Endocytosis-pathway polygenic scores affects the hippocampal network connectivity and individualized identification across the high-risk of Alzheimer's disease

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.