Brain morphology mediating the effect of genetic risk variants on Alzheimer’s disease

Abstract

INTRODUCTION: Late-onset Alzheimers disease (LOAD) has been associated with alterations in the morphology of multiple brain structures and it is likely that disease mechanisms differ between brain regions. Coupling genetic determinants of LOAD with measures of brain morphology could localize and identify primary causal neurobiological pathways. METHODS: Mediation and Mendelian randomization (MR) analysis were performed using common genetic variation, T1 MRI and clinical data collected by UK Biobank and Alzheimers Disease Neuroimaging Initiative. RESULTS: Thickness of the entorhinal cortex and the volumes of the hippocampus, amygdala, choroid plexus and inferior lateral ventricle mediated the effect of APOE E4 on LOAD. MR showed that a thinner entorhinal cortex, a smaller hippocampus and amygdala, and a larger volume of the choroid plexus and inferior lateral ventricles, increased the risk of LOAD as well as vice versa. DISCUSSION: Combining neuroimaging and genetic data can give insight into the causal neuropathological pathways of LOAD.