O4-01-02: Effects of the SORL1 Alzheimer's disease risk gene across the human lifespan

Variants within a 5′ haplotype of the sortilin-related receptor, L-class, A repeat-containing (SORL1) gene have been repeatedly implicated in late-onset AD. To characterize risk posed by these variants across the lifespan, we analyzed their effects on 1) white matter integrity using diffusion tensor imaging (DTI), 2) prefrontal SORL1 mRNA levels, and 3) postmortem amyloid plaque and tau tangle pathology. Imaging-genetics analysis was performed on two samples: 118 healthy subjects (CAMH, age 18–86) on a 1.5T GE scanner with 23 directions, and 68 healthy Caucasian subjects (Zucker Hillside, age 8–40) on a 3T GE scanner, with 31 directions. TBSS was used to assess the effect of genotypic group on voxel-wise fractional anisotropy (FA), co-varying for age, sex, and APOE-ε4 status where possible. Prefrontal SORL1 mRNA was quantified in the BrainCloud dataset (access through dbGaP, NCBI, n=269) using Illumina microarrays. Immunohistochemical analysis was performed on a sample of postmortem Caucasian HC, MCI, and AD brains (Rush University Memory and Aging Project/Religious Orders Study, Chicago, Il, USA: n=782) to quantify amyloid plaque and paired helical filament-tau separately for mesial temporal and neocortical structures. All samples were genotyped for risk SNPs within the SORL1 5′ haplotype. rs689021 was associated with reductions in fronto-temporal WM FA in both the CAMH and Zucker Hillside samples, at a 5% FWE corrected threshold (See Figure). The effects were independent of age, manifesting as early as childhood and adolescence. In BrainCloud, the rs689021 risk genotype significantly predicted a period of reduced gene expression in Caucasians during adolescence (F=7.03, p=0.0003). Postmortem pathology analysis revealed associations of rs668387 with amyloid plaques in the whole sample (t=4.84, p=0.028) and neocortical tangles in healthy subset only (t=9.03, p=0.0027).