title: 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.
authors.affiliation: Laboratory of Neuro Imaging, Department of Neurology, University of California, School of Medicine, Los Angeles, California 90095, USA.
authors.forename: Meredith N
authors.initials: MN
authors.lastname: Braskie
authors.forename: Neda
authors.initials: N
authors.lastname: Jahanshad
authors.forename: Jason L
authors.initials: JL
authors.lastname: Stein
authors.forename: Marina
authors.initials: M
authors.lastname: Barysheva
authors.forename: Katie L
authors.initials: KL
authors.lastname: McMahon
authors.forename: Greig I
authors.initials: GI
authors.lastname: de Zubicaray
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Wright
authors.forename: John M
authors.initials: JM
authors.lastname: Ringman
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Toga
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
mesh_terms: D000328:Adult; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D000704:Analysis of Variance; D001921:Brain / Q000473:pathology*; D001931:Brain Mapping; D051152:Clusterin / Q000235:genetics*; D056324:Diffusion Tensor Imaging; D004200:Diseases in Twins / Q000235:genetics / Q000473:pathology*; D005260:Female; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D009483:Neuropsychological Tests; D012306:Risk; D014427:Twins
chemical_list: C495242:CLU protein, human; D051152:Clusterin