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Clusterin as an Alzheimer Biomarker

Clusterin as an Alzheimer Biomarker Plasma Clusterin and the Risk of Alzheimer Disease Abstract Context:  Variants in the clusterin gene are associated with the risk of Alzheimer disease (AD) and clusterin levels have been found to be increased in brain and cerebrospinal fluid of patients with AD. Plasma clusterin was reported to be associated with brain atrophy, baseline disease severity, and rapid clinical progression in patients with AD. Objective:  To evaluate the potential of plasma clusterin as a biomarker of the presence, severity, and risk of AD. Design, Setting, and Participants:  A case-cohort study nested within the Rotterdam Study, a prospective population-based cohort study conducted in Rotterdam, the Netherlands. Plasma levels of clusterin were measured at baseline (1997-1999) in 60 individuals with prevalent AD, a random subcohort of 926 participants, and an additional 156 participants diagnosed with AD during follow-up until January 1, 2007 (mean [SD], 7.2 [2.3] years). Main Outcome Measures:  Prevalent AD, severity of AD measured by the Mini-Mental State Examination (MMSE) score, and the risk of developing AD during follow-up. Results:  The likelihood of prevalent AD increased with increasing plasma levels of clusterin (odds ratio [OR] per SD increase of plasma clusterin level, 1.63; 95% confidence interval [CI], 1.21-2.20; adjusted for age, sex, education level, apolipoprotein E status, diabetes, smoking, coronary heart disease, and hypertension). Among patients with AD, higher clusterin levels were associated with more severe disease (adjusted difference in MMSE score per SD increase in clusterin levels, −1.36; 95% CI, −2.70 to −0.02; P = .047). Plasma clusterin levels were not related to the risk of incident AD during total follow-up (adjusted HR, 1.00; 95% CI, 0.85-1.17; P for trend = .77) or within 3 years of baseline (adjusted HR, 1.09; 95% CI, 0.84-1.42; P for trend = .65). Conclusion:  Plasma clusterin levels were significantly associated with baseline prevalence and severity of AD, but not with incidence of AD. In a remarkable series of little-noticed studies, May et al1 and Poirier et a12 carried out entorhinal lesions in adult rats to see which genes were acutely upregulated. Their reasoning was that such response genes would be candidate genes for Alzheimer disease. Remarkably, they picked out just 2 genes: apolipoprotein E (ApoE) and clusterin (Clu ; apolipoprotein J). While APOE was shown to be a locus for Alzheimer disease within a couple years,3 the realization that CLU was a locus for the disease was made only with the advent of genome-wide association studies4 clearly documenting that genetic variability at the locus contributed to risk. Unlike APOE, where the major (but not the only) risk is encoded by protein coding change,5 in CLU there is not a common coding variant in European populations even though there are a lot of rare variants.6 Rather, it seems that genetic variability in expression is the underlying reason the CLU locus appears as a risk locus for disease. This genetic variability in expression does not relate to the resting expression of this reactive protein (which is not different based on genotype), but rather most likely relates to genetic variability in damage response expression.6 This background is worth considering in relation to the articles published in recent issues of the Archives and JAMA. Using an unbiased proteomic strategy applied to plasma, Thambisetty et al7 identified clusterin as a potential biomarker whose level was higher in rapidly progressing Alzheimer disease than in more slowly progressing disease. They went on to show a relationship between severity of disease and plasma clusterin levels. These results are confirmed and extended by Schrijvers et al.8 They confirm that higher clusterin levels are associated with both the occurrence of Alzheimer disease and disease severity, and they additionally show that, within the power of the study, there is little evidence of higher plasma clusterin levels predicting disease occurrence. These recent findings are remarkably consistent with the earlier literature. They suggest that as the entorhinal pathway becomes damaged by the early stages of the disease process (presumably plaque formation), clusterin levels increase in a reasonably selective way, and genetic variability in this response is an important determinant in disease risk. While levels of clusterin clearly increase in disease and increase more as the disease gets worse, we cannot be sure whether those who respond more or those who respond less are at greater risk for disease: the genetic data point at the locus but do not immediately tell us whether we should be thinking of potentiating or antagonizing CLU function. Nonsense mutations in CLU occur at an appreciable frequency in both cases and controls,6,9 and our view on whether we should potentiate or antagonize CLU function will be informed by whether these are shown to occur more frequently in cases or controls. We do, however, have evidence that it is amyloid that potentiates clusterin expression. There is a significant association between plasma levels of clusterin and evidence for amyloid deposition in the brain in nondemented elderly people as measured using positron emission tomographic imaging and, more remarkably, an increase in plasma clusterin in a transgenic mouse with plaque formation.7 Other evidence suggests that clusterin is one of several amyloid chaperones; when plaque-generating mice were bred with a mouse lacking either ApoE or Clu, the resulting offspring had the same amount of amyloid in their brains but somewhat less fibrillized amyloid. On the other hand, when the mice lacked both ApoE and Clu, the amount of amyloid deposited was substantially increased and was deposited earlier.10 Related to this, in another unbiased proteomic study comparing individuals with high (positron emission tomography–detected) amyloid with individuals with low amyloid, apolipoprotein E was the predominant blood-based correlate of brain amyloid—data suggesting that these apolipoproteins are acting as amyloid response agents.11 These data from mouse and man suggest that apolipoproteins E and J are acting as disease response agents, specifically amyloid response agents. The mouse data suggest that they are beneficial agents, perhaps acting to remove amyloid, although interpreting these complex genetically manipulated animals is difficult. Moreover, some critically important questions remain. Schrijvers et al8 show that clusterin increased in people with Alzheimer disease but not in people 3 years before onset of disease. Thambisetty et al7 show a significant correlation with amyloid deposition in healthy people. These findings beg the question, at what point does the plasma clusterin level increase? A second, even more challenging and indeed interesting question is, from where does this plasma clusterin come? Is it generated peripherally in response to brain pathology or does it cross the blood-brain barrier, perhaps even accompanied by amyloid? Getting to the bottom of these questions will be essential before embarking on therapeutic strategies based on the newfound prominence of clusterin. For now, though, we have in the last year or two learned 2 things that look set to influence the Alzheimer disease field for many years to come. First, it is abundantly clear that clusterin, and its gene CLU, are as centrally important to response to the pathology of Alzheimer disease as its related protein apolipoprotein E. Second, there is unambiguously a change in proteins in blood in relation to disease. Whether that change goes beyond clusterin or can be turned into a clinically useful biomarker remains to be seen. Back to top Article Information Correspondence: Dr Hardy, Departments of Molecular Neuroscience and Clinical Neuroscience, Reta Lila Weston Research Laboratories, Institute of Neurology, University College London, Queen Square House, Ninth Floor, Queen Square, London WC1N 3BG, England (j.hardy@ion.ucl.ac.uk). Author Contributions:Study concept and design: Hardy, Guerreiro, and Lovestone. Drafting of the manuscript: Hardy and Lovestone. Critical revision of the manuscript for important intellectual content: Hardy and Guerreiro. Study supervision: Hardy. Financial Disclosure: Dr Lovestone is a named inventor on intellectual property held jointly by King's College London and Proteome Sciences relating to biomarkers for dementia and including clusterin. References 1. May PC, Lampert-Etchells M, Johnson SA, Poirier J, Masters JN, Finch CE. Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat. Neuron. 1990;5(6):831-8391702645PubMedGoogle ScholarCrossref 2. Poirier J, Hess M, May PC, Finch CE. Cloning of hippocampal poly(A) RNA sequences that increase after entorhinal cortex lesion in adult rat. Brain Res Mol Brain Res. 1991;9(3):191-1951674353PubMedGoogle ScholarCrossref 3. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261(5123):921-9238346443PubMedGoogle ScholarCrossref 4. Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009;41(10):1088-109319734902PubMedGoogle ScholarCrossref 5. Chartier-Harlin MC, Parfitt M, Legrain S, et al. Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. Hum Mol Genet. 1994;3(4):569-5748069300PubMedGoogle ScholarCrossref 6. Guerreiro RJ, Beck J, Gibbs JR, et al. Genetic variability in CLU and its association with Alzheimer's disease. PLoS One. 2010;5(3):e951020209083PubMedGoogle ScholarCrossref 7. Thambisetty M, Simmons A, Velayudhan L, et al. Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. Arch Gen Psychiatry. 2010;67(7):739-74820603455PubMedGoogle ScholarCrossref 8. Schrijvers EM, Koudstaal PJ, Hofman A, Breteler MM. Plasma clusterin and the risk of Alzheimer disease. JAMA. 2011;305(13):1322-132621467285PubMedGoogle ScholarCrossref 9. Tycko B, Feng L, Nguyen L, et al. Polymorphisms in the human apolipoprotein-J/clusterin gene: ethnic variation and distribution in Alzheimer's disease. Hum Genet. 1996;98(4):430-4368792817PubMedGoogle ScholarCrossref 10. DeMattos RB, Cirrito JR, Parsadanian M, et al. ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. Neuron. 2004;41(2):193-20214741101PubMedGoogle ScholarCrossref 11. Thambisetty M, Tripaldi R, Riddoch-Contreras J, et al. Proteome-based plasma markers of brain amyloid-β deposition in non-demented older individuals. J Alzheimers Dis. 2010;22(4):1099-110920930274PubMedGoogle Scholar http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Neurology American Medical Association

Clusterin as an Alzheimer Biomarker

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Publisher
American Medical Association
Copyright
Copyright © 2011 American Medical Association. All Rights Reserved.
ISSN
0003-9942
eISSN
1538-3687
DOI
10.1001/archneurol.2011.1000
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Abstract

Plasma Clusterin and the Risk of Alzheimer Disease Abstract Context:  Variants in the clusterin gene are associated with the risk of Alzheimer disease (AD) and clusterin levels have been found to be increased in brain and cerebrospinal fluid of patients with AD. Plasma clusterin was reported to be associated with brain atrophy, baseline disease severity, and rapid clinical progression in patients with AD. Objective:  To evaluate the potential of plasma clusterin as a biomarker of the presence, severity, and risk of AD. Design, Setting, and Participants:  A case-cohort study nested within the Rotterdam Study, a prospective population-based cohort study conducted in Rotterdam, the Netherlands. Plasma levels of clusterin were measured at baseline (1997-1999) in 60 individuals with prevalent AD, a random subcohort of 926 participants, and an additional 156 participants diagnosed with AD during follow-up until January 1, 2007 (mean [SD], 7.2 [2.3] years). Main Outcome Measures:  Prevalent AD, severity of AD measured by the Mini-Mental State Examination (MMSE) score, and the risk of developing AD during follow-up. Results:  The likelihood of prevalent AD increased with increasing plasma levels of clusterin (odds ratio [OR] per SD increase of plasma clusterin level, 1.63; 95% confidence interval [CI], 1.21-2.20; adjusted for age, sex, education level, apolipoprotein E status, diabetes, smoking, coronary heart disease, and hypertension). Among patients with AD, higher clusterin levels were associated with more severe disease (adjusted difference in MMSE score per SD increase in clusterin levels, −1.36; 95% CI, −2.70 to −0.02; P = .047). Plasma clusterin levels were not related to the risk of incident AD during total follow-up (adjusted HR, 1.00; 95% CI, 0.85-1.17; P for trend = .77) or within 3 years of baseline (adjusted HR, 1.09; 95% CI, 0.84-1.42; P for trend = .65). Conclusion:  Plasma clusterin levels were significantly associated with baseline prevalence and severity of AD, but not with incidence of AD. In a remarkable series of little-noticed studies, May et al1 and Poirier et a12 carried out entorhinal lesions in adult rats to see which genes were acutely upregulated. Their reasoning was that such response genes would be candidate genes for Alzheimer disease. Remarkably, they picked out just 2 genes: apolipoprotein E (ApoE) and clusterin (Clu ; apolipoprotein J). While APOE was shown to be a locus for Alzheimer disease within a couple years,3 the realization that CLU was a locus for the disease was made only with the advent of genome-wide association studies4 clearly documenting that genetic variability at the locus contributed to risk. Unlike APOE, where the major (but not the only) risk is encoded by protein coding change,5 in CLU there is not a common coding variant in European populations even though there are a lot of rare variants.6 Rather, it seems that genetic variability in expression is the underlying reason the CLU locus appears as a risk locus for disease. This genetic variability in expression does not relate to the resting expression of this reactive protein (which is not different based on genotype), but rather most likely relates to genetic variability in damage response expression.6 This background is worth considering in relation to the articles published in recent issues of the Archives and JAMA. Using an unbiased proteomic strategy applied to plasma, Thambisetty et al7 identified clusterin as a potential biomarker whose level was higher in rapidly progressing Alzheimer disease than in more slowly progressing disease. They went on to show a relationship between severity of disease and plasma clusterin levels. These results are confirmed and extended by Schrijvers et al.8 They confirm that higher clusterin levels are associated with both the occurrence of Alzheimer disease and disease severity, and they additionally show that, within the power of the study, there is little evidence of higher plasma clusterin levels predicting disease occurrence. These recent findings are remarkably consistent with the earlier literature. They suggest that as the entorhinal pathway becomes damaged by the early stages of the disease process (presumably plaque formation), clusterin levels increase in a reasonably selective way, and genetic variability in this response is an important determinant in disease risk. While levels of clusterin clearly increase in disease and increase more as the disease gets worse, we cannot be sure whether those who respond more or those who respond less are at greater risk for disease: the genetic data point at the locus but do not immediately tell us whether we should be thinking of potentiating or antagonizing CLU function. Nonsense mutations in CLU occur at an appreciable frequency in both cases and controls,6,9 and our view on whether we should potentiate or antagonize CLU function will be informed by whether these are shown to occur more frequently in cases or controls. We do, however, have evidence that it is amyloid that potentiates clusterin expression. There is a significant association between plasma levels of clusterin and evidence for amyloid deposition in the brain in nondemented elderly people as measured using positron emission tomographic imaging and, more remarkably, an increase in plasma clusterin in a transgenic mouse with plaque formation.7 Other evidence suggests that clusterin is one of several amyloid chaperones; when plaque-generating mice were bred with a mouse lacking either ApoE or Clu, the resulting offspring had the same amount of amyloid in their brains but somewhat less fibrillized amyloid. On the other hand, when the mice lacked both ApoE and Clu, the amount of amyloid deposited was substantially increased and was deposited earlier.10 Related to this, in another unbiased proteomic study comparing individuals with high (positron emission tomography–detected) amyloid with individuals with low amyloid, apolipoprotein E was the predominant blood-based correlate of brain amyloid—data suggesting that these apolipoproteins are acting as amyloid response agents.11 These data from mouse and man suggest that apolipoproteins E and J are acting as disease response agents, specifically amyloid response agents. The mouse data suggest that they are beneficial agents, perhaps acting to remove amyloid, although interpreting these complex genetically manipulated animals is difficult. Moreover, some critically important questions remain. Schrijvers et al8 show that clusterin increased in people with Alzheimer disease but not in people 3 years before onset of disease. Thambisetty et al7 show a significant correlation with amyloid deposition in healthy people. These findings beg the question, at what point does the plasma clusterin level increase? A second, even more challenging and indeed interesting question is, from where does this plasma clusterin come? Is it generated peripherally in response to brain pathology or does it cross the blood-brain barrier, perhaps even accompanied by amyloid? Getting to the bottom of these questions will be essential before embarking on therapeutic strategies based on the newfound prominence of clusterin. For now, though, we have in the last year or two learned 2 things that look set to influence the Alzheimer disease field for many years to come. First, it is abundantly clear that clusterin, and its gene CLU, are as centrally important to response to the pathology of Alzheimer disease as its related protein apolipoprotein E. Second, there is unambiguously a change in proteins in blood in relation to disease. Whether that change goes beyond clusterin or can be turned into a clinically useful biomarker remains to be seen. Back to top Article Information Correspondence: Dr Hardy, Departments of Molecular Neuroscience and Clinical Neuroscience, Reta Lila Weston Research Laboratories, Institute of Neurology, University College London, Queen Square House, Ninth Floor, Queen Square, London WC1N 3BG, England (j.hardy@ion.ucl.ac.uk). Author Contributions:Study concept and design: Hardy, Guerreiro, and Lovestone. Drafting of the manuscript: Hardy and Lovestone. Critical revision of the manuscript for important intellectual content: Hardy and Guerreiro. Study supervision: Hardy. Financial Disclosure: Dr Lovestone is a named inventor on intellectual property held jointly by King's College London and Proteome Sciences relating to biomarkers for dementia and including clusterin. References 1. May PC, Lampert-Etchells M, Johnson SA, Poirier J, Masters JN, Finch CE. Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat. Neuron. 1990;5(6):831-8391702645PubMedGoogle ScholarCrossref 2. Poirier J, Hess M, May PC, Finch CE. Cloning of hippocampal poly(A) RNA sequences that increase after entorhinal cortex lesion in adult rat. Brain Res Mol Brain Res. 1991;9(3):191-1951674353PubMedGoogle ScholarCrossref 3. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261(5123):921-9238346443PubMedGoogle ScholarCrossref 4. Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009;41(10):1088-109319734902PubMedGoogle ScholarCrossref 5. Chartier-Harlin MC, Parfitt M, Legrain S, et al. Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. Hum Mol Genet. 1994;3(4):569-5748069300PubMedGoogle ScholarCrossref 6. Guerreiro RJ, Beck J, Gibbs JR, et al. Genetic variability in CLU and its association with Alzheimer's disease. PLoS One. 2010;5(3):e951020209083PubMedGoogle ScholarCrossref 7. Thambisetty M, Simmons A, Velayudhan L, et al. Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. Arch Gen Psychiatry. 2010;67(7):739-74820603455PubMedGoogle ScholarCrossref 8. Schrijvers EM, Koudstaal PJ, Hofman A, Breteler MM. Plasma clusterin and the risk of Alzheimer disease. JAMA. 2011;305(13):1322-132621467285PubMedGoogle ScholarCrossref 9. Tycko B, Feng L, Nguyen L, et al. Polymorphisms in the human apolipoprotein-J/clusterin gene: ethnic variation and distribution in Alzheimer's disease. Hum Genet. 1996;98(4):430-4368792817PubMedGoogle ScholarCrossref 10. DeMattos RB, Cirrito JR, Parsadanian M, et al. ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. Neuron. 2004;41(2):193-20214741101PubMedGoogle ScholarCrossref 11. Thambisetty M, Tripaldi R, Riddoch-Contreras J, et al. Proteome-based plasma markers of brain amyloid-β deposition in non-demented older individuals. J Alzheimers Dis. 2010;22(4):1099-110920930274PubMedGoogle Scholar

Journal

Archives of NeurologyAmerican Medical Association

Published: Nov 14, 2011

References