Research Brief: Clusterin Grabs Spotlight Among Elite Few LOAD Genes

Among the few genes recently linked to late-onset Alzheimer disease (LOAD) in multiple genomewide screens (see Seshadri et al., 2010; Carrasquillo et al., 2010; Corneveaux et al., 2010), clusterin has stolen the show in two new papers. In the first, Simon Lovestone, King’s College London, and colleagues report in this month’s Archives of General Psychiatry that plasma levels of clusterin track with AD severity, pathology, and clinical progression. And in the second report, published online June 4 in the Neurobiology of Aging, researchers led by Michael Barmada, University of Pittsburgh, Pennsylvania, provide additional support for clusterin’s involvement in AD (see also ARF related news story on other confirmatory genetic association studies). The researchers confirmed its LOAD association, as well as that of phosphatidylinositol-binding clathrin assembly protein (PICALM), in a case-control sample of more than 2,700 people.

Over the years, the hunt for blood-based AD biomarkers has found as much frustration (see ARF related news story) as fanfare (see ARF news story). Cerebrospinal fluid and brain imaging measures are, at this point, more reliable for predicting disease risk and tracking progression, but hopes of doing this with a cheaper, simpler blood test sustains the search for plasma AD biomarkers.

In the first paper, lead author Madhav Thambisetty and colleagues used two-dimensional gel electrophoresis and mass spectrometry to identify blood factors that met various criteria for LOAD association in two small, separate cohorts. The researchers probed blood samples from the first group (44 white U.K. citizens) for proteins that correlated with atrophy in AD and mild cognitive impairment (MCI). In the second group (51 white European AD patients), the scientists looked for blood proteins expressed more in fast but less in slow progressors, as judged by rate of cognitive decline measured by ADAS-Cog scores. The only member common to both lists—which contained eight proteins apiece, many of them inflammatory factors involved in the complement system—was clusterin, an extracellular chaperone that regulates amyloid formation and clearance.

The researchers re-examined clusterin in a group of 689 people (464 AD, 115 MCI, 110 controls) that included the 95 subjects from the two-pronged initial discovery phase. In the expanded cohort, Lovestone’s team found that those with higher plasma clusterin levels had greater atrophy in the entorhinal cortex, more amyloid in the medial temporal lobe, and poorer performance on the Mini-Mental State Examination. Furthermore, the researchers found elevated concentrations of plasma clusterin in AD transgenic mice that overexpress mutated amyloid precursor protein (APP) and presenilin 1, and higher clusterin mRNA levels in blood cells of AD patients, compared with MCI and control subjects. However, one sticking point with the paper was that none of the seven clusterin variants tested—including several that associated with LOAD in recent genomewide studies (Lambert et al., 2009; Harold et al., 2009)—seemed to affect clusterin mRNA levels or protein expression in blood. Whether clusterin turns out to be a useful biomarker remains to be seen, but the new data lend credence to the idea that the protein may play some role in AD pathogenesis.

The Neurobiology of Aging paper lends further support to this hypothesis. First author Ilyas Kamboh and colleagues confirmed the LOAD associations of clusterin and PICALM in a case-control sample of 2,707 Caucasian Americans (about half non-demented, half with probable/definite AD). Clusterin and PICALM were two of the three genes identified in a pair of independent GWASs published in the same issue of Nature Genetics last year (see ARF related news story). The third gene from the 2009 studies, CR1 (complement receptor 1), did not show statistically significant LOAD association in the new replication study, which might have been underpowered to detect the extremely small effect sizes of CR1 variants in the larger genomewide screens, the authors say.—Esther Landhuis

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References

News Citations

  1. Repeat Offenders—CLU, CR1, PICALM Hold Up in Association Studies
  2. Plasma Aβ Testing Beset by Questions of Assays, Biology, Timing
  3. Stayin’ Alive—Huge Study Quickens Quest for Plasma AD Biomarker
  4. Paper Alert: GWAS Hits Clusterin, CR1, PICALM Formally Published

Paper Citations

  1. Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, Bis JC, Smith AV, Carassquillo MM, Lambert JC, Harold D, Schrijvers EM, Ramirez-Lorca R, Debette S, Longstreth WT, Janssens AC, Pankratz VS, Dartigues JF, Hollingworth P, Aspelund T, Hernandez I, Beiser A, Kuller LH, Koudstaal PJ, Dickson DW, Tzourio C, Abraham R, Antunez C, Du Y, Rotter JI, Aulchenko YS, Harris TB, Petersen RC, Berr C, Owen MJ, Lopez-Arrieta J, Varadarajan BN, Becker JT, Rivadeneira F, Nalls MA, Graff-Radford NR, Campion D, Auerbach S, Rice K, Hofman A, Jonsson PV, Schmidt H, Lathrop M, Mosley TH, Au R, Psaty BM, Uitterlinden AG, Farrer LA, Lumley T, Ruiz A, Williams J, Amouyel P, Younkin SG, Wolf PA, Launer LJ, Lopez OL, van Duijn CM, Breteler MM, . Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010 May 12;303(18):1832-40. PubMed.
  2. Carrasquillo MM, Belbin O, Hunter TA, Ma L, Bisceglio GD, Zou F, Crook JE, Pankratz VS, Dickson DW, Graff-Radford NR, Petersen RC, Morgan K, Younkin SG. Replication of CLU, CR1, and PICALM associations with alzheimer disease. Arch Neurol. 2010 Aug;67(8):961-4. PubMed.
  3. Corneveaux JJ, Myers AJ, Allen AN, Pruzin JJ, Ramirez M, Engel A, Nalls MA, Chen K, Lee W, Chewning K, Villa SE, Meechoovet HB, Gerber JD, Frost D, Benson HL, O'Reilly S, Chibnik LB, Shulman JM, Singleton AB, Craig DW, Van Keuren-Jensen KR, Dunckley T, Bennett DA, De Jager PL, Heward C, Hardy J, Reiman EM, Huentelman MJ. Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals. Hum Mol Genet. 2010 Aug 15;19(16):3295-301. PubMed.
  4. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, , de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1094-9. PubMed.
  5. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1088-93. PubMed.

Other Citations

  1. ADAS-Cog

Further Reading

Papers

  1. Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, Bis JC, Smith AV, Carassquillo MM, Lambert JC, Harold D, Schrijvers EM, Ramirez-Lorca R, Debette S, Longstreth WT, Janssens AC, Pankratz VS, Dartigues JF, Hollingworth P, Aspelund T, Hernandez I, Beiser A, Kuller LH, Koudstaal PJ, Dickson DW, Tzourio C, Abraham R, Antunez C, Du Y, Rotter JI, Aulchenko YS, Harris TB, Petersen RC, Berr C, Owen MJ, Lopez-Arrieta J, Varadarajan BN, Becker JT, Rivadeneira F, Nalls MA, Graff-Radford NR, Campion D, Auerbach S, Rice K, Hofman A, Jonsson PV, Schmidt H, Lathrop M, Mosley TH, Au R, Psaty BM, Uitterlinden AG, Farrer LA, Lumley T, Ruiz A, Williams J, Amouyel P, Younkin SG, Wolf PA, Launer LJ, Lopez OL, van Duijn CM, Breteler MM, . Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010 May 12;303(18):1832-40. PubMed.
  2. Carrasquillo MM, Belbin O, Hunter TA, Ma L, Bisceglio GD, Zou F, Crook JE, Pankratz VS, Dickson DW, Graff-Radford NR, Petersen RC, Morgan K, Younkin SG. Replication of CLU, CR1, and PICALM associations with alzheimer disease. Arch Neurol. 2010 Aug;67(8):961-4. PubMed.
  3. Corneveaux JJ, Myers AJ, Allen AN, Pruzin JJ, Ramirez M, Engel A, Nalls MA, Chen K, Lee W, Chewning K, Villa SE, Meechoovet HB, Gerber JD, Frost D, Benson HL, O'Reilly S, Chibnik LB, Shulman JM, Singleton AB, Craig DW, Van Keuren-Jensen KR, Dunckley T, Bennett DA, De Jager PL, Heward C, Hardy J, Reiman EM, Huentelman MJ. Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals. Hum Mol Genet. 2010 Aug 15;19(16):3295-301. PubMed.
  4. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, , de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1094-9. PubMed.
  5. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1088-93. PubMed.

Primary Papers

  1. Thambisetty M, Simmons A, Velayudhan L, Hye A, Campbell J, Zhang Y, Wahlund LO, Westman E, Kinsey A, Güntert A, Proitsi P, Powell J, Causevic M, Killick R, Lunnon K, Lynham S, Broadstock M, Choudhry F, Howlett DR, Williams RJ, Sharp SI, Mitchelmore C, Tunnard C, Leung R, Foy C, O'Brien D, Breen G, Furney SJ, Ward M, Kloszewska I, Mecocci P, Soininen H, Tsolaki M, Vellas B, Hodges A, Murphy DG, Parkins S, Richardson JC, Resnick SM, Ferrucci L, Wong DF, Zhou Y, Muehlboeck S, Evans A, Francis PT, Spenger C, Lovestone S. Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. Arch Gen Psychiatry. 2010 Jul;67(7):739-48. PubMed.
  2. Kamboh MI, Minster RL, Demirci FY, Ganguli M, Dekosky ST, Lopez OL, Barmada MM. Association of CLU and PICALM variants with Alzheimer's disease. Neurobiol Aging. 2012 Mar;33(3):518-21. PubMed.

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