Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Open Life Sciences

formerly Central European Journal of Biology

Editor-in-Chief: Ratajczak, Mariusz

IMPACT FACTOR 2018: 0.504
5-year IMPACT FACTOR: 0.583

CiteScore 2018: 0.63

SCImago Journal Rank (SJR) 2018: 0.266
Source Normalized Impact per Paper (SNIP) 2018: 0.311

ICV 2017: 154.48

Open Access
See all formats and pricing
More options …
Volume 3, Issue 1


Volume 10 (2015)

ACE I/D polymorphism in Alzheimer’s disease

Marianna Trebunova / Eva Slaba / Viera Habalova / Zuzana Gdovinova
Published Online: 2008-03-01 | DOI: https://doi.org/10.2478/s11535-007-0051-9


Angiotensin-converting enzyme (ACE) has been reported to show altered activity in patients with neurological diseases. The recent studies found that a 287 bp insertion/deletion (I/D) polymorphism of the ACE gene may be associated with susceptibility to Alzheimer’s disease (AD) but the results have been heterogenous between studies in Europe. In the present study we examined for the first time the association of ACE I/D polymorphism along with APOE genotype in 70 sporadic AD and 126 control subjects in Slovak Caucasians (Central Europe). An increased risk for AD was observed in subjects with at least one APOE*E4 allele (OR=3.99, 95% CI=1.97–8.08). No significant differences for the genotype distribution or the allele frequency were revealed comparing controls and patients for ACE gene. Gene-gene interaction analysis showed increase of the risk to develop AD in subjects carrying both the ACE DD genotype and the APOE*E4 allele (OR=10.32, 95% C.I. 2.67–39.81).

Keywords: Alzheimer’s disease (AD); Angiotensin-converting enzyme (ACE); Polymorphism; APOE; Gene-gene interaction

  • [1] Farrer L.A., O’sullivan D.M., Cupples L.A., Growdon J.H., Myers R.H., Assessment of genetic risk for Alzheimer’s disease among first-degree relatives, Ann. Neurol., 1989, 25, 485–493 http://dx.doi.org/10.1002/ana.410250511CrossrefGoogle Scholar

  • [2] Korten A.E., Jorm A.F., Henderson A.S., Broe G.A., Creasey H., Mc Cusker E., Assessing the risk of Alzheimer’s disease in first-degree relatives of Alzheimer’s disease cases, Psychol. Med., 1993, 23, 915–923 http://dx.doi.org/10.1017/S0033291700026386CrossrefGoogle Scholar

  • [3] Erdős E., Skingel R.A., The angiotensin I-converting enzyme, Lab. Invest., 1987, 56, 345–348 Google Scholar

  • [4] Reid I. A., Interactions between ANG II, sympathetic nervous system, and baroreflexes in regulation of blood pressure, Am. J. Physiol., 1992, 262, 763–778 Google Scholar

  • [5] Kakinuma Y., Hama H., Sugiyama F., Yagami K., Goto K., Murakami K., et al., Impaired blood-brain barrier function in angiotensinogen-deficient mice, Nat. Med., 1998, 4, 1078–1080 http://dx.doi.org/10.1038/2070CrossrefGoogle Scholar

  • [6] Skoog I., Wallin A., Fredman P., A population study on blood-brain barrier function in 85-year olds, Neurology, 1998, 50, 966–971 CrossrefGoogle Scholar

  • [7] Zubenko G.S., Volicer L., Direnfeld L.K., Freeman M., Lanflais P.J., Nixon R.A., Cerebrospinal fluid levels of angiotensin-converting enzyme in Alzheimer’s disease, Parkinson’s disease and progressive supranuclear palsy, Brain. Res., 1985, 328, 215–221 http://dx.doi.org/10.1016/0006-8993(85)91032-7CrossrefGoogle Scholar

  • [8] Barnes N.M., Cheng C.H., Costall B., Naylor R.J., Williams T.J., Wischnik C.M., Angiotensin converting enzyme density is increased in temporal cortex from patients with Alzheimer’s disease, Eur. J. Pharmacol., 1991, 200, 289–292 http://dx.doi.org/10.1016/0014-2999(91)90584-DCrossrefGoogle Scholar

  • [9] Savaskan E., Hock C., Olivieri G., Bruttel S., Rosenberg C., Hulette Ch., et al., Cortical alterations of angiotensin converting enzyme, angiotensin II and AT1 receptor in Alzheimer’s dementia, Neurobiol. Aging., 2001, 22, 541–546 http://dx.doi.org/10.1016/S0197-4580(00)00259-1Google Scholar

  • [10] He M., Ohrui T., Maruyama M., Tomita N., Nakayama K., Higuchi M., et al., ACE activity in CSF of patients with mild cognitive impairtment and Alzheimer disease, Neurology, 2006, 67, 1309–1310 http://dx.doi.org/10.1212/01.wnl.0000238102.04582.ecCrossrefGoogle Scholar

  • [11] Hu J., Igarashi A., Kamata M., Nagawa H., Angiotensin-converting enzyme degrades Alzheimer amyloid β-peptide (Aβ), retards Aβ aggregation, deposition, fibril formation and inhibits cytotoxicity, J. Biol. Chem., 2001, 267, 47863–47868 Google Scholar

  • [12] Arbustini E., Grasso M., Fasani R., Klersy C., Diegoli M., Porcu E., et al., Angiotensin-converting enzyme gene deletion allele is independently and strongly associated with coronary artherosclerosis and myocardial infarction, Br. Heart J., 1995, 74, 584–591 http://dx.doi.org/10.1136/hrt.74.6.584CrossrefGoogle Scholar

  • [13] Tiret L., Rigat B., Visvikis S., Breda C., Corvol P., Cambien F., Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels, Am. J. Hum. Genet., 1992, 51, 197–205 Google Scholar

  • [14] Rigat B., Hubert C., Alhens-Gelas F., Cambien F., Corvol P., Soubrier F., An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accouming for half the variance of serum enzyme levels, J. Clin. Invest, 1990, 86,1343–1346 http://dx.doi.org/10.1172/JCI114844CrossrefGoogle Scholar

  • [15] Arregui A., Perry E.K., Rossor M., Tomlinson B.E., Angiotensin-converting enzyme in Alzheimer’s disease: increased activity in caudate nucleus and cortical areas, J. Neurochem., 1982, 38, 1490–1492 http://dx.doi.org/10.1111/j.1471-4159.1982.tb07930.xCrossrefGoogle Scholar

  • [16] Chapman J., Estupinan J., Asherov A., Goldfarb L.G., A simple and efficient method for apolipoprotein E genotype determination, Neurology, 1996, 46, 1484–1485 CrossrefGoogle Scholar

  • [17] Ribichini F., Steffenino G., Dellavelle A., Matullo G., Colajanni E., Camilla T., et al., Plasma Activity and Insertion/ Deletion Polymorphism of Angiotensin I-Converting Enzyme, Clinical Investigation and Reports. Circulation, 1998, 97, 147–154 Google Scholar

  • [18] Fogarty D.G., Maxwell A.P., Doherty C.C., Hughes A.E., Nevin N.C., Ace gene typing, Lancet., 1994, 343, 851 http://dx.doi.org/10.1016/S0140-6736(94)92050-8CrossrefGoogle Scholar

  • [19] Lindpaintner K., Pfeffer M.A., Kreutz R., Stamfed M.J., Grodstein F., Lamotte F., et al., A prospective evaluation of an angiotensin-converting enzyme gene polymorphism and risk of ischemic heart disease, N. Engl. J. Med., 1995, 332, 706–711 http://dx.doi.org/10.1056/NEJM199503163321103CrossrefGoogle Scholar

  • [20] Chartier-Harlin M.C., Parfitt M., Legrain S., Pérez-Tur J., Brousseau T., Evans A., et al., Apolipoprotein E, E4 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, 569–574 http://dx.doi.org/10.1093/hmg/3.4.569CrossrefGoogle Scholar

  • [21] Okulzumi K., Onodera O., Tanaka H., ApoE-E4 and early-onset Alzheimer’s, Nat. Genet., 1994, 7, 10–11 http://dx.doi.org/10.1038/ng0594-10bCrossrefGoogle Scholar

  • [22] Rebeck G.W., Peris T.T., West H.L., Sodhi P., Lipsitz L.A., Hyman B.T., Reduced apolipoprotein E4 allele frequency in the oldest old Alzheimer’s patients and cognitively normal individuals, Neurology, 1994, 44, 1513–1516 CrossrefGoogle Scholar

  • [23] Van Duijin C.M., De Knijff P., Cruts M., Wehnert A., Havekes L.M., Hofman A., et al., Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer’s disease, Nat. Genet., 1994, 7, 74–78 http://dx.doi.org/10.1038/ng0594-74CrossrefGoogle Scholar

  • [24] Corder E.H., Basun H., Lannfelt L., Vilanen M., Winbland B., Attenuation of apolipoprotein E E4 allele gene dose in late age, Lancet., 1996, 347, 542 http://dx.doi.org/10.1016/S0140-6736(96)91173-3CrossrefGoogle Scholar

  • [25] Farrer L.A., Cupples L.A., Haines J.L., Hyman B., Kukull W. A., Mayeux R., et al., Effects of age, gender and ethnicity on the association of apolipoprotein E genotype and Alzheimer disease, JAMA., 1997, 278, 1349–1356 http://dx.doi.org/10.1001/jama.278.16.1349CrossrefGoogle Scholar

  • [26] Farrer L.A., Sherbatich T., Keryanov S.A., Korovaitseva G.I., Rogaeva E. A., Petruk S., et al., Association between angiotensin-converting enzyme and Alzheimer’s disease, Neurology, 2000, 57, 210–214 http://dx.doi.org/10.1001/archneur.57.2.210CrossrefGoogle Scholar

  • [27] Myllykangas L., Polvikoski T., Sulkava R., Verkoniemi A., Tienari P., Niinisto L. et al., Cardiovascular risk factors and Alzheimer’s disease: A genetic association study in a population aged 85 or over, Neurosci. Lett., 2000, 292, 195–198 http://dx.doi.org/10.1016/S0304-3940(00)01467-1CrossrefGoogle Scholar

  • [28] Lendon C.L., Thaker U., Harris J.M., Mc Donagh A.M., Lambert J.C., Chartier-Harlin M.C., et al., The angiotensin 1-converting enzyme insertion (I)/ deletion (D) polymorphism does not influence the extent of amyloid or tau pathology in patients with sporadic Alzheimer’s disease, Neurosci. Lett., 2002, 328, 314–318 http://dx.doi.org/10.1016/S0304-3940(02)00553-0Google Scholar

  • [29] Carbonell J., Allen R., Kalsi G., McQuillin A., Livingston G., Katonba C., et al., Variation in the DCP1 gene, encoding the angiotensin converting enzyme ACE, is not associated with increased susceptibility to Alzheimer’s disease, Psychiatr. Genet., 2003, 13, 47–50 http://dx.doi.org/10.1097/00041444-200303000-00008CrossrefGoogle Scholar

  • [30] Nacmias B., Bagnoli S., Tedde A., Cellini E., Besi V., Guarnieri B., et al., Angiotensin converting enzyme insertion/ deletion polymorphism in sporadic and familial Alzheimer’s disease and longevity, Arch. Gerontol. Geriatr., 2006, 45, 201–206 http://dx.doi.org/10.1016/j.archger.2006.10.011CrossrefGoogle Scholar

  • [31] Meng Y., Baldwin C. T., Bowirrat A., Waraska K., Inzelberg R., Friedland R. P., et al., Association of Polymorphisms in the Angiotensin-Converting Enzyme Gene with Alzheimer Disease in an Israeli Arab Community, Am. J. Hum. Genet., 2006, 78, 871–877 http://dx.doi.org/10.1086/503687CrossrefGoogle Scholar

  • [32] Amouyel P., Richard F., Cottel D., Amant C., Cordon V., Helbecque N., The deletion allele of the angiotensin-converting enzyme gene as a genetic susceptibility factor for cognitive impairment, Neurosci. Lett., 1996, 217, 203–205 http://dx.doi.org/10.1016/0304-3940(96)13092-5CrossrefGoogle Scholar

  • [33] Palumbo B., Cadini D., Nocentini G., Filipponi E., Fravolini M.L., Senin U., Angiotensin-converting enzyme deletion allele in different kinds of dementia disorders, Neurosci. Lett., 1999, 267, 97–100 http://dx.doi.org/10.1016/S0304-3940(99)00329-8CrossrefGoogle Scholar

  • [34] Zhang J.W., Li X.Q., Zhang Z. X., Chen D., Zhao H.L., Wu Y.N., et al., Association between angiotensin-converting enzyme gene polymorphism and Alzheimer’s disease in a Chinese population, Dement. Geriatr. Cogn. Disord., 2005, 20, 52–56 http://dx.doi.org/10.1159/000085075CrossrefGoogle Scholar

  • [35] Sleegers K., Den Heijter T., Van Dijk E.J., Hofman A., Bertoli-Avella A.M., Koudstall P.J. et al., ACE gene is associated with Alzheimer’s disease and atrophy of hippocampus and amygdala, Neurobiol. Aging., 2005, 26, 1153–1159 http://dx.doi.org/10.1016/j.neurobiolaging.2004.09.011CrossrefGoogle Scholar

  • [36] Elkins J.S., Vanja C., Johnston S.C., Alzheimer disease risk and genetic variation in ACE. A meta-analysis, Neurology, 2004, 62, 363–368 CrossrefGoogle Scholar

  • [37] Lehmann D.J., Cortino-Borja M., Warden D.R., Smith A.D., Sleegers K., Warden D.R., et al., Large Meta-analysis establihes the ACE Insertion-Deletion Polymorphism as a Marker of Alzheimer’s disease, Am. J. Epidemiol., 2005, 162, 305–317 http://dx.doi.org/10.1093/aje/kwi202CrossrefGoogle Scholar

  • [38] Tian J., Shi J., Bailey K., Harris J.M., Pritchard A., Lambert J.C., et al., A polymorphism in the angiotensin 1-converting enzyme gene is associated with damage to cerebral cortical white matter in Alzheimer’s disease, Neurosci. Lett., 2004, 354, 103–106 http://dx.doi.org/10.1016/j.neulet.2003.09.072CrossrefGoogle Scholar

  • [39] Muthumala A., Cooper J., Humphries S.E., on behalf of the HIFMECH Study Group, European differences in the association between ACE I/D polymorphism and incidence of MI may be explained by gene-lipid interaction, Atherosclerosis, 2006, 89, 474–477 http://dx.doi.org/10.1016/j.atherosclerosis.2006.05.008CrossrefGoogle Scholar

  • [40] Panza F., Solfrizzi V., D’Introno A., Colacicco A.M., Capurso C., Capurso A., et al., Shifts in Angiotensin I converting enzyme insertion allele frequency across Europe: Implications for Alzheimer’s disease risk, J. Neurol. Neurosurg. Psychiatry, 2003, 74, 1159–1161 http://dx.doi.org/10.1136/jnnp.74.8.1159CrossrefGoogle Scholar

  • [41] Panza F., Solfrizzi V., Torres F., Mastroianni F, Colacicco A.M, Basile A.M. et al., Apolipoprotein E in Southern Italy: protective effect of epsilon 2 allele in early-and late-onset sporadic Alzheimer’s disease, Neurosci. Lett., 2000, 292, 79–82 http://dx.doi.org/10.1016/S0304-3940(00)01447-6Google Scholar

  • [42] Tysoe C., Galinsky D., Robinson D., Brayne C.E., Easton D.F., Huppert F.A. et al., Analysis of α-1 antichymotripsin, presenilin-1, angiotensin-converting enzyme, and methylenetetrahydrofolate reductase loci as candidates for dementia, Am. J. Med. Genet., 1997, 74, 207–212 http://dx.doi.org/10.1002/(SICI)1096-8628(19970418)74:2<207::AID-AJMG20>3.0.CO;2-LCrossrefGoogle Scholar

  • [43] Kehoe P.G., Katzov H., Feuk L., Bennet A.M., Johansson B., Wiman B., et al., Haplotypes extending across ACE are associated with Alzheimer’s disease, Hum. Mol. Genet., 2003, 12, 859–867 http://dx.doi.org/10.1093/hmg/ddg094CrossrefGoogle Scholar

About the article

Published Online: 2008-03-01

Published in Print: 2008-03-01

Citation Information: Open Life Sciences, Volume 3, Issue 1, Pages 49–54, ISSN (Online) 2391-5412, DOI: https://doi.org/10.2478/s11535-007-0051-9.

Export Citation

© 2008 Versita Warsaw. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

Comments (0)

Please log in or register to comment.
Log in