Abstract
Background: Alzheimer’s disease (AD) manifests differently in males and females. However, the neuro-mechanism and influence factors are still unknown.Objective: To explore sex differences in brain network topology during AD disease progression and its association with cognition and possible influencing factors.Methods: Resting-state functional magnetic resonance imaging (MRI) data and cognitive scores were collected from 82 AD patients (50 females), 56 amnestic mildly cognitive impaired patients (29 females), and 63 healthy controls (38 females). Global and regional topological network metrics and modular architecture were calculated. Two-way ANOVA was performed to explore group and sex interactions and their main effects. Mediation analysis was used to explore the relationship among education, inter/intra-network connectivity, and the Mini-Mental State Examination (MMSE) score.Results: Lower levels of education, lower MMSE scores, and a positive correlation between the level of education and MMSE scores were found in female AD patients (p = 0.024, r = 0.319). Significantly lower connectivity strength within the sensorimotor network, dorsal attention network, ventral attention network (VAN), and between the sensorimotor and VAN were observed in male AD patients (p = 0.006, 0.028, 0.046, and 0.013, respectively). Group and sex interactions were also found in nodal properties, mainly in the frontal lobe, temporal lobe, middle cingulum, precuneus, and postcentral gyrus. Several of the altered brain network properties were associated with cognitive behavior in male AD patients. Education regulated the MMSE score through the mediation of connection strength between the default mode and limbic networks (LN) in the patient group (aMCI and AD combined).Conclusion: Our results demonstrate that sex differences exist at the brain network level in AD. Sex differences in network topology and education are correlated with sex differences in cognition during AD progression.
Highlights
Alzheimer’s disease (AD) is the most common type of dementia in senile individuals, characterized by progressive and irreversible decline of cognition (Ewers et al, 2011; Scheltens et al, 2016)
A positive correlation between education and Mini-Mental State Examination (MMSE) was detected in female AD patients (p = 0.024, r = 0.319)
In male patients, education was positively correlated with MMSE, auditory verbal learning test (AVLT) immediate, and digital scale (DS) forward and backward scores (p = 0.039, 0.028, 0.004 and 0.007, r = 0.270, 0.287, 0.367 and 0.350 respectively)
Summary
Alzheimer’s disease (AD) is the most common type of dementia in senile individuals, characterized by progressive and irreversible decline of cognition (Ewers et al, 2011; Scheltens et al, 2016). The higher prevalence of females with AD, cognitive decline was found to be more rapid in females than in males. An 8 year longitudinal study showed that cognitive deterioration in females with aMCI was twice as fast as for males (Lin et al, 2015). The annual conversion rate of female aMCI patients to a full AD diagnosis was 2%–3% higher than that of male patients (Tifratene et al, 2015). Male AD patients are more likely to exhibit apathy, agitation, and abusive and socially inappropriate behavior, while female patients are more prone to depression, mood instability, and affective symptoms (Mazure and Swendsen, 2016; Ferretti et al, 2018). The neuro-mechanism and influence factors are still unknown
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