APOE genotype moderates the relationship between LRP1 polymorphism and cognition across the Alzheimer's disease spectrum via disturbing default mode network

<jats:title>Abstract</jats:title><jats:sec><jats:title>Aims</jats:title><jats:p>This study aims to investigate the mechanisms by which apolipoprotein E (<jats:italic>APOE</jats:italic>) genotype modulates the relationship between low‐density lipoprotein receptor‐related protein 1 (<jats:italic>LRP1</jats:italic>) rs1799986 variant on the default mode network (DMN) and cognition in Alzheimer's disease (AD) spectrum populations.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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 <jats:italic>LRP1</jats:italic> and disease on the DMN. Moderation and interactive analyses were performed to assess the relationships among <jats:italic>APOE</jats:italic>, <jats:italic>LRP1</jats:italic>, and cognition. A support vector machine model was used to classify AD spectrum with altered connectivity as an objective diagnostic biomarker.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The main effects and interaction of <jats:italic>LRP1</jats:italic> 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 <jats:italic>LRP1</jats:italic>‐T carriers, but not in non‐carriers. <jats:italic>APOE</jats:italic> regulated the effect of <jats:italic>LRP1</jats:italic> on cognitive performance. The functional connectivity of numerous brain regions within <jats:italic>LRP1</jats:italic>‐T carriers yielded strong power for classifying AD spectrum.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>These findings suggested <jats:italic>LRP1</jats:italic> could affect DMN and provided a stage‐dependent neuroimaging biomarker for classifying AD spectrum populations.</jats:p></jats:sec>