Unique contributions of brain amyloid load and APOE4 Status to Regional Brain Volume

Abstract

AbstractBackgroundBrain amyloid and tau, and volumetric atrophy on MRI, are defining features of AD (Jack et al., 2018). Despite growing interest in these component processes, their relationship is still poorly understood.We evaluated the unique contributions of APOE4 allele (E4+/E4−) and brain amyloid (Aβ) status (Amy+/Amy−) to brain volume in the elderly to identify associations with neurodegeneration in regions vulnerable to Alzheimer’s disease (AD).MethodAccelerated 3T T1‐weighted brain MRI scans (N=1,353) obtained at screening for three distinct phases of ADNI with available information on APOE status and/or Amyloid positive/negative status were identified for the following subjects: 561 healthy controls (CN) (age: 71.8±6.3 y, 330F/231M), 599 MCI (mild cognitive impairment; age: 71.9 ± 7.5 y, 264 F/335 M), and 193 AD (age: 74.4±8.2 y, 79 F/114 M). Amyloid status was based on standardized cut‐off values in amyloid sensitive PET scans (Royse et al., 2021).We applied unbiased tensor‐based morphometry (TBM; Leow et al., 2009; Hua et al., 2011) to each scan to measure relative volume differences between each subject and a common minimal deformation template (MDT), resulting in 3D Jacobian maps to represent relative expansion or contraction at each brain voxel.At each voxel, a linear regression model was fit to relate regional brain volumes to amyloid status, and APOE4, after adjusting for covariates. P‐value maps were generated to visualize the pattern of voxel‐wise model contributions and statistical significance while enforcing a standard 5% false discovery rate (FDR) correction for multiple statistical comparisons across the brain (Benjamini et al., 1995).ResultAmyloid positive status was associated with significantly lower regional volume in the temporal lobes and higher volume in the ventricles, i.e., ventricular expansion. APOE4 positive status was associated with lower volume in the temporal lobes (see Fig. 1). ConclusionThe highly localized effects of APOE4 status and amyloid load on brain volumes are consistent with greatest effects of AD pathologic processes in the temporal lobes and similar associations found for Amy+ and E4+ status with cortical thinning (Li et al. (2017).Continued analysis of longitudinal ADNI data will offer further insight into effects of amyloid and APOE4 allele status on atrophy estimates.