Polygenic Effects of the Lipid Metabolic Pathway Accelerated Pathological Changes and Disrupted Default Mode Network Trajectory Across the Alzheimer’s Disease Spectrum

Objective: Dyslipidemia is a controversial risk for Alzheimer's disease (AD) with unknown mechanisms. This study aimed to investigate polygenic effects of the lipid metabolic pathway on cerebrospinal fluid (CSF) core biomarkers, cognition, and default mode network (DMN).Methods: Cross-sectional data on serum lipids, CSF core biomarkers, and functional MRI findings for 113 participants (25 cognitively normal, 20 with subjective cognitive decline, 24 early amnestic, 23 with late mild cognitive impairment, and 21 with AD) from the Alzheimer's Disease Neuroimaging Initiative were included. Different cognitive stages were categorized based on neuropsychological assessments. Multivariable linear regression analyses were conducted to investigate the polygenic and interactive effects on the DMN. The correlations of lipid-related polygenes and serum lipids with cognitive performance were also studied via regression analyses.Results: The polygenic scores were significantly correlated with CSF levels of core biomarkers (P < .05) but not with cognition. Several serum lipids were associated with total tau. CSF core biomarkers and 6 serum lipids both could impact cognition in a nonlinear manner. Polygenic effects exhibited diverse trajectories on the DMN subsystems across the AD spectrum. Extensive genetic and interactive effects were mainly concentrated in the cortical frontal-parietal network and subcortical regions. Brain regions of lipid metabolites linking to DMN involved sensorimotor network and occipital lobe.Conclusions: Polygenic effects of the lipid metabolic pathway could accelerate pathological changes and disrupted DMN subsystem trajectory across the AD spectrum. These results deepen the understanding of the mechanism of lipid metabolism affecting the neural system and provide several lipid indicators that enable the impairments of lipid metabolism on the brain to be monitored.