Neural hyperactivation in carriers of the Alzheimer's risk variant on the clusterin gene

School of Medical Sciences, Bangor University, UK.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology (Impact Factor: 4.37). 03/2011; 21(12):880-4. DOI: 10.1016/j.euroneuro.2011.02.001
Source: PubMed


Recent GWAS identified a risk variant for Alzheimer's disease (AD) at a locus (rs11136000) of the clusterin gene (CLU). Here we use functional magnetic resonance imaging (fMRI) during working memory to probe the effect of the risk variant on brain activation in healthy individuals. Participants with the CLU risk genotype had higher activity than participants with the protective allele in frontal and posterior cingulate cortex and the hippocampus, particularly during high memory demand. These results inform pathophysiological models of the preclinical progression of AD.

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    • "lso nondemented carriers of a clusterin ( CLU ) allele that recently was identified as a risk factor for AD ( Harold et al . , 2009 ; Lambert et al . , 2009 ) show higher activity levels in the frontal and posterior cingulate cortex and the hippocampus , particularly during working memory tasks , compared with subjects with the protective allele ( Lancaster et al . , 2011 ) . Finally , Quiroz et al . ( 2010 ) compared hip - pocampal activation in young healthy carriers of the E280A muta - tion in the presenilin 1 gene ( PSEN1 ) with matched controls . The presymptomatic PS1 mutation carriers performed equally well as the control group on an encoding task , but this was associated with an increased activa"
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    ABSTRACT: Neuronal activity directly promotes the production and secretion of amyloid β (Aβ). Interestingly, neuronal hyperactivity can be observed in presymptomatic stages of both sporadic and familial Alzheimer's disease (AD) and in several AD mouse models. In this review, we will highlight the recent evidence for neuronal hyperactivity before or during the onset of cognitive defects in mild cognitive impairment. Furthermore, we review specific molecular mechanisms through which neuronal hyperactivity affects Aβ production and degradation. With these data, we will provide more insight into the 2-faced nature of neuronal hyperactivity: does enhanced neuronal activity during the presymptomatic stages of AD provide protection against the earliest disease processes or is it a pathogenic contributor to AD? Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 09/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.08.014 · 5.01 Impact Factor
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    • "The CLU risk variant rs11136000 was found to be associated with reduced integrity of broad white matter regions, as observed with diffusion tensor imaging in young healthy adults (Braskie et al., 2011). fMRI study showed aberrant activation in the frontal and posterior cingulate cortex and the hippocampus during working memory performance in healthy young individuals carrying CLU AD risk genotype (Lancaster et al., 2011). "
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    ABSTRACT: Polymorphism in the genomic region harboring the CLU gene (rs11136000) has been associated with the risk for Alzheimer's disease (AD). CLU C allele is assumed to confer risk for AD and the allele T may have a protective effect. We investigated the influence of the AD-associated CLU genotype on a common neurophysiological trait of brain activity (resting-state alpha-rhythm activity) in non-demented adults and elucidated whether this influence is modified over the course of aging. We examined quantitative electroencephalography (EEG) in a cohort of non-demented individuals (age range 20-80) divided into young (age range 20-50) and old (age range 51-80) cohorts and stratified by CLU polymorphism. To rule out the effect of the apolipoprotein E (ApoE) genotype on EEG characteristics, only subjects without the ApoE ε4 allele were included in the study. The homozygous presence of the AD risk variant CLU CC in non-demented subjects was associated with an increase of alpha3 absolute power. Moreover, the influence of CLU genotype on alpha3 was found to be higher in the subjects older than 50 years of age. The study also showed age-dependent alterations of alpha topographic distribution that occur independently of the CLU genotype. The increase of upper alpha power has been associated with hippocampal atrophy in patients with mild cognitive impairment (Moretti etal., 2012a). In our study, the CLU CC-dependent increase in upper alpha rhythm, particularly enhanced in elderly non-demented individuals, may imply that the genotype is related to preclinical dysregulation of hippocampal neurophysiology in aging and that this factor may contribute to the pathogenesis of AD.
    Frontiers in Aging Neuroscience 12/2013; 5:86. DOI:10.3389/fnagi.2013.00086 · 4.00 Impact Factor
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    ABSTRACT: Alzheimer’s disease (AD) is a progressive neurodegenerative disease. It is of great importance that we find efficient preclinical markers that can be used in clinics. The neuropathological features associated with AD brain include the progressive formation of insoluble amyloid plaques and vascular deposits consisting of the amyloid β peptide in the brain and neuron loss that innervates regions such as the hippocampus and the cortex. These lesions are considered to cause the abnormal sensory information processing and brain dysfunction of AD patients. Combined cognitive and sensory as well as neuroimaging approaches have advantages to find the altered cognitive symptoms and brain dysfunction in the early stage in AD involved mild memory or planning problems. This review provides an overview of the neuropsychological impairments in patients with AD, which may be used as potential biomarkers for early diagnosis of AD.
    06/2012; 1(2). DOI:10.1007/s13670-012-0007-4
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