Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults

Abstract

There is a strong genetic risk for late-onset Alzheimer's disease (AD), but so far few gene variants have been identified that reliably contribute to that risk. A newly confirmed genetic risk allele C of the clusterin (CLU) gene variant rs11136000 is carried by ∼88% of Caucasians. The C allele confers a 1.16 greater odds of developing late-onset AD than the T allele. AD patients have reductions in regional white matter integrity. We evaluated whether the CLU risk variant was similarly associated with lower white matter integrity in healthy young humans. Evidence of early brain differences would offer a target for intervention decades before symptom onset. We scanned 398 healthy young adults (mean age, 23.6 ± 2.2 years) with diffusion tensor imaging, a variation of magnetic resonance imaging sensitive to white matter integrity in the living brain. We assessed genetic associations using mixed-model regression at each point in the brain to map the profile of these associations with white matter integrity. Each C allele copy of the CLU variant was associated with lower fractional anisotropy--a widely accepted measure of white matter integrity--in multiple brain regions, including several known to degenerate in AD. These regions included the splenium of the corpus callosum, the fornix, cingulum, and superior and inferior longitudinal fasciculi in both brain hemispheres. Young healthy carriers of the CLU gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing AD later in life.

Figures

Figure 1.

FA association with CLU-C displayed on a study-specific FA template. a, Highlighted areas are the p values indicating voxels in which CLU-C is associated with lower FA after adjusting for age and sex (FDR critical p value = 0.023). In b, we show regression coefficients at significant voxels that encompass many regions that degenerate in AD. The left brain hemisphere is displayed on the right. Coordinates listed are for the Z (for axial slices) and X (for the sagittal slice) directions in ICBM space. SLF and ILF denote the superior and inferior longitudinal fasciculi. IFO is the inferior fronto-occipital fasciculus.

Figure 2.

Statistical models. Highlighting represents un-normalized regression coefficients or beta values in all white matter voxels tested. It demonstrates the CLU-C association with lower FA (after adjusting for age and sex). a, b, Shown here as post hoc explorations are the C/C versus T carrier model (a) and the T/T versus C carrier model (b). Units are in FA unit difference between groups for these models, while they are in FA units per allele for the additive model (Fig. 1). The per-voxel effect is similar in location using all models, but only the initially hypothesized and most powerful additive model passes FDR correction, as shown in Figure 1 (FDR critical p value = 0.023). The effect appears to depend on the allele dose rather than the presence or absence of a given allele. The left brain hemisphere is displayed on the right.

Figure 3.

Radial diffusivity. Drad but not Dax showed a significant CLU genotype effect after adjusting for age and sex. In highlighted voxels, Drad is significantly greater with each CLU allele C (multiple comparisons corrected: critical p < 0.022 for an FDR of 5%). The left brain hemisphere is shown on the right.