Effect of Alzheimer's Disease Risk Variant rs3824968 at SORL1 on Regional Gray Matter Volume and Age-Related Interaction in Adult Lifespan

Abstract

Sortilin receptor 1 (SORL1) is involved in cellular trafficking of amyloid precursor protein and plays an essential role in amyloid-beta peptide generation in Alzheimer disease (AD). The major A allele in a SORL1 single nucleotide polymorphism (SNP), rs3824968, is associated with an increased AD risk. However, the role of SORL1 rs3824968 in the normal ageing process has rarely been examined in relation to brain structural morphology. This study investigated the association between SORL1 rs3824968 and grey matter (GM) volume in a nondemented Chinese population of 318 adults within a wide age range (21-92 years). Through voxel-based morphometry, we found that participants carrying SORL1 allele A exhibited significantly smaller GM volumes in the right posterior cingulate, left middle occipital, medial frontal, and superior temporal gyri. Considerable interaction between age and SORL1 suggested a detrimental and accelerated ageing effect of allele A on putamen. These findings provide evidence that SORL1 rs3824968 modulates regional GM volume and is associated with brain trajectory during the adult lifespan.

Figure 1. Age effect: GM differences in a nondemented elderly participants.

Regions of significant GM differences from 318 normal participants superimposed on surface space. T-score maps show clusters at a voxel threshold with P of <0.005 as well as extended voxel sizes of 298, all of the clusters remained significant and survived from the criteria of corrected P_alpha of <0.05 by Monte Carlo simulation.

Figure 2. Regional GM volume differences among the three SORL1 rs3824968 genotypic groups.

T-score map shows significant smaller GM volume in SORL1 A allele carriers compared with those carrying TT (A). The clusters were set at a voxel threshold with P of <0.005 as well as extended voxel sizes of 298, all of the clusters remained significant and survived from the criteria of corrected P_alpha of <0.05 by Monte Carlo simulation. Bottom bar graph shows the GM volume difference between the SORL1 genotypes and the regions with significant gene main effect in the left middle occipital gyrus (B), right cerebellum tonsil (C), left medial frontal gyrus (D), right posterior cingulate gyrus (E), and left superior temporal gyrus (F). ^*Bonferroni-corrected P < 0.05 (post hoc tests in analysis of covariance).

Figure 3. Interaction between the SORL1 genotype and age on right putamen GM volume.

The scatter plot demonstrates the interaction between the SORL1 genotype and age on right putamen GM volume using voxel-wised covariate analysis with the SORL1 genotypes as the condition and age as the covariate, while controlling for sex and education level as nuisance variables (corrected P_alpha of <0.05 by Monte Carlo simulation)).