Journal of Neurology

, Volume 253, Issue 2, pp 181–185 | Cite as

Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE ε4 allele

  • E. Rodríguez
  • I. Mateo
  • J. Infante
  • J. Llorca
  • J. Berciano
  • O. CombarrosEmail author


Cholesterol regulates the production of amyloid beta (Aβ), which is central to the pathogenesis of Alzheimer's disease (AD), with high cellular cholesterol promoting and low cellular cholesterol reducing Aβ in vitro and in vivo. High density lipoprotein (HDL) plays a central role in the removal of excess cholesterol from cells, and cholesteryl ester transfer protein (CETP) is a crucial protein involved in the regulation of HDL levels. Two common polymorphisms in the promoter region (C–629A) and exon 14 I405V of the CETP gene are associated with CETP activity and HDL levels. To investigate if these sequence variants in CETP might be of importance in mediating susceptibility to AD, independently or in concert with apolipoprotein E (APOE) ε4 allele, we studied a sample of 286 Spanish AD patients and 315 healthy controls. In APOE ε4 carriers, homozygous for the CETP (–629) A allele had approximately a three times lower risk of developing AD (odds ratio 2.33, 95% CI 1.01–5.37), than homozygous and heterozygous carriers of the CETP (–629) C allele (odds ratio 7.12, 95% CI 4.51–11.24, P for APOE ε4/CETP (–629) AA genotype interaction < 0.001). Our data suggest that CETP behaves as a modifier gene of the AD risk associated with the APOE ε4 allele, possibly through modulation of brain cholesterol metabolism.

Key words

cholesteryl ester transfer protein Alzheimer's disease cholesterol apolipoprotein E polymorphism 


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  1. 1.
    Albers JJ, Tollefson JH, Wolfbauer G, Albright RE Jr (1992) Cholesteryl ester transfer protein in human brain. Int J Clin Lab Res 21:264–266PubMedGoogle Scholar
  2. 2.
    Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR (2003) Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA 290:2030–2040CrossRefPubMedGoogle Scholar
  3. 3.
    Blankenberg S, Rupprecht HJ, Bickel C, Jiang XC, Poirier O, Lackner KJ, Meyer J, Cambien F, Tiret L (2003) Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease. J Am Coll Cardiol 41:1983–1989CrossRefPubMedGoogle Scholar
  4. 4.
    Boekholdt SM, Thompson JF (2003) Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease. J Lipid Res 44:1080–1093PubMedGoogle Scholar
  5. 5.
    Brewer HB (2004) Increasing HDL cholesterol levels. N Engl J Med 350:1491–1494CrossRefPubMedGoogle Scholar
  6. 6.
    Dachet C, Poirier O, Cambien F, Chapman J, Rouis M (2000) New functional promoter polymorphism, CETP (–629), in cholesteryl ester transfer protein (CETP) gene related to CETP mass and high density lipoprotein cholesterol levels. Role of Sp1/Sp3 in transcriptional regulation. Arterioscler Thromb Vasc Biol 20:507–515PubMedGoogle Scholar
  7. 7.
    Dietschy JM, Turley SD (2001) Cholesterol metabolism in the brain. Curr Opin Lipidol 12:105–112CrossRefPubMedGoogle Scholar
  8. 8.
    Fidani L, Goulas A, Crook R, Petersen RC, Tangalos E, Kotsis A, Hardy J (2004) An association study of the cholesteryl ester transfer protein TaqI B polymorphism with late onset Alzheimer's disease. Neurosci Lett 357:152–154CrossRefPubMedGoogle Scholar
  9. 9.
    Gong JS, Kobayashi M, Hayashi H, Zou K, Sawamura N, Fujita SC, Yanagisawa K, Michikawa M (2002) Apolipoprotein E (ApoE) isoform–dependent lipid release from astrocytes prepared from human ApoE3 and ApoE4 knock–in mice. J Biol Chem 277:29919–29926PubMedGoogle Scholar
  10. 10.
    Gopalraj RK, Zhu H, Kelly JF, Mendiondo M, Pulliam JF, Bennett DA, Estus S (2005) Genetic association of low density lipoprotein receptor and Alzheimer's disease. Neurobiol Aging 26:1–7CrossRefPubMedGoogle Scholar
  11. 11.
    Lambert JC, Luedecking–Zimmer E, Merrot S, Hayes A, Thaker U, Desai P, Houzet A, Hermant X, Cottel D, Pritchard A, Iwatsubo T, Pasquier F, Frigard B, Conneally PM, Chartier– Harlin MC, DeKosky ST, Lendon C, Mann D, Kamboh MI, Amouyel P (2003) Association of 3'–UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease. J Med Genet 40:424–430CrossRefPubMedGoogle Scholar
  12. 12.
    Macé S, Cousin E, Ricard S, Génin E, Spanakis E, Lafargue–Soubigou C, Génin B, Fournel R, Roche S, Haussy G, Massey F, Soubigou S, Bréfort G, Benoit P, Brice A, Campion D, Hollis M, Pradier L, Benavides J, Deleuze JF (2005) ABCA2 is a strong genetic risk factor for early–onset Alzheimer's disease. Neurobiol Dis 18:119–125PubMedGoogle Scholar
  13. 13.
    McKhaan G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer's disease: Report of the NINCDA–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 34:934–944Google Scholar
  14. 14.
    Michikawa M (2003) The role of cholesterol in pathogenesis of Alzheimer's disease. Dual metabolic interaction between amyloid β–protein and cholesterol. Mol Neurobiol 27:1–12PubMedGoogle Scholar
  15. 15.
    Olesen OF, Dago (2000) High density lipoprotein inhibits assembly of amyloid β–peptides into fibrils. Biochem Biophys Res Commun 270:62–66CrossRefPubMedGoogle Scholar
  16. 16.
    Papassotiropoulos A, Streffer JR, Tsolaki M, Schmid S, Thal D, Nicosia F, Iakovidou V, Maddalena A, Lütjohann D, Ghebremedhin E, Hegi T, Pasch T, Träxler M, Brühl A, Benussi L, Binetti G, Braak H, Nitsch RM, Hock C (2003) Increased brain β–amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch Neurol 60:29–35PubMedGoogle Scholar
  17. 17.
    Poirier J (2003) Apolipoprotein E and cholesterol metabolism in the pathogenesis and treatment of Alzheimer's disease. Trends Mol Med 9:94–101CrossRefPubMedGoogle Scholar
  18. 18.
    Puglielli L, Tanzi RE, Kovacs DM (2003) Alzheimer's disease: the cholesterol connection. Nat Neurosci 6: 345–351CrossRefPubMedGoogle Scholar
  19. 19.
    Sánchez–Guerra M, Combarros O, Infante J, Llorca J, Berciano J, Fontalba A, Fernández–Luna JL, Peña N, Fernández– Viadero C (2001) Case–control study and meta–analysis of low density lipoprotein receptor–related protein gene exon 3 polymorphism in Alzheimer's disease. Neurosci Lett 316:17–20PubMedGoogle Scholar
  20. 20.
    Thompson JF, Lira ME, Durham K, Clark RW, Bamberger MJ, Milos PM (2003) Polymorphisms in the CETP gene and association with CETP mass and HDL levels. Atherosclerosis 167:195–204PubMedGoogle Scholar
  21. 21.
    Thompson JF, Lloyd DB, Lira ME, Milos PM (2004) Cholesteryl ester transfer protein promoter singlenucleotide polymorphisms in Sp1– binding sites affect transcription and are associated with high–density lipoprotein cholesterol. Clin Genet 66:223–228CrossRefPubMedGoogle Scholar
  22. 22.
    van der Steeg WA, Kuivenhoven JA, Klerkx AH, Boekholdt SM, Hovingh GK, Kastelein JJP (2004) Role of CETP inhibitors in the treatment of dyslipidemia. Curr Opin Lipidol 15:631–636CrossRefPubMedGoogle Scholar
  23. 23.
    Wolozin B (2004) Cholesterol, statins and dementia. Curr Opin Lipidol 15:667–672CrossRefPubMedGoogle Scholar
  24. 24.
    Wollmer MA, Streffer JR, Lütjohann D, Tsolaki M, Iakovidou V, Hegi T, Pasch T, Jung HH, von Bergmann K, Nitsch RM, Hock C, Papassotiropoulos A (2003) ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer's disease. Neurobiol Aging 24:421–426CrossRefPubMedGoogle Scholar
  25. 25.
    Wollmer MA, Streffer JR, Tsolaki M, Grimaldi LME, Lütjohann D, Thal D, von Bergmann K, Nitsch RM, Hock C, Papassotiropoulos A (2003) Genetic association of acyl–coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer's disease. Mol Psychiatry 8:635–638CrossRefPubMedGoogle Scholar
  26. 26.
    Yamada T, Kawata M, Arai H, Fukusawa M, Inoue K, Sato T (1995) Astroglial localization of cholesteryl ester transfer protein in normal and Alzheimer's disease brain tissues. Acta Neuropathol (Berl) 90:633–636PubMedGoogle Scholar
  27. 27.
    Yanagisawa K (2002) Cholesterol and pathological processes in Alzheimer's disease. J Neurosci Res 70:361–366CrossRefPubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2005

Authors and Affiliations

  • E. Rodríguez
    • 1
  • I. Mateo
    • 1
  • J. Infante
    • 1
  • J. Llorca
    • 2
  • J. Berciano
    • 1
  • O. Combarros
    • 1
    Email author
  1. 1.Neurology ServiceUniversity Hospital "Marqués de Valdecilla", University of Cantabria39008-SantanderSpain
  2. 2.Division of Preventive MedicineUniversity of Cantabria, School of MedicineSantanderSpain

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