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: 5.4). 03/2011; 21(12):880-4. DOI: 10.1016/j.euroneuro.2011.02.001
Source: PubMed

ABSTRACT 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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    ABSTRACT: Identifying pathways by which genetic Alzheimer's disease (AD) risk factors exert neurocognitive effects in young adults is essential for the effort to develop early interventions to forestall or prevent AD onset. Here, in a brain-imaging cohort of 59 young adults, we investigated effects of a variant within the clusterin (CLU) gene on working memory function and grey matter volume in cortical areas that support working memory. In addition, we investigated the extent to which effects of CLU genotype on working memory were independent of variation in the strongest AD risk factor gene apolipoprotein E (APOE). CLU is among the strongest genetic AD risk factors and, though it appears to share AD pathogenesis-related features with, APOE, it has been far less well studied. CLU genotype was associated with working memory performance in our study cohort. Notably, we found that variation in grey matter volume in a parietal region, previously implicated in maintenance of information for working memory, mediated the effect of CLU on working memory performance. APOE genotype did not affect working memory within our sample, and did not interact with CLU genotype. To our knowledge, this work represents the first evidence of a behavioral effect of CLU genotype in young people. In addition, this work identifies the first gene-brain-cognition mediation effect pathway for the transmission of the effect of an AD risk factor. Relative to conventional pairwise associations in cognitive neurogenetic research, gene-brain-cognition mediation modeling provides a more integrated understanding of how genetic effects transmit from gene to brain to cognitive function.
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    ABSTRACT: Background Clusterin protein in plasma has been found to differentiate between people with and without cognitive changes. However, these findings are not conclusive, despite the clusterin gene variations repeatedly being linked to increased risk for dementia, in particular Alzheimer's disease (AD).Method We analysed the level of clusterin in platelet and plasma in 25 subjects with a clinical diagnosis of AD and 26 subjects with no cognitive impairment.ResultsIn the current study, we report that the levels of both plasma and platelet clusterin are similar between AD and cognitively intact individuals. Clusterin plasma and platelet levels, as well as the plasma/platelet clusterin ratio, were not affected by age, gender, cognitive impairment and/or overt behavioural symptomatology, including presence of hallucinations and delusions, as well as depression. However, the plasma/platelet clusterin ratio was positively associated in with the Neuropsychiatric Inventory measures of agitation, apathy, irritability and motor aberrant behaviour in AD subjects.Conclusion Previous inconsistencies in reported blood clusterin levels may be a result of underlying non-cognitive symptoms in people with AD. Our findings need now to be replicated in larger group of dementia subjects.
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    ABSTRACT: Alzheimer's disease (AD) represents the main form of dementia, and is a major public health problem. Despite intensive research efforts, current treatments have only marginal symptomatic benefits and there are no effective disease-modifying or preventive interventions. AD has a strong genetic component, so much research in AD has focused on identifying genetic causes and risk factors. This chapter will cover genetic discoveries in AD and their consequences in terms of improved knowledge regarding the disease and the identification of biomarkers and drug targets. First, we will discuss the study of the rare early-onset, autosomal dominant forms of AD that led to the discovery of mutations in three major genes, APP, PSEN1, and PSEN2. These discoveries have shaped our current understanding of the pathophysiology and natural history of AD as well as the development of therapeutic targets and the design of clinical trials. Then, we will explore linkage analysis and candidate gene approaches, which identified variants in Apolipoprotein E (APOE) as the major genetic risk factor for late-onset, "sporadic" forms of AD (LOAD), but failed to robustly identify other genetic risk factors, with the exception of variants in SORL1. The main focus of this chapter will be on recent genome-wide association studies that have successfully identified common genetic variations at over 20 loci associated with LOAD outside of the APOE locus. These loci are in or near-novel AD genes including BIN1, CR1, CLU, phosphatidylinositol-binding clathrin assembly protein (PICALM), CD33, EPHA1, MS4A4/MS4A6, ABCA7, CD2AP, SORL1, HLA-DRB5/DRB1, PTK2B, SLC24A4-RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, and TRIP4 and each has small effects on risk of AD (relative risks of 1.1-1.3). Finally, we will touch upon the ongoing effort to identify less frequent and rare variants through whole exome and whole genome sequencing. This effort has identified two novel genes, TREM2 and PLD3, and shown a role for APP in LOAD. The identification of these recently identified genes has implicated previously unsuspected biological pathways in the pathophysiology of AD.