Different atrophy profiles detected in AD patients who carry APOE4 versus non‐carriers: An ENIGMA‐VBM Multicohort Analysis (N=1,893)

AbstractBackgroundAlzheimer’s disease (AD) is the most common neurodegenerative disorder and apolipoprotein E (APOE) ε4 allele is the greatest common genetic risk factor for late‐onset AD. In one of the largest multi‐cohort VBM analyses to date, we aimed to a) map regional brain cortical volume deficits in people with dementia vs controls (CTL) and b) investigate how atrophy patterns in AD were modulated by carrying the APOE4 genotype.MethodThe ENIGMA voxel based morphometry (VBM; https://sites.google.com/view/enigmavbm) pipeline was used to perform a mega‐analysis and a multi‐cohort meta‐analysis on T1‐weighted brain MRI data from 1,893 subjects (Table 1) across four different cohorts, namely the Alzheimer’s Disease Neuroimaging Initiative (ADNI), phases 1, GO/2, 3, and the Open Access Series of Imaging Studies (OASIS3). 488 participants with AD had APOE genotype data with 172 non‐carriers (ε3/3) and 316 carriers (ε3/4, ε4/4). Protective APOE ε2 carriers were excluded. Within the 488 participants with AD, effects of carrying the APOE4 allele were tested using a VBM analysis adjusting for age, sex, intracranial volumes and differences in cohorts.ResultAs expected, compared to controls (CTL), participants with dementia demonstrated cortical brain volume deficits in medial temporal lobes, notably the bilateral hippocampus, entorhinal cortex, amygdala and fusiform gyrus in Mega‐ & Meta‐analysis (Fig. 1). In those with AD, APOE4 carriers demonstrated relatively higher gray matter volumes in the primary motor cortex, medial frontal gyrus and posterior middle temporal gyrus, compared to non‐carriers (P<0.001, uncorrected; Fig. 2). As expected, APOE ε4 carriers demonstrated lower medial temporal lobe and precuneal gray matter volumes.ConclusionAn expected strong pattern of medial temporal lobe volume reduction was noted in the dementia group compared to CTL. Interestingly, within the dementia group, APOE ε4 carriers showed higher gray matter density in the primary motor cortex, a region not routinely associated with AD nor with amyloid deposition, as shown in a smaller prior study. APOE ε4 carriers showed typical medial temporal and precuneal volume reductions which commonly show amyloid deposition, consistent with the notion that APOE ε4 mediates atrophy mainly via an amyloid dependent mechanism.References: 1) Ashburner J, Friston KJ. doi:10.1006/nimg.2000.0582. 2) Liu, Ying. doi:10.1016/j.neuron.2014.11.020. 3) La Joie, Renaud. doi:10.1126/scitranslmed.aau5732. 4) Gutiérrez‐Galve L. doi:10.1159/000258100 et al. 2009;28(5):461‐70.