Abstract
BACKGROUND: Late-onset Alzheimer's 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. OBJECTIVE: To determine causal pathways from genetic risk variants of LOAD via brain morphology to LOAD. METHODS: Mediation and Mendelian randomization (MR) analysis were performed using common genetic variation, T1 MRI and clinical data collected by UK Biobank and Alzheimer's Disease Neuroimaging Initiative. RESULTS: Thickness of the entorhinal cortex and the volumes of the hippocampus, amygdala and inferior lateral ventricle mediated the effect of APOE ε4 on LOAD. MR showed that a thinner entorhinal cortex, a smaller hippocampus and amygdala, and a larger volume of the inferior lateral ventricles, increased the risk of LOAD as well as vice versa. CONCLUSIONS: Combining neuroimaging and genetic data can give insight into the causal neuropathological pathways of LOAD.