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BY-NC-ND 3.0 license Open Access Published by De Gruyter Open Access April 3, 2012

Gene polymorphisms of CETP and apolipoprotein E in elderly subjects with cognitive impairment

Loredan Niculescu, Laura Toma, Olga Ianas and Anca Sima
From the journal Open Life Sciences

Abstract

The association of cholesteryl ester transfer protein (CETP) and apolipoprotein E (APOE) gene polymorphisms with mild cognitive impairment (MCI) is under debate. Our aim was to evaluate the relationship between APOE and CETP genotypes with healthy ageing. We analysed 267 elderly subjects (55 to 80+ years), 163 with MCI and 104 healthy, and 50 healthy control subjects (35 to 55 years) from a Romanian population. Biochemical parameters and thyroid hormones were assayed in plasma. APOE and CETP TaqIB gene polymorphisms were determined. Elderly subjects had higher frequency of ɛ3/ɛ2 genotype (14.6% vs. 4%, P<0.001) than controls. Elderly subjects with MCI had lower high density lipoproteins (HDL) cholesterol (P=0.031), apoA-I (P=0.018), T3 (P=0.002), T4 (P=0.028) and TSH (P=0.001) hormone levels, higher systolic blood pressure (P=0.005), lower frequency of CETP B2 allele than the age-matched subjects. Healthy elderly subjects had CETP B2 allele associated with higher plasma apoA-I (P=0.021), lower circulating collagen (P=0.001) levels, and an increased frequency of the combined APOE ɛ2- CETP B2 genotype (18.3%) relative to MCI elderly subjects (7.6%, P=0.011). Healthy elderly subjects are characterized by higher HDL cholesterol, apoA-I levels and higher frequency of the combined APOE ɛ2 and CETP B2 alleles, indicating this pattern as representative for healthy ageing.

[1] Humphries S.E., Morgan L., Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches, Lancet Neurol., 2004, 3, 227–235 http://dx.doi.org/10.1016/S1474-4422(04)00708-210.1016/S1474-4422(04)00708-2Search in Google Scholar

[2] Seripa D., D’Onofrio G., Panza F., Cascavilla L., Masullo C., Pilotto A., The genetics of the human APOE polymorphism, Rejuvenation Res, 2011, 14, 491–500 http://dx.doi.org/10.1089/rej.2011.116910.1089/rej.2011.1169Search in Google Scholar

[3] Corder E.H., Saunders A.M., Strittmatter W.J., Schmechel D.E., Gaskell P.C., Small G.W., et al., Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families, Science, 1993, 261, 921–923 http://dx.doi.org/10.1126/science.834644310.1126/science.8346443Search in Google Scholar

[4] Bender A.R., Raz N., Age-related differences in memory and executive functions in healthy APOE varepsilon4 carriers: The contribution of individual differences in prefrontal volumes and systolic blood pressure, Neuropsychologia, 2012 10.1016/j.neuropsychologia.2011.12.025Search in Google Scholar

[5] West H.L., Rebeck G.W., Hyman B.T., Frequency of the apolipoprotein E epsilon 2 allele is diminished in sporadic Alzheimer disease, Neurosci. Lett., 1994, 175, 46–48 http://dx.doi.org/10.1016/0304-3940(94)91074-X10.1016/0304-3940(94)91074-XSearch in Google Scholar

[6] Berlau D.J., Corrada M.M., Head E., Kawas C.H., APOE epsilon2 is associated with intact cognition but increased Alzheimer pathology in the oldest old, Neurology, 2009, 72, 829–834 http://dx.doi.org/10.1212/01.wnl.0000343853.00346.a410.1212/01.wnl.0000343853.00346.a4Search in Google Scholar

[7] Dixit M., Bhattacharya S., Mittal B., Association of CETP TaqI and APOE polymorphisms with type II diabetes mellitus in North Indians: a case control study, BMC Endocr Dis, 2005, 5, 7 http://dx.doi.org/10.1186/1472-6823-5-710.1186/1472-6823-5-7Search in Google Scholar

[8] Drayna D., Lawn R., Multiple RFLPs at the human cholesteryl ester transfer protein (CETP) locus, Nucleic Acids Res., 1987, 15, 4698 http://dx.doi.org/10.1093/nar/15.11.469810.1093/nar/15.11.4698Search in Google Scholar

[9] Ordovas J.M., Cupples L.A., Corella D., Otvos J.D., Osgood D., Martinez A., et al., Association of cholesteryl ester transfer protein-TaqIB polymorphism with variations in lipoprotein subclasses and coronary heart disease risk: the Framingham study, Arterioscler. Thromb. Vasc. Biol., 2000, 20, 1323–1329 http://dx.doi.org/10.1161/01.ATV.20.5.132310.1161/01.ATV.20.5.1323Search in Google Scholar

[10] Murphy E.A., Roddey J.C., McEvoy L.K., Holland D., Hagler D.J., Jr., Dale A.M., et al., CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer’s disease risk in an APOE-dependent manner, Brain Imaging Behav, 2012, 6, 16–26 http://dx.doi.org/10.1007/s11682-011-9137-010.1007/s11682-011-9137-0Search in Google Scholar

[11] Folstein M.F., Folstein S.E., McHugh P.R., “Minimental state”. A practical method for grading the cognitive state of patients for the clinician, J Psychiatr Res, 1975, 12, 189–198. http://dx.doi.org/10.1016/0022-3956(75)90026-610.1016/0022-3956(75)90026-6Search in Google Scholar

[12] Hixson J.E., Vernier D.T., Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI, J. Lipid Res., 1990, 31, 545–548 10.1016/S0022-2275(20)43176-1Search in Google Scholar

[13] Arai Y., Hirose N., Yamamura K., Nakazawa S., Shimizu K., Takayama M., et al., Deficiency of choresteryl ester transfer protein and gene polymorphisms of lipoprotein lipase and hepatic lipase are not associated with longevity, J Mol Med (Berl)., 2003, 81, 102–109 10.1007/s00109-002-0407-6Search in Google Scholar

[14] Chiodini B.D., Franzosi M.G., Barlera S., Signorini S., Lewis C.M., D’Orazio A., et al., Apolipoprotein E polymorphisms influence effect of pravastatin on survival after myocardial infarction in a Mediterranean population: the GISSI-Prevenzione study, Eur. Heart J., 2007, 28, 1977–1983 http://dx.doi.org/10.1093/eurheartj/ehm19610.1093/eurheartj/ehm196Search in Google Scholar

[15] Sima A., Iordan A., Stancu C., Apolipoprotein E polymorphism-a risk factor for metabolic syndrome, Clin Chem Lab Med., 2007, 45, 1149–1153 http://dx.doi.org/10.1515/CCLM.2007.25810.1515/CCLM.2007.258Search in Google Scholar

[16] Evans R.M., Hui S., Perkins A., Lahiri D.K., Poirier J., Farlow M.R., Cholesterol and APOE genotype interact to influence Alzheimer disease progression, Neurology, 2004, 62, 1869–1871 10.1212/01.WNL.0000125323.15458.3FSearch in Google Scholar

[17] Mahley R.W., Huang Y., Weisgraber K.H., Detrimental effects of apolipoprotein E4: potential therapeutic targets in Alzheimer’s disease, Curr. Alzheimer Res., 2007, 4, 537–540 http://dx.doi.org/10.2174/15672050778301833410.2174/156720507783018334Search in Google Scholar

[18] Kulminski A., Ukraintseva S.V., Arbeev K.G., Manton K.G., Oshima J., Martin G.M., et al., Association between APOE epsilon 2/epsilon 3/epsilon 4 polymorphism and disability severity in a national long-term care survey sample, Age Ageing., 2008, 37, 288–293 http://dx.doi.org/10.1093/ageing/afn00310.1093/ageing/afn003Search in Google Scholar

[19] Garcia A.N., da Silva H.A., Silva R.C., Leal E.M., Rodrigues L., da Silva V.C., et al., APOE-epsilon4 polymorphism and cognitive deficit among the elderly population of Fernando de Noronha, Arqu. Neuropsiquiatr., 2008, 66, 298–302 http://dx.doi.org/10.1590/S0004-282X200800030000210.1590/S0004-282X2008000300002Search in Google Scholar

[20] Alexander D.M., Williams L.M., Gatt J.M., Dobson-Stone C., Kuan S.A., Todd E.G., et al., The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades, Biol. Psychol., 2007, 75, 229–238 http://dx.doi.org/10.1016/j.biopsycho.2007.03.00110.1016/j.biopsycho.2007.03.001Search in Google Scholar

[21] Brainerd C.J., Reyna V.F., Petersen R.C., Smith G.E., Taub E.S., Is the apolipoprotein e genotype a biomarker for mild cognitive impairment? Findings from a nationally representative study, Neuropsychology, 2011, 25, 679–689 http://dx.doi.org/10.1037/a002448310.1037/a0024483Search in Google Scholar

[22] Cosentino S., Scarmeas N., Helzner E., Glymour M.M., Brandt J., Albert M., et al., APOE epsilon 4 allele predicts faster cognitive decline in mild Alzheimer disease, Neurology, 2008, 70, 1842–1849 http://dx.doi.org/10.1212/01.wnl.0000304038.37421.cc10.1212/01.wnl.0000304038.37421.ccSearch in Google Scholar

[23] Ramakers I.H., Visser P.J., Aalten P., Bekers O., Sleegers K., van Broeckhoven C.L., et al., The association between APOE genotype and memory dysfunction in subjects with mild cognitive impairment is related to age and Alzheimer pathology, Dement. Geriatr. Cogn. Disord., 2008, 26, 101–108 http://dx.doi.org/10.1159/00014407210.1159/000144072Search in Google Scholar

[24] Nebel A., Kleindorp R., Caliebe A., Nothnagel M., Blanche H., Junge O., et al., A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals, Mech Ageing Dev, 2011, 132, 324–330 http://dx.doi.org/10.1016/j.mad.2011.06.00810.1016/j.mad.2011.06.008Search in Google Scholar

[25] Martins C.A., Oulhaj A., de Jager C.A., Williams J.H., APOE alleles predict the rate of cognitive decline in Alzheimer disease: a nonlinear model, Neurology, 2005, 65, 1888–1893. http://dx.doi.org/10.1212/01.wnl.0000188871.74093.1210.1212/01.wnl.0000188871.74093.12Search in Google Scholar

[26] van Osch L.A., Hogervorst E., Combrinck M., Smith A.D., Low thyroid-stimulating hormone as an independent risk factor for Alzheimer disease, Neurology, 2004, 62, 1967–1971 10.1212/01.WNL.0000128134.84230.9FSearch in Google Scholar

[27] Rockwood K., Nassar B., Mitnitski A., Apolipoprotein E-polymorphism, frailty and mortality in older adults, J. Cell Mol. Med., 2008, 12, 2754–2761 http://dx.doi.org/10.1111/j.1582-4934.2008.00270.x10.1111/j.1582-4934.2008.00270.xSearch in Google Scholar

[28] Brousseau M.E., O’Connor J.J., Jr., Ordovas J.M., Collins D., Otvos J.D., Massov T., et al., Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial, Arterioscler. Thromb. Vasc. Biol., 2002, 22, 1148–1154 http://dx.doi.org/10.1161/01.ATV.0000024566.57589.2E10.1161/01.ATV.0000024566.57589.2ESearch in Google Scholar

[29] Muendlein A., Saely C.H., Marte T., Schmid F., Koch L., Rein P., et al., Synergistic effects of the apolipoprotein E epsilon3/epsilon2/epsilon4, the cholesteryl ester transfer protein TaqIB, and the apolipoprotein C3 -482 C>T polymorphisms on their association with coronary artery disease, Atherosclerosis, 2008, 199, 179–186 http://dx.doi.org/10.1016/j.atherosclerosis.2007.10.03010.1016/j.atherosclerosis.2007.10.030Search in Google Scholar

Published Online: 2012-4-3
Published in Print: 2012-6-1

© 2012 Versita Warsaw

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

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