Does APOE genotype impact brain structure and function in healthy older adults?




Lacey, Colleen

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Background: Healthy cognitive ageing entails a number of neurobiological processes which may contribute to optimal functioning and quality of life in ageing. While the full extent of the underlying mechanisms of healthy ageing are yet to be described, there is an important interplay between brain structure, function, and genetic makeup that determines ageing trajectories. Notably, the Apolipoprotein E (APOE) gene has been established in the Alzheimer’s disease (AD) literature to impact brain structure and function, and may also show congruent effects in healthy older adults, although findings in this population are much less consistent. Structural Magnetic Resonance Imaging (MRI), Diffusion Tensor Imaging (DTI), and neuropsychological measures present as useful, non-invasive tools to investigate the impact of APOE allele status on grey matter structure, white matter integrity, and cognitive functioning, respectively. Few studies have used these measures together to describe healthy ageing, and findings are mixed (e.g., no differences seen, different suggested regions of difference, etc.). The current study aims to describe the impact of APOE genotype on brain structure and function in healthy older adults using multimodal methods. Method: Data were obtained from the Alzheimer’s Disease Initiative phase 3 (ADNI3) database. Baseline MRI, DTI and cognitive composite scores for memory (ADNI-Mem) and EF (ADNI-EF) were acquired from 116 healthy controls. Participants were grouped according to APOE allele presence (APOE-ε2+ N= 17, APOE-ε3ε3 N= 64, APOE-ε4+ N=35). Voxel-based morphometry (VBM) and tract based spatial statistics (TBSS) were used to compare grey matter volume (GMV) and white matter integrity respectively between APOE-ε2+ and APOE-ε3ε3 controls, and again between APOE-ε4+ and APOE-ε3ε3 controls. Multivariate analysis of covariance (MANCOVA) was used to examine the effects of APOE polymorphism on memory and EF across all APOE groups with covariates of age, sex, and education, and cognitive scores were correlated (Pearson r) with imaging metrics within groups. Results: No significant differences were seen across groups or within-groups in MRI metrics or cognitive performance (p>0.05, corrected for multiple comparisons). Non-significant trend-level results suggested 1) Increased fractional anisotropy (FA) and GMV was present in APOE-ε2+ compared to APOE-ε3ε3. 2) Increased mean diffusivity (MD) and decreased GMV was present in APOE-ε4+ compared to APOE-ε3ε3 (p<0.2, corrected for multiple comparisons). Non-significant moderate effect sizes were seen for a positive trend between GMV and EF (r= 0.36, p= 0.18) in APOE-ε2+ and a negative trend between MD and EF in APOE-ε4+ (r= -0.33, p= 0.05). Conclusions: APOE polymorphisms do not appear to impact brain structure and function differently in healthy ageing. Trend-level findings align with reports from previous research, although results remain mixed. Overall, this study suggests neurostructural and functional differences across APOE genotype are not present in cognitively healthy older adults, and future studies should aim to clarify APOE mechanisms in healthy ageing with the addition of other variables (e.g., imaging, cognitive, & lifestyle factors), longitudinal design, and in a larger sample.



Neuroimaging, Ageing, Cognition, Neuropsychology, APOE