Longitudinal effects of sex differences and apolipoprotein E genotype on white matter engagement among elderly

Abstract

The apolipoprotein E (APOE) ɛ4 allele is the primary genetic risk factor that influences lipid metabolism and contributes to distinctive Alzheimer's disease pathologies, including increased hippocampal atrophy and accelerated cognitive decline. Synaptic dysfunction can occur in APOE4 carriers even before the appearance of any clinical symptoms. Recent evidence has suggested that this genetic risk factor impacts males and females differently. The sex-specific vulnerability for females to cognitive decline, particularly memory, intensifies post-menopause and emphasizes the need for further investigation. White matter abnormalities, APOE4 allele and disruptions in default mode network connectivity serve as early indicators that are crucial for better understanding Alzheimer's disease progression. This study aims to explore relationships between biological sex, APOE4, default mode network-white matter activity and memory function as measured by the Selective Reminding Test. Participants were categorized by risk level on their APOE4 status. Using longitudinal data from the Harvard Aging Brain Study, we examined sex differences in default mode network-white matter engagement among older individuals with and without the APOE4 allele. Our findings demonstrated a significant reduction in default mode network-white matter activity in the right posterior corona radiata in the high-risk group compared to the low-risk group. High-risk females showed reduction in default mode network-white matter activity in the right superior longitudinal fasciculus, which positively correlated with free recall performance, compared to their low-risk counterparts. Unlike females, males showed no significant changes between the low- and high-risk groups. These results underscore the effectiveness of white matter engagement mapping in differentiating longitudinal changes in memory function related to the genetic risk factor APOE4 and biological sex.

Keywords: APOE4; default mode network; memory; sex difference; white matter engagement maps.

Graphical Abstract

Figure 1

Schematic representation of the overall pipeline of the algorithm of WM engagement maps. (A) For each participant, group-based GM and WM masks were created using a template generated by the DARTEL tool. We applied a lenient threshold (>0.6) to the GM probability image to inclusively capture GM voxels, while a stricter threshold (>0.95) was used for the WM mask to ensure anatomical accuracy. (B and C) These thresholded WM and GM masks were then applied to the fMRI brain images. (D) The mean time series was computed by averaging the fMRI signals across all voxels within each of the 38 DMN regions. (E) Pairwise Pearson's correlation coefficients were calculated between the mean time series of all region pairs. In addition, to assess connectivity independent of local WM signals, we generated partial correlation matrices (M'ₓ) using the time series of each WM voxel (x) as a control. (F) Global connectivity metrics were computed by averaging the values from both the full correlation matrix (G(M)) and each partial correlation matrix (G(M'ₓ)). The difference between these metrics (ΔGₓ = G(M) − G(M'ₓ)) was mapped across all WM voxels to create preliminary engagement maps. (G) The values on the WM engagement map were standardized using Z-scoring to normalize the data distribution for subsequent group-level analyses. GM, grey matter; WM, white matter; rs-fMRI, resting-state functional magnetic resonance imaging; DMN, default mode network; BNA, Brainnetome Atlas; M, 38 × 38 full functional connectivity matrix; M'ₓ, partial correlation matrices using each WM voxel (x)'s time series as a regressor; G(M), mean values of the full correlation matrix M; G(M'ₓ), mean value of the partial correlation matrix.

Figure 2

Within-group comparison of WM engagement with the DMN across two time visits. (A) Neuroimaging results from the study showing a comparison of WM engagement with the DMN between two visits (Visit 2–Visit 1) in the high-risk group, analysed using a paired t-test (t > 2.7, significance confirmed via GRF correction with cluster-level P < 0.05, voxel-level P < 0.01 and minimum cluster sizes exceeding 10 voxels). (B) Scatter plots depicting partial correlations between the average changes in WM engagement (Visit 2–Visit 1) in the right posterior corona radiata and the differences in SRT_str scores (Visit 2–Visit 1). The correlations are adjusted for sex and years of education and are presented for both high-risk and low-risk groups. WM, white matter; DMN, default mode network; SRT_str, Selective Reminding Test—short-term retrieval.

Figure 3

Between-group differences in WM engagement with the DMN by genetic risk level in females. Neuroimaging results from the study reveal two significant clusters identified through between-group comparisons (high-risk minus low-risk) in females using a two-sample t-test (t > 2.7, significance confirmed via GRF correction with cluster-level P < 0.05, voxel-level P < 0.01 and minimum cluster sizes exceeding 10 voxels): (A) Cluster 1 located in the right SLF and (B) in the right anterior corona radiata. (C) Scatter plots depicting partial correlations between the average WM engagement changes in the right SLF and FCsrt_Free scores (Visit 2–Visit 1), controlling for age and years of education, across female and male groups. WM, white matter; DMN, default mode network; FCsrt_Free, Free and Cued Selective Reminding Test—total of free recall.

Figure 4

Between-group differences in WM engagement with the DMN by sex in high-risk group. (A) Neuroimaging results from the study reveal one significant cluster identified through between-group comparisons (female minus male) in high-risk group using a two-sample t-test (t > 2.7, significance confirmed via GRF correction with cluster-level P < 0.05, voxel-level P < 0.01 and minimum cluster sizes exceeding 10 voxels): located in the right posterior thalamic radiation. (B) Scatter plots depicting partial correlations between the average WM engagement changes in the right posterior thalamic radiation and FCsrt_Free scores (Visit 2–Visit 1), controlling for age and years of education, across high-risk and low-risk groups. WM, white matter; DMN, default mode network; FCsrt_Free, Free and Cued Selective Reminding Test—total of free recall.