+1 Recommend
1 collections
      • Record: found
      • Abstract: found
      • Article: found

      Estrogen-Metabolizing Gene COMT Polymorphism Synergistic APOE ε4 Allele Increases the Risk of Alzheimer Disease

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Alzheimer disease (AD) is a polygenic multifactorial disorder. Several studies suggested that the neuroprotective effect of estrogen was based on an APOE-dependent mechanism. The goals of the current study were to determine if the genes involved in estrogen metabolism were linked to the risk of AD and find out if there was an interaction between estrogen-metabolizing gene polymorphisms and the APOE Ε4 allele in the risk of prevalent AD. We investigated 66 patients with AD and 86 age- and gender-matched normal subjects. The polymorphisms of APOE and estrogen-metabolizing genes CYP17, CYP1A1 and COMT were examined. No association was found between each estrogen-metabolizing gene polymorphism and AD. However, the COMT HH genotype and APOE Ε4 allele had a synergistic effect on the risk of AD. Taking subjects with Ε4–Ε4–/HH– as reference, the risk of developing AD in subjects with one Ε4 allele (Ε4+Ε4–/HH–) was 2.6 (95% confidence interval, CI, 0.7– 9.1); however, the risk in subjects with both HH and one Ε4 (Ε4+Ε4–/HH+) increased to 3.6 (95% CI 1.2–10.6). The subjects with homozygous Ε4 still had the highest risk in developing AD (odds ratio 6.6, 95% CI 0.6–69.6). The p value of the linear trend test for this regression model was 0.004. It is possible that a high metabolism of estrogen by COMT may have reduced the protective effect of estrogen in AD. Further studies to clarify this interaction may improve our understanding of the generic risks for AD.

          Related collections

          Most cited references 21

          • Record: found
          • Abstract: found
          • Article: not found

          Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease.

          Apolipoprotein E (apoE) is critical in the modulation of cholesterol and phospholipid transport between cells of different types. Human apoE is a polymorphic protein with three common alleles, APO epsilon 2, APO epsilon 3, and APO epsilon 4. ApoE4 is associated with sporadic and late-onset familial Alzheimer disease (AD). Gene dose was shown to have an effect on risk of developing AD, age of onset, accumulation of senile plaques in the brain, and reduction of choline acetyltransferase (ChAT) activity in the hippocampus of AD subjects. To characterize the possible impact of the apoE4 allele on cholinergic markers in AD, we examined the effect of apoE4 allele copy number on pre- and postsynaptic markers of cholinergic activity. ApoE4 allele copy number showed an inverse relationship with residual brain ChAT activity and nicotinic receptor binding sites in both the hippocampal formation and the temporal cortex of AD subjects. AD cases lacking the apoE4 allele showed ChAT activities close or within age-matched normal control values. The effect of the apoE4 allele on cholinomimetic drug responsiveness was assessed next in a group (n = 40) of AD patients who completed a double-blind, 30-week clinical trial of the cholinesterase inhibitor tacrine. Results showed that > 80% of apoE4-negative AD patients showed marked improvement after 30 weeks as measured by the AD assessment scale (ADAS), whereas 60% of apoE4 carriers had ADAS scores that were worse compared to baseline. These results strongly support the concept that apoE4 plays a crucial role in the cholinergic dysfunction associated with AD and may be a prognostic indicator of poor response to therapy with acetylcholinesterase inhibitors in AD patients.
            • Record: found
            • Abstract: found
            • Article: not found

            Molecular mechanisms of estrogen carcinogenesis.

             J G Liehr,  Eric Yager (1995)
            In western society, the causes of several cancers--including breast, endometrium, ovary, liver, and prostate--have been linked to inappropriate and/or prolonged exposure to synthetic or endogenous steroidal hormones. In this review, we discuss the mechanisms of estrogen carcinogenesis with a focus on estrogen metabolism to 16 alpha-hydroxy estrone and 2- and 4-hydroxy catechol estrogens and the potential effects of these metabolites in vitro and in vivo on hamster liver and kidney and rat liver carcinogenesis models. The examples demonstrate that the parent compounds and their metabolites cause both nongenotoxic cell proliferative effects as well as direct and indirect genotoxic effects, which illustrates the complex nature of estrogen carcinogenesis. These effects, in combination with the metabolic state of the tissue and the timing of its exposure, may determine the cell type (organ) of tumor development and the severity of disease.
              • Record: found
              • Abstract: not found
              • Article: not found

              Estrogen Therapy in Postmenopausal Women


                Author and article information

                Dement Geriatr Cogn Disord
                Dementia and Geriatric Cognitive Disorders
                S. Karger AG
                February 2005
                11 February 2005
                : 19
                : 2-3
                : 120-125
                aThe Neurological Institute and Departments of bPsychiatry and cMedical Research and Education, Taipei Veterans General Hospital, and dInstitute of Pharmacology and eSchool of Medicine, National Yang-Ming University, Taipei, Taiwan; fDepartment of Biomedical Engineering, Brown University, Providence, R.I., USA
                82663 Dement Geriatr Cogn Disord 2005;19:120–125
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Tables: 2, References: 37, Pages: 6
                Original Research Article


                Comment on this article