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      The COMT Val158 Met polymorphism as an associated risk factor for Alzheimer disease and mild cognitive impairment in APOE 4 carriers

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          Abstract

          Background

          The aim of this study is to examine the influence of the catechol-O-methyltranferase (COMT) gene (polymorphism Val158 Met) as a risk factor for Alzheimer's disease (AD) and mild cognitive impairment of amnesic type (MCI), and its synergistic effect with the apolipoprotein E gene (APOE).

          A total of 223 MCI patients, 345 AD and 253 healthy controls were analyzed. Clinical criteria and neuropsychological tests were used to establish diagnostic groups.

          The DNA Bank of the University of the Basque Country (UPV-EHU) (Spain) determined COMT Val158 Met and APOE genotypes using real time polymerase chain reaction (rtPCR) and polymerase chain reaction (PCR), and restriction fragment length polymorphism (RFLPs), respectively. Multinomial logistic regression models were used to determine the risk of AD and MCI.

          Results

          Neither COMT alleles nor genotypes were independent risk factors for AD or MCI. The high activity genotypes (GG and AG) showed a synergistic effect with APOE ε4 allele, increasing the risk of AD (OR = 5.96, 95%CI 2.74-12.94, p < 0.001 and OR = 6.71, 95%CI 3.36-13.41, p < 0.001 respectivily). In AD patients this effect was greater in women.

          In MCI patients such as synergistic effect was only found between AG and APOE ε4 allele (OR = 3.21 95%CI 1.56-6.63, p = 0.02) and was greater in men (OR = 5.88 95%CI 1.69-20.42, p < 0.01).

          Conclusion

          COMT (Val158 Met) polymorphism is not an independent risk factor for AD or MCI, but shows a synergistic effect with APOE ε4 allele that proves greater in women with AD.

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          Most cited references 39

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          Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

          The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
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            Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease.

            Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N=511), and results were also stratified by apolipoprotein E (APOE) genotype (n=323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE epsilon4 allele status and ADAS-Cog (P=0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE epsilon4-negative patients on 8 mg RSG (P=0.024; not corrected for multiplicity). APOE epsilon4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P=0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE epsilon4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE epsilon4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.
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              A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging.

              Previous reports have suggested that estrogen replacement therapy (ERT) in women may exert a protective effect on their risk of developing Alzheimer's disease (AD). We investigated this relationship in the Baltimore Longitudinal Study of Aging (BLSA), a prospective multidisciplinary study of normal aging conducted by the National Institute on Aging. The sample consisted of 472 post- or perimenopausal women followed for up to 16 years in the BLSA. We documented ERT prospectively at each BLSA visit, and we categorized women who had used oral or transdermal estrogens at anytime as ERT users. We used Cox proportional hazards models with time-dependent covariates to estimate the relative risk of developing AD after ERT as compared with women who had not used estrogen replacement. Approximately 45% of the women in the cohort had used ERT, and we diagnosed 34 incident cases of AD (NINCDS/ADRDA criteria) during follow-up, including nine estrogen users. After adjusting for education, the relative risk for AD in ERT users as compared with nonusers was 0.46 (95% CI, 0.209-0.997), indicating a reduced risk of AD for women who had reported the use of estrogen. Our data did not show an effect for duration of ERT usage. Our finding offers additional support for a protective influence of estrogen in AD. Randomized clinical trials are necessary to confirm this association, which could have significant public health impact.
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                Author and article information

                Journal
                BMC Neurosci
                BMC Neuroscience
                BioMed Central
                1471-2202
                2009
                30 September 2009
                : 10
                : 125
                Affiliations
                [1 ]Neurology Department, Hospital de Cruces, Baracaldo, Vizcaya, Spain
                [2 ]Research General Service, Bank of DNA and Dpt. of Z. and Cellular Biology, Faculty of Pharmacy, University of Basque Country UPV/EHU, Vitoria-Gasteiz, Álava, Spain
                [3 ]Neurology Department, Hospital de Txagorritxu, Vitoria-Gasteiz, Álava, Spain
                [4 ]Neurology Deparment, Hospital de Basurto, Bilbao, Vizcaya, Spain
                [5 ]Neurology Department, Hospital Donosti, San Sebastian, Guipuzcoa, Spain
                [6 ]Neurology Department, Hospital de Galdakao, Galdakao, Vizcaya, Spain
                [7 ]Neurology Department, Hospital Santiago Apóstol, Vitoria-Gazteiz, Álava, Spain
                Article
                1471-2202-10-125
                10.1186/1471-2202-10-125
                2765959
                19793392
                Copyright © 2009 Martínez et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Research Article

                Neurosciences

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