simultaneous wide-field fluorescent calcium (WF-Ca2+) and BOLD (blood-oxygen-level dependent) functional magnetic resonance imaging (fMRI) reveal modality- and biological sex-specific differences in cortical connectivity during prodromal Alzheimer's disease (AD). AD-related changes in connectivity emerged earlier in females, was apparent in WF-Ca2+ prior to BOLD-fMRI and showed diverging patterns across modes. Impact: Relative to men, women face twice the lifetime risk of AD-related cognitive impairment. Causes of this discrepancy are unknown and understudied-especially in animal models. We report a novel dual-imaging framework for studying sex- and AD-related network disruption in mice.