Associations of APOE e2/e4 dosage and lifestyle on neuroimaging markers in the UK Biobank

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Abstract
Background: Variation in the Apolipoprotein E (APOE) gene is a key genetic determinant of Alzheimer’s disease (AD) risk and is associated with AD-related neuroimaging changes. Lifestyle factors are also associated with AD risk and may interact with APOE to influence neuroimaging biomarkers. However, evidence on these interactions remains limited and inconsistent, particularly regarding composite healthy lifestyle scores in large-scale cohorts. Methods: We analyzed neuroimaging data from 21,014 UK Biobank participants (mean age: 55) to examine neuroimaging markers relevant to AD and assess the independent and interactive effects of APOE ε2/ ε4 dosage and healthy lifestyle risk factors. These biomarkers included diffusion tensor imaging (DTI) metrics-fractional anisotropy (FA) and mean diffusivity (MD), white matter hyperintensity (WMH) burden, and volumetric measures of medial temporal lobe regions such as the entorhinal cortex, parahippocampal region, amygdala, and hippocampus. Results: In the APOE dosage model, ε4 dosage was associated with lower bilateral hippocampal volume, left parahippocampal volume and lower WM integrity, particularly in the posterior thalamic radiation and cingulum-hippocampus and sagittal stratum. A higher healthy lifestyle score was broadly associated with lower WMH burden and higher WM integrity. No statistically significant evidence was found for effect modification by lifestyle on the association between APOE and MRI markers. Conclusions: Our results do not provide support for the idea that healthy lifestyle factors buffer or mitigate the detrimental effects of the APOE dosage on MRI markers, but rather support a primarily outright association between APOE ε4 dosage and worse MRI markers.

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