Brain morphology mediating the effect of genetic risk variants on Alzheimers disease

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. ### Competing Interest Statement Dr. Andreassen has received speaker fees from Lundbeck, Janssen, Otsuka, and Sunovion and is a consultant to Cortechs.ai. All other authors report no potential conflicts of interest. ### Funding Statement This research was supported through funding by Alzheimers Netherlands (WE.03-2021-17), Research Council of Norway (#324252). S. Guloksuz is supported by the Ophelia research project, ZonMw under Grant 636340001 and the YOUTH-GEMs project, funded by the European Union Horizon Europe program under Grant Agreement Number: 101057182. EP is supported by a ZonMw Memorabel/Alzheimer Nederland Grant (733050516). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. 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