4 Impact of APOE-ε Alleles on Brain Structure and Function in Healthy Older Adults: A VBM and DTI Replication Study

Objective: 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. Magnetic Resonance Imaging (MRI), Diffusion Tensor Imaging (DTI), and neuropsychological measures present as useful, non-invasive tools to investigate the impact of APOE-e allele status on grey matter structure, white matter integrity, and cognitive functioning, respectively. Nonetheless, studies to date have revealed mix findings and few studies have taken a multimodal approach to investigating APOE’s effects. Thus, the objective of the current study was to replicate and expand upon the multimodal neuroimaging study conducted by Honea et al. (2009), that examined the impact of APOE-e4 presence on brain structure and cognitive function in healthy older adults, with the addition of APOE-e2 carriers and cognitive composite measures. The aim of the current replication study was to identify reliable changes to grey matter volume and white matter integrity in healthy older adults as it relates to APOE-e allele presence and cognitive performance. This represents one of the first studies to investigate both the risk and protective effects of APOE-e alleles (e4 and e2 respectively) on measures of cognitive performance, GMV and white matter integrity in healthy older adults. Participants and Methods: 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 executive function (ADNI-EF) were acquired from 116 healthy controls. Participants were grouped according to APOE allele presence (APOE-e2+ N= 17, APOE-e3e3 N= 64, APOE-e4+ 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-e2+ and APOE-e3e3 controls, and again between APOE-e4+ and APOE-e3e3 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, education, and cognitive scores were correlated with imaging metrics within groups (Pearson r) to examine associations between cognitive performance and brain structure. Results: Consistent with findings from Honea et al. (2009), no significant differences were seen across APOE groups, within-groups in MRI metrics, or cognitive performance (p>0.05, corrected for multiple comparisons). Taking a similar approach to Honea and company, nonsignificant, trend-level results were examined (p<0.2, corrected for multiple comparisons) and suggested: 1) Decreased GMV and increased mean diffusivity (MD) were present in APOE-e4+ compared to APOE-e3e3 and 2) Increased GMV and fractional anisotropy (FA) were present in APOE-e2+ compared to APOE-e3e3. Conclusions: The current study replicated and extended previous findings. Trend-level findings across both the current and replicated study suggests there may be subtle neurostructural differences in healthy aging as a function of APOE-e4 status. The current study additionally found potential subtle differences in GMV and white matter integrity in APOE-e2 carriers at the trend-level, consistent with previous reports of APOE-e2 's protective effects against neurodegeneration. Although these findings should be interpreted with caution, trend-level effects seen in the current study are consistent with previous research and may hold important implications for APOE neuromechanisms.

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