Different APOE genotypes have distinct effect on white matter (WM) and cognitive development trajectory. Previous studies reported carrying APOE ε4 allele was related to more severe WMH burden and faster age-related cognitive decline. Conversely, APOE ε2 allele was linked to faster processing of information and superior executive function (1). However, little neuroimage studies have focused on this putative “protective” APOE allele. Meanwhile, limited researches focused on lobar distribution of WMH; actually, varied regions of WMH had totally different clinical implication (2). The purpose of this study was to understand the biologic impact of APOE genotype on WM by measuring regional WMH volume. Besides, we examined whether APOE genotype-related neural endophenotype on WM were associated with clinical behavior performance.158 right-handed cognitively intact healthy participants were enrolled, comprised of 30 APOE ε2 carriers, 45 ε4 carriers and 83 ε3 homozygotes, who had undergone MPRAGE scans, T2 FLAIR scans, and neuropsychological assessments. The MPRAGE images and T2FLAIR images were used to create WMH ROIs for each subject, and then each created ROI was divided into 4 smaller ROIs according to lobes. We tested the group differences of WMH volume using ANOVA, and tested the correlations of log-transformed volume of WMH with behavior data.There were no significant differences regarding age, gender, or education among the groups. Moreover, the gender ratio and history of disease including diabetes, hypertension and smoking were equally distributed among three groups. Besides, no difference in neuropsychological assessments across groups was found. The ε4 carriers had significant increased WMH burden in parietal, occipital and frontal region over other 2 groups; ε2 carriers had a trend of decreased WMH volume in occipital and frontal region relative to the ε3 homozygotes (Fig. 1). Correlation analysis showed, especially in APOE ε4 carriers, WMH volumes of parietal and occipital were significantly related with TMT-A score, and TMT-B score (Details in Fig.2 and Table 1).

Our results showed that ε4 carriers had more WMH burden than ε3 homozygotes in frontal and posterior regions. It is known that APOE ε4 allele is associated with aggregation of Aβ protein. Based on these, one of the underlying mechanisms of our observations might be that, the slightly increased amyloid deposition in asymptomatic ε4 carriers affected arterial wall and reduced the vessel lumen, which leads to chronic hypoperfusion in WM (3). Besides, in the periventricular WM (most located in parietal and frontal lobe), the arteriole supplying these areas have traveled long and the anastomoses are scarce. WM in these regions therefore may particularly susceptible to ischemic events resulting from APOE ε4 status (4). Thus, chronic hypoperfusion in these regions were exacerbated by perilous blood supply. Meanwhile, the current study failed to observe a statistically significant “protective” effect of APOE ε2 allele compared to the controls. Given this study was performed in cognitively intact subjects, the low WMH burden in both ε2 carriers and controls may reduce our ability to find any differences.

In addition, our results indicated increased WMH burden in frontal, parietal and occipital regions was significantly related with degeneration of processing speed and executive function. Functionally, the processing of sensory-related information is mainly mediated by dorsal system, including the frontal and posterior parietal area (5). Besides, the parietal/occipital regions served as the “hubs” within the healthy functional brain network, especially the precuneus, had disproportionately numerous connections to other brain regions, was energy demanding and was pivotal for information processing (6). Thus, increased WMH in these regions may disrupt strategic WM tracts and cause a structural “disconnection”, further, disconnect the components of distributed neurocognitive networks. Notably, the correlation was even stronger in ε4 carriers. In contrast, the correlation was weaker or even no longer significant in ε2 carriers and ε3 homozygotes. Such differences in correlation might be explained by the low WMH burden, since mild WMH is generally considered age-related and clinically insignificant.

Conclusively, in this cross-sectional study, we found that the detrimental effect APOE had on WM but failed to spot its “protective” effect; and that WMH may act as a link between APOE ε4 allele and cognitive performance.