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Aims: The study aims to examine the changing trajectory characteristics of dynamic functional network connectivity (dFNC) and its correlation with lipid metabolism‐related factors across the Alzheimer's disease (AD) spectrum populations. Methods: Data from 242 AD spectrum subjects, including biological, neuroimaging, and general cognition, were obtained from the Alzheimer's Disease Neuroimaging Initiative for this cross‐sectional study. The study utilized a sliding‐window approach to assess whole‐brain dFNC, investigating group differences and associations with biological and cognitive factors. Abnormal dFNC was used in the classification of AD spectrum populations by support vector machine. Mediation analysis was performed to explore the relationships between lipid‐related indicators, dFNC, cerebrospinal fluid (CSF) biomarkers, and cognitive performance. Results: Significant group difference concerning were observed in relation to APOE‐ε4 status, CSF biomarkers, and cognitive scores. Two reoccurring connectivity states were identified: state‐1 characterized by frequent but weak connections, and state‐II characterized by less frequent but strong connections. Pre‐AD subjects exhibited a preference for spending more time in state‐I, whereas AD patients tended remain in state‐II for longer periods. Group difference in dFNC was primarily found between AD and non‐AD participants within each state. The dFNC of state‐I yielded strong power to distinguish AD from other groups compared with state‐II. APOE‐ε4+, high polygenic score, and high serum lipid group were strongly associated with network disruption between association cortex system and sensory cortex system that characterized elevation of cognitive function, which may suggest a compensatory mechanism of dFNC in state‐I, whereas differential connections of state‐II mediated the relationships between APOE‐ε4 genotype and CSF biomarkers, and cognitive indicators. Conclusion: The dysfunction of dFNC temporal–spatial patterns and increased cognition in individuals with APOE‐ε4, high polygenic score, and higher serum lipid levels shed light on the lipid‐related mechanisms of dynamic network reorganization in AD. [ABSTRACT FROM AUTHOR]

Aims: This study aims to investigate the mechanisms by which apolipoprotein E (APOE) genotype modulates the relationship between low‐density lipoprotein receptor‐related protein 1 (LRP1) rs1799986 variant on the default mode network (DMN) and cognition in Alzheimer's disease (AD) spectrum populations. Methods: Cross‐sectional 168 subjects of AD spectrum were obtained from Alzheimer's Disease Neuroimaging Initiative database with resting‐state fMRI scans and neuropsychological scores data. Multivariable linear regression analysis was adopted to investigate the main effects and interaction of LRP1 and disease on the DMN. Moderation and interactive analyses were performed to assess the relationships among APOE, LRP1, and cognition. A support vector machine model was used to classify AD spectrum with altered connectivity as an objective diagnostic biomarker. Results: The main effects and interaction of LRP1 and disease were mainly focused on the core hubs of frontal‐parietal network. Several brain regions with altered connectivity were correlated with cognitive scores in LRP1‐T carriers, but not in non‐carriers. APOE regulated the effect of LRP1 on cognitive performance. The functional connectivity of numerous brain regions within LRP1‐T carriers yielded strong power for classifying AD spectrum. Conclusion: These findings suggested LRP1 could affect DMN and provided a stage‐dependent neuroimaging biomarker for classifying AD spectrum populations. [ABSTRACT FROM AUTHOR]

The neural mechanisms underlying the polygenic effects of the endocytosis pathway on the brain function of Alzheimer's Disease (AD) remain unclear, especially in the prodromal stages of AD from early mild cognitive impairment (EMCI) to late mild cognitive impairment (LMCI). We used an imaging genetic approach to investigate the polygenic effects of the endocytosis pathway on the hippocampal network across the prodromal stages of AD. The subjects' data were selected from the Alzheimer's Disease Neuroimaging Initiative. Hippocampal volumes were examined in subjects of cognitive normal (CN), EMCI and LMCI groups. Multivariate linear regression analysis was employed to measure the effects of disease and endocytosis-based multilocus genetic risk scores (MGRS) on the hippocampal network which was constructed using the bilateral hippocampal regions. We identified hippocampal volumes in LMCI group were smaller than those in CN and EMCI groups. Endocytosis-based MGRS was widely influenced the neural structures within the hippocampal network, especially in the prefrontal-occipital regions and striatum. Compared to low endocytosis-based MGRS carriers, high MGRS carriers showed the opposite trajectory of hippocampal network functional connectivity (FC) across the prodromal stages of AD. Further, a model composed of selected hippocampal FCs and hippocampal volume yielded strong classification powers of EMCI and LMCI. These findings expand our understanding of the pathophysiology of polygenic effects underlying brain network in the prodromal stages of AD. [ABSTRACT FROM AUTHOR]