Independent and interactive effects of APOEε4 and β‐amyloid on cortical thickness in Alzheimer’s disease

Abstract Background The apolipoprotein (APOE) ε4 allele is a major risk factor for Alzheimer’s disease (AD) and potentiates β‐amyloid (Aβ) accumulation. Both APOEε4 and Aβ individually contribute to neurodegeneration in the aging brain. Here, we investigate the independent and interactive effects of APOEε4 and global Aβ load on cortical thickness and disease severity across the AD continuum. Method We used FreeSurfer v7.1.1 to derive brain morphometry measures from regions‐of‐interest (ROIs) in 796 subjects (N=475 controls (CN), N=77 participants with mild cognitive impairment (MCI), N=244 with dementia; Table 1 ) to analyze associations between cortical thickness, APOEε4, and Aβ using available T1‐weighted MRI scans from ADNI phases 2 and 3. Multiple linear regression models were run, covarying for age and sex, to examine the effects of APOEε4 status, global Aβ, and their interaction on morphometric measures from ROIs known to be vulnerable to Aβ deposition in aging and disease ( Figure 1 ‐ adapted from La Joie et al.). Result In the MCI and dementia groups, higher global Aβ was associated with lower cortical thickness in middle temporal, fusiform, and parietal regions ( p <0.05), but was not associated with cortical thickness in controls. In the dementia group, there was a significant effect of Aβ ( p <0.001) and an APOEε4 by Aβ interaction ( p =0.01) in the inferior parietal gyrus ( Figure 2 ). The interaction effect requires replication due to the multiple hypothesis testing. Conclusion Unlike in healthy aging, as disease severity increases, the interactive effect of Aβ and APOEε4 status significantly affects cortical thickness in regions associated with Aβ deposition. This suggests that APOEε4 differentially affects cortical thinning during different stages of disease severity.