White matter hyperintensities are associated with amyloid burden in APOE4 non-carriers

Abstract

Previous preclinical studies have suggested a close relationship between cerebrovascular disease (CVD) and Alzheimer's disease. However, a direct correlation between CVD and amyloid burden has not yet been shown in humans. If there is a relationship between CVD and amyloid burden, it is possible that the apolipoprotein E4 (APOE4) genotype may have an effect on this relationship because APOE4 is a risk factor for the development of AD. We therefore evaluated the effects of APOE4 on the relationship between white matter hyperintensities (WMH), a marker of CVD, and amyloid burden, measured by 11C-Pittsburgh compound B (PiB) PET. We recruited 53 patients with subcortical vascular cognitive impairments, who had both WMH on MRI and amyloid deposition assessed by PiB PET. Twenty-two of these patients were APOE4 carriers (41.5%). In the APOE4 non-carriers, a significant positive correlation was shown between the volume of WMH and PiB retention (β = 7.0 × 10-3, p = 0.034) while no significant correlation was found in APOE4 carriers (β = -9.0 × 10-3, p = 0.085). Statistical parametric mapping analyses in APOE4 non-carriers showed that WMH were associated with PiB retention in the bilateral medial occipitotemporal gyrus, cuneus, and superior cerebellum. Our results suggested that WMH are correlated with amyloid burden especially in the posterior brain regions in APOE4 non-carriers. However, this correlation was not observed in APOE4 carriers, perhaps because in these subjects the influence of APOE4 overrides the effect of CVD.

Keywords: Alzheimer's disease; amyloid burden; apolipoprotein E4; cerebrovascular disease.

Fig. 1

Scatter plot graph between the volume of white matter hyperintensities (WMH) (cm³) and global PiB retention ratio. Multiple linear regression analyses were performed using WMH as an independent factor and the global PiB retention ratio as a dependent variable with adjustment for age and gender. A) Positive correlation with statistical significance was shown between WMH volumes and PiB retention areas in APOE4 non-carrier (β = 7.0 × 10⁻³, SE(β) = 3.0 × 10⁻³, p = 0.034). B) Significant correlation was not shown between WMH volumes and PiB retention in APOE4 carrier (β = −9.0 × 10⁻³, SE(β) = 5.0 × 10⁻³, p = 0.085).

Fig. 2

SPM multiple regression analysis of PiB retention in the APOE4 non-carriers. A) t value map: The red or yellow colored regions represents the significant positive correlation between white matter hyperintensities volumes and PiB retention ratio with adjustment for age and gender (uncorrected p < 0.001). B) Beta map: Strength of associations is illustrated with color-labeled standardized beta-values.

Fig. 3

SPM multiple regression analysis of PiB retention in the APOE4 carriers. There were no regions showing the significant correlation between WMH volumes and PiB retention ratio. A) t value map: The blue or sky blue colored regions represent the negative correlation between WMH and PiB retention ratio with adjustment for age and gender (uncorrected p < 0.01). B) Beta map: Strength of associations is illustrated with color-labeled standardized beta-values.