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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.

SUBMITTER: Braskie MN

PROVIDER: S-EPMC3176803 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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

Braskie Meredith N MN Jahanshad Neda N Stein Jason L JL Barysheva Marina M McMahon Katie L KL de Zubicaray Greig I GI Martin Nicholas G NG Wright Margaret J MJ Ringman John M JM Toga Arthur W AW Thompson Paul M PM

The Journal of neuroscience : the official journal of the Society for Neuroscience 20110501 18

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 ...[more]

PMID: 21543606

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Project description:BackgroundMagnetic resonance imaging (MRI) studies have shown differences in volume and structure in the brains of individuals with alcohol use disorder (AUD). Most research has focused on neuropathological effects of alcohol that appear after years of chronic alcohol misuse. However, few studies have investigated white matter (WM) microstructure and diffusion MRI-based (DWI) connectivity during early stages of AUD. Therefore, the goal of this work was to investigate WM integrity and structural connectivity in emerging adulthood AUD subjects using both conventional DWI metrics and a novel connectomics approach.MethodsTwenty-two AUD and 18 controls (CON) underwent anatomic and diffusion MRI. Outcome measures were scalar diffusion metrics and structural network connectomes. Tract-Based Spatial Statistics was used to investigate group differences in diffusion measures. Structural connectomes were used as input into a community structure procedure to obtain a coclassification index matrix (an indicator of community association strength) for each subject. Differences in coclassification and structural connectivity (indexed by streamline density) were assessed via the Network Based Statistics Toolbox.ResultsAUD had higher fractional anisotropy (FA) values throughout the major WM tracts, but also had lower FA values in WM tracts in the cerebellum and right insula (pTFCE < 0.05). Mean diffusivity was generally lower in the AUD group (pTFCE < 0.05). AUD had lower coclassification of nodes between ventral attention and default mode networks and higher coclassification between nodes of visual, default mode, and somatomotor networks. Additionally, AUD had higher fiber density between an adjacent pair of nodes within the default mode network.ConclusionsOur results indicate that emerging adulthood AUD subjects may have differential patterns of FA and distinct differences in structural connectomes compared with CON. These data suggest that such alterations in microstructure and structural connectivity may uniquely characterize early stages of AUD and/or a predisposition for development of AUD.

Project description:Neighborhood disadvantage and community violence are common in poor, urban communities and are risk factors for emotional dysfunction. Emotional processes are supported by neural circuitry that includes the prefrontal cortex (PFC), hippocampus, amygdala, and hypothalamus. These brain regions are connected by white matter pathways that include the cingulum bundle, uncinate fasciculus, stria terminalis, and fornix. Emotional function varies with the microstructure of these white matter pathways. However, it is not clear whether the microstructure of these pathways varies with risk factors for emotional dysfunction (e.g., neighborhood disadvantage and violence exposure). Therefore, determining the relationships between neighborhood disadvantage, violence exposure, and white matter microstructure may offer insight into the neural mechanisms by which adverse life experiences alter developing neural systems. The current study investigated the association that exposure to neighborhood disadvantage and violence have with the quantitative anisotropy (QA), a measure of the amount of directional water diffusion, of the cingulum bundle, uncinate fasciculus, stria terminalis, and fornix. Neighborhood disadvantage (Mage = 11.20) and violence exposure (MW1age = 11.20; MW2age = 13.05; MW3age = 16.20; MW4age = 19.25) were assessed during adolescence and participants returned for magnetic resonance imaging as young adults (N = 303; Mage = 20.25, SD = 1.55), during which diffusion weighted brain images were collected. The QA of the cingulum bundle, uncinate fasciculus, and stria terminalis/fornix varied negatively with neighborhood disadvantage such that the QA of these white matter tracts decreased as neighborhood disadvantage increased. Violence exposure was not related to QA in any tract (i.e., cingulum bundle, uncinate fasciculus, and stria terminalis/fornix) after correction for multiple comparisons. These results suggest that an adolescent's neighborhood may play an important role in the microstructure (i.e., QA) of white matter pathways that connect brain regions that support emotional function.

Dataset Information

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

Publications

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

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