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• W2098533587 abstract "BackgroundOestrogen use by postmenopausal women has many health benefits, but findings on the effect of oestrogen in Alzheimer's disease are conflicting. Oestrogen promotes the growth and survival of cholinergic neurons and could decrease cerebral amyloid deposition, both of which may delay the onset or prevent Alzheimer's disease. To investigate whether use of oestrogen during the postmenopausal period affects the risk of Alzheimer's disease, we studied 1124 elderly women who were initially free of Alzheimer's disease, Parkinson's disease, and stroke, and who were taking part in a longitudinal study of ageing and health in a New York City community.MethodsRelative risks and age-at-onset distributions were calculated from simple and adjusted Cox proportional hazards models. Standard annual clinical assessments and criterion-based diagnoses were used in follow-up (range 1–5 years).FindingsOverall, 156 (12·5%) women reported taking oestrogen after onset of menopause. The age at onset of Alzheimer's disease was significantly later in women who had taken oestrogen than in those who did not and the relative risk of the disease was significantly reduced (9/156 [5·8%] oestrogen users vs 158/968 [16·3%] non-users; 0·40 [95% CI 0·22–0·85], p<0 01), even after adjustment for differences in education, ethnic origin, and apolipoprotein-E genotype. Women who had used oestrogen for longer than 1 year had a greater reduction in risk; none of 23 women who were taking oestrogen at study enrolment has developed Alzheimer's disease.InterpretationOestrogen use in postmenopausal women may delay the onset and decrease the risk of Alzheimer's disease. Prospective studies are needed to establish the dose and duration of oestrogen required to provide this benefit and to assess its safety in elderly postmenopausal women. Oestrogen use by postmenopausal women has many health benefits, but findings on the effect of oestrogen in Alzheimer's disease are conflicting. Oestrogen promotes the growth and survival of cholinergic neurons and could decrease cerebral amyloid deposition, both of which may delay the onset or prevent Alzheimer's disease. To investigate whether use of oestrogen during the postmenopausal period affects the risk of Alzheimer's disease, we studied 1124 elderly women who were initially free of Alzheimer's disease, Parkinson's disease, and stroke, and who were taking part in a longitudinal study of ageing and health in a New York City community. Relative risks and age-at-onset distributions were calculated from simple and adjusted Cox proportional hazards models. Standard annual clinical assessments and criterion-based diagnoses were used in follow-up (range 1–5 years). Overall, 156 (12·5%) women reported taking oestrogen after onset of menopause. The age at onset of Alzheimer's disease was significantly later in women who had taken oestrogen than in those who did not and the relative risk of the disease was significantly reduced (9/156 [5·8%] oestrogen users vs 158/968 [16·3%] non-users; 0·40 [95% CI 0·22–0·85], p<0 01), even after adjustment for differences in education, ethnic origin, and apolipoprotein-E genotype. Women who had used oestrogen for longer than 1 year had a greater reduction in risk; none of 23 women who were taking oestrogen at study enrolment has developed Alzheimer's disease. Oestrogen use in postmenopausal women may delay the onset and decrease the risk of Alzheimer's disease. Prospective studies are needed to establish the dose and duration of oestrogen required to provide this benefit and to assess its safety in elderly postmenopausal women. IntroductionUse of oestrogen by postmenopausal women has many health benefits.1Bush TL Cowan LD Barrett-Connor E et al.Estrogen use and all-cause mortality: preliminary results from the Lipid Research Clinics Program Follow-Up Study.JAMA. 1983; 249: 903-906Crossref PubMed Scopus (234) Google Scholar, 2Ettinger B Friedman GD Bush T Quesenberry CP Reduced mortality associated with long-term postmenopausal estrogen therapy.Obstet Gynecol. 1996; 87: 6-12Crossref PubMed Scopus (317) Google Scholar Oestrogen has been used as a treatment3Fillit H Weinreb H Cholst I et al.Observations in a preliminary open trial of estradiol therapy for senile dementia—Alzheimer's type.Psychoneuroendocrinology. 1986; 11: 337-345Summary Full Text PDF PubMed Scopus (345) Google Scholar, 4Henderson VW Paganini-Hill A Emanuel CK Dunn ME Buckwalter JG Estrogen replacement therapy in older women: comparisons between Alzheimer's disease cases and nondemented control subjects.Arch Neurol. 1994; 51: 896-900Crossref PubMed Scopus (604) Google Scholar for Alzheimer's disease, which affects a substantial proportion of elderly women.5Rocca WA Amaducci LA Schoenberg BS Epidemiology of clinically diagnosed Alzheimer's disease.Ann Neurol. 1986; 19: 415-424Crossref PubMed Scopus (251) Google Scholar One study reported that oestrogen use was associated with a lower risk of mortality related to Alzheimer's disease,6Paganini-Hill A Henderson VW Estrogen deficiency and risk of Alzheimer's disease in women.Am J Epidemiol. 1994; 140: 256-261PubMed Google Scholar although a subsequent case-control study did not confirm this association.7Brenner DE Kukull WA Stergachis A et al.Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: a population-based case-control study.Am J Epidemiol. 1994; 140: 262-267Crossref PubMed Scopus (281) Google Scholar Oestrogen promotes the growth of cholinergic neurons,8Toran-Allerand CD Miranda RC Bentham WD et al.Estrogen receptors colocalize with low affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain.Proc Natl Acad Sci USA. 1992; 89: 4668-4672Crossref PubMed Scopus (428) Google Scholar, 9Simpkins JW Singh M Bishop J The potential role for estrogen replacement therapy in the treatment of the cognitive decline and neuro degeneration associated with Alzheimer's disease.Neurobiol Aging. 1994; 15: S195-S197Summary Full Text PDF PubMed Scopus (151) Google Scholar stimulates the secretase metabolism of the amyloid precursor protein,10Jaffe AB Toran-Allerand CD Greengard P Gandy SE Estrogen regulates metabolism of Alzheimer's amyloid beta precursor protein.J Biol Chem. 1994; 269: 13065-13068Summary Full Text PDF PubMed Google Scholar and may interact with apolipoprotein E.11Honjo H Tanaka K Kashiwagi T et al.Senile dementia-Alzheimer's type and estrogen.Hormone Metab Res. 1995; 27: 204-207Crossref PubMed Scopus (120) Google Scholar All these factors could affect the risk of Alzheimer's disease.We examined the effect of a history of oestrogen use on the development of Alzheimer's disease among elderly women living in New York. Our hypothesis was that oestrogen use might lower the risk of incident Alzheimer's disease.Methods1282 non-demented elderly women were identified in a community-based study of ageing in northern Manhattan, New York City. The Health Care Financing Administration provided access to a random sample of Medicare recipients in the community. Additional potential participants were consecutively identified from records at senior centres and elderly housing sites in the same community. We wrote to potential participants identified by either method explaining that they had been selected to take part in a study of ageing. Participation rates were 77% at the senior centres and housing sites and 72% in the Medicare sample; these rates did not differ by ethnic origin. Each participant underwent a 90 min face-to-face interview then a standard assessment, which included a medical history, physical and neurological examination, and a brief (about 1 h) battery of neuropsychological tests.12Stern Y Andrews H Pittman J et al.Diagnosis of dementia in a heterogeneous population: development of a neuropsychological paradigm and quantified correction for educated.Arch Neurol. 1992; 49: 453-460Crossref PubMed Scopus (359) Google Scholar, 13Pittman J Andrews H Tatemichi T et al.Diagnosis of dementia in a heterogeneous population: a comparison of paradigm-based diagnosis and physician's diagnosis.Arch Neurol. 1992; 49: 461-467Crossref PubMed Scopus (72) Google Scholar The criteria for eligibility were: no evidence of cognitive impairment on detailed psychometric assessment at the initial interview; no history of stroke or Parkinson's disease; and at least one subsequent annual follow-up assessment.Information about oestrogen use was available for 1227 (95·7%) women. From this group we excluded 52 (4·2%) women with Parkinson's disease, 45 (3·7%) with stroke, and six (0·5%) with both disorders. Thus, we restricted the analysis to 1124 women—352 (31%) women identified at the senior centres and housing sites and 772 (69%) from the Medicare sample. The Columbia University Institutional Review Board reviewed and approved this project.A standard history of oral oestrogen use was obtained from all women at study entry by a trained interviewer as part of the risk-factor questionnaire. The test-retest reliability of the overall questionnaire had been previously established.14Mayeux R Ottman R Tang M-X et al.Genetic susceptibility and head injury as risk factors for Alzheimer's disease among community-dwelling elderly persons and the first-degree relatives.Ann Neurol. 1993; 33: 494-501Crossref PubMed Scopus (194) Google Scholar Questions about oestrogen use had good test-retest reliability (κ=0·65). If a woman had ever taken oestrogen, she was asked the ages at which she began and stopped. She was asked how old she was at the onset of the menopause and whether it occurred naturally or as a result of surgery. We asked the women to name the type of oestrogen preparation they used but not the dosages.For diagnosis of dementia, medical records and imaging studies were used, as well as data from the initial and follow-up study examinations. The diagnosis was established by consensus among an independent group of physicians and neuro-psychologists from this information. This group were not aware of information on oestrogen use at any point during the diagnostic process. The diagnosis of dementia15American Psychiatric Association Diagnostic and statistical manual of mental disorders, 3rd edn, revised. American Psychiatric Association, Washington, DC1987: 205-224Google Scholar required evidence of cognitive decline on the neuropsychological test battery and impairment in social or occupational function. All data were examined to identify the aetiology of dementia with standard criteria16McKhann G Drachman D Folstein M Katzman R Price D Stadland E Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's disease.Neurology. 1984; 34: 939-944Crossref PubMed Google Scholar for the diagnosis of Alzheimer's disease.Ethnic origin was classified by self-report on the format of the 1990 United States Census Bureau (Census of Population and Housing, 1990).For apolipoprotein E (APOE) genotyping, genomic DNA was amplified by PCR, and subjected to CfoI restriction analysis with APOE primers and conditions modified from those described by Hixson and Vernier.17Hixson J Vernier D Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhAl.J Lipid Res. 1991; 31: 545-548Google Scholar, 18Maestre G Ottman R Stern Y et al.Apolipoprotein-E and Alzheimer's disease: ethnic variation in genotypic risks.Ann Neurol. 1995; 37: 254-259Crossref PubMed Scopus (234) Google ScholarDemographic characteristics and a history of oestrogen use in women who did and did not develop Alzheimer's disease were compared by means of χ2Ettinger B Friedman GD Bush T Quesenberry CP Reduced mortality associated with long-term postmenopausal estrogen therapy.Obstet Gynecol. 1996; 87: 6-12Crossref PubMed Scopus (317) Google Scholar tests for categorical variables and ANOVA for continuous variables. Age, ethnic origin, and education were compared among women who did and women who did not use oestrogen, and then among those who did and did not develop Alzheimer's disease.The Cox proportional hazard model was used to calculate the relative risk of developing Alzheimer's disease associated with use of oestrogen, and survival analysis was used to plot the age-at-onset distributions for women who did and did not use oestrogen. Subsequent models were stratified to assess the effects of education, APOE genotype, and ethnic origin on the relative risk; these covariates were then included in multivariate models. Because older women entering the study had a higher probability of developing Alzheimer's disease than younger women, we stratified the analysis by the median age at baseline to reduce a possible age cohort effect. We used martingale methods to check the proportional hazards assumption.19Collet D Modelling survival data in medical research. Chapman and Hall, London1994: 153-154Google Scholar The annual incidence rate was estimated and the incidence rate ratio was calculated by standard methods.ResultsThe mean age of the participating women was 74·2 years (SD 7·0) and the mean duration of education 9·2 years (SD 4·6). 400 (36%) of the women were African-American, 431 (38%) were Hispanic, and 293 (26%) were caucasian. During follow-up, which ranged from 1 to 5 years after the initial interview, 167 (14·9%) women developed Alzheimer's disease. The women who developed Alzheimer's disease were older than those who did not (78·5 [7·7] vs 73·7 [6·6] years, p=0·001) and had had fewer years of education (6·7 [4·2] vs 9·6 [4·5] years, p=0·001). Age at menopause was similar for women who did and did not develop Alzheimer's disease.156 women reported that they had used oestrogen after the onset of the menopause. The average duration of oestrogen use was 6–8 years (range 2 months to 49 years). Women who had used oestrogen were younger than those who had not (73·0 [6·3] vs 74·4 [7·1] years, p=0·01) and had had more years of education (10·2 [4·8] vs 9·0 [4·5] years, p=0·005). Fewer African-American women than caucasian or Hispanic women had used oestrogen (41 [10·3%] vs 115 [15·9%], p=0·007). Women who took oestrogen were more likely than those who did not to have had a hysterectomy (78 [50·0%] vs 256 [26·4%], p=0·0001), and to have had onset of the menopause at an earlier age (45·4 [8·1] vs 47·0 [7·7], p=0·06). A greater proportion of women who had undergone hysterectomy than of those who had natural menopauses had used oestrogen for longer than 1 year (23/227 [10·1%] vs 35/897 [4·0%], p=0·0001). The majority of women used tablets containing conjugated oestrogens (Premarin). The most frequent reasons for discontinuation of oestrogen use were uterine bleeding, fear of cancer, or physician's advice.A history of oestrogen use was significantly less common among women who developed Alzheimer's disease than in women who remained free of the disease (table 1, p=0·0006). There was no difference in the use of oestrogen between the women excluded at baseline for Parkinson's disease or stroke and the disease-free women (Parkinson's disease 17%, stroke 10%, disease-free 16%, p=0·51).Table 1Relative risk of incident Alzheimer's disease associated with use of oestrogen during postmenopausal periodAt riskAlzheimer's disease*Total number of incident cases over whole study period (cumulative incidence).HealthyRelative risk (95%CI)No oestrogen use968158 (16·3%)8101·0Oestrogen use1569 (5·8%)1470·40 (0·22–0·85)Total1124167 (14·9%)957* Total number of incident cases over whole study period (cumulative incidence). Open table in a new tab The age at onset for Alzheimer's disease, stratified by the median age at entry into the study, was significantly later among women who used oestrogen than among women who never used oestrogen (log-rank test p<0·01). The relative risk of Alzheimer's disease associated with a history of oestrogen use was 0·40 (95% CI 0·22–0·85; p=0·01, table 1). Adjustment for ethnic group, years of education, and participation group (senior centre or housing vs Medicare sample) did not significantly change the relative risk (0·5 [0·25–0·9], p=0·02).The Cox proportional hazards model was also used to examine the effect of duration of oestrogen use on the risk of Alzheimer's disease (table 2). 31 (20%) oestrogen users did not recall their duration of oestrogen use. The association with Alzheimer's disease among these women (unknown group in table 2) was not significantly different from that in non-users, which suggests that they may not have used oestrogen at all or for only a brief period. Women who took oestrogen for 1 year or less (average 4 months) had a lower risk of Alzheimer's disease than never-users, of borderline statistical significance (p=0·06). The relative risk of Alzheimer's disease for women who took oestrogen for longer than a year (average 13·6 years) was significantly reduced (0·13 [0·02–0·92], p<0·01). There was a significant linear trend in the effect of duration of oestrogen use on disease risk (log-rank test, p=0-0034, figure). 23 women were still taking oestrogen at enrolment in the study, and none has developed Alzheimer's disease during the study period.Table 2Duration of oestrogen useOestrogen useAt riskAlzheimer's disease*Total number of incident cases over whole study period (cumulative incidence).HealthyRelative risk (95%CI)None968158 (16·3%)8101·0Unknown313 (9·7%)281·3 (0·40–4·20)≤1 year675 (7·5%)620·47 (0·20–1·10)>1 year581 (1·7%)570·13 (0·02–0·92)* Total number of incident cases over whole study period (cumulative incidence). Open table in a new tab To check the assumptions of the Cox regression model, we plotted the martingale residuals against age at onset.19Collet D Modelling survival data in medical research. Chapman and Hall, London1994: 153-154Google Scholar Data for all but three subjects fell within the predicted horizontal band around 0, satisfying the assumptions of proportional hazards.Among women whose data satisfied criteria for inclusion in the analysis, 181 (16·1%) had no additional follow-up information. These women were similar to the 943 with additional follow-up in age (mean 75·4 [SD 7·8] vs 74·2 [6·8] years), education (9·3 [4·7] vs 9·2 [4·6] years), ethnic origin (African-American 62 [34·3%] vs other 338 [35·8%]), and oestrogen use (22 [12·5%] vs 134 [14·2%]). For women with additional follow-up, the duration did not differ significantly by history of oestrogen use or by the development of Alzheimer's disease (p=0·7).APOEgenotypes were available for 604 (53·7%) of the 1124 women. The risk of incident Alzheimer's disease was higher for women with APOEεA than for those with other genotypes (ε4/ε4 3·9 [1·5–9·8]; one ε4 allele 1·2 [0·7–1·6]). None of the nine APOEεA homozygous women had taken oestrogen (three cases, six controls). The relative risk for Alzheimer's disease associated with oestrogen use among APOEεA heterozygous women was reduced (0·13 [0·02–0·95]) as was that among women with other APOE genotypes (0·4 [0·2–0·9]).The estimated annual incidence rate of Alzheimer's disease was 2·7% among women who took oestrogen compared with 8·4% among those who did not take oestrogen. The overall incidence rate ratio was 0·4 (0·2–0·7), similar to that estimated in the Cox proportional hazards model. 68 patients (41% of the 167 patients) showed mild impairment of cognitive function but met criteria for inclusion. We repeated the analysis after excluding these mildly impaired women to estimate the relative risk of more advanced disease (n=99), but the results of the Cox model were similar (relative risk [0·25–0·9], p=0·04) as was the incidence rate ratio (0·24 [0·09–0·69]; incidence rate oestrogen 1·2% vs no oestrogen 5·4%). The annual incidence rates are within the ranges reported previously in East Boston.20Herbert LE Scherr PA Beckett LA et al.Age-specific incidence of Alzheimer's disease in a community population.JAMA. 1995; 273: 1354-1359Crossref PubMed Scopus (387) Google ScholarDiscussionThese results suggest that a history of oestrogen use during the postmenopausal period significantly delays the onset of Alzheimer's disease and lowers the risk of disease. The duration of oestrogen use seems to be important in risk reduction because women with a history of long-term use had the lowest risk. Our study differs from previous investigations of Alzheimer's disease6Paganini-Hill A Henderson VW Estrogen deficiency and risk of Alzheimer's disease in women.Am J Epidemiol. 1994; 140: 256-261PubMed Google Scholar, 7Brenner DE Kukull WA Stergachis A et al.Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: a population-based case-control study.Am J Epidemiol. 1994; 140: 262-267Crossref PubMed Scopus (281) Google Scholar in that all women were interviewed about the use of oestrogen and examined before the onset of disease.Paganini-Hill and Henderson6Paganini-Hill A Henderson VW Estrogen deficiency and risk of Alzheimer's disease in women.Am J Epidemiol. 1994; 140: 256-261PubMed Google Scholar reported a reduction with oestrogen use in mortality related to Alzheimer's disease in a nested case-control study; 13 979 (61%) participants completed a health survey by mail, but follow-up was limited to health records and death certificates. Longer periods of oestrogen use and younger age at menarche were also associated with lower mortality.Graves et al21Graves AB White E Koepsell TD et al.A case-control study of Alzheimer's disease.Ann Neurol. 1990; 28: 766-774Crossref PubMed Scopus (197) Google Scholar found no difference between patients with Alzheimer's disease and controls in the frequency of oestrogen replacement, though sex distribution was not described. Brenner and colleagues7Brenner DE Kukull WA Stergachis A et al.Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: a population-based case-control study.Am J Epidemiol. 1994; 140: 262-267Crossref PubMed Scopus (281) Google Scholar found no evidence that oestrogen replacement therapy affected the risk of Alzheimer's disease; though no significant association was observed, the odds ratio for oral oestrogen use associated with Alzheimer's disease was less than one. That study7Brenner DE Kukull WA Stergachis A et al.Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: a population-based case-control study.Am J Epidemiol. 1994; 140: 262-267Crossref PubMed Scopus (281) Google Scholar had sufficient power to detect a reduction in risk similar to that in our study but the study design3Fillit H Weinreb H Cholst I et al.Observations in a preliminary open trial of estradiol therapy for senile dementia—Alzheimer's type.Psychoneuroendocrinology. 1986; 11: 337-345Summary Full Text PDF PubMed Scopus (345) Google Scholar may explain why the outcomes differ. Brenner and colleagues' main comparison was of the odds that patients with Alzheimer's disease used oestrogen and the odds that controls used oestrogen. By contrast, we classified women on the basis of a history of oestrogen use and compared the cumulative risk that Alzheimer's disease would develop among oestrogen-users and never-users. Our results (figure) show that oestrogen use does not prevent Alzheimer's disease, but that it seems to delay the onset of the disease. The case-control design used by Brenner et al7Brenner DE Kukull WA Stergachis A et al.Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: a population-based case-control study.Am J Epidemiol. 1994; 140: 262-267Crossref PubMed Scopus (281) Google Scholar would not allow examination of differences in the age-at-onset distribution.Toran-Allerand and colleagues8Toran-Allerand CD Miranda RC Bentham WD et al.Estrogen receptors colocalize with low affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain.Proc Natl Acad Sci USA. 1992; 89: 4668-4672Crossref PubMed Scopus (428) Google Scholar identified colocalisation of oestrogen-receptor binding sites with the mRNA for nerve growth factors and their receptors in developing neurons of rodent basal forebrain.22Miranda RC Sohrabji F Toran-Allerand CD Estrogen target neurons co-localize the mRNAs for the neutrophins and their receptors during development: a basis for the interactions of estrogen and the neurotrophins.Mol Cell Neurosci. 1993; 4: 510-525Crossref PubMed Scopus (86) Google Scholar The degeneration of these regions in Alzheimer's disease may cause the loss of memory and other cognitive functions. Their findings imply that oestrogen and nerve growth factors influence synthesis and release of nerve growth factors or alternatively promote survival, differentiation, regeneration, and plasticity. In a study of rats that had undergone oophorectomy, those treated with 17β-oestradiol did better on a memory task than those deprived of oestrogen; these animals also showed preservation of neurons in the basal forebrain as well as a return to near-normal concentrations of mRNA for nerve growth factors.9Simpkins JW Singh M Bishop J The potential role for estrogen replacement therapy in the treatment of the cognitive decline and neuro degeneration associated with Alzheimer's disease.Neurobiol Aging. 1994; 15: S195-S197Summary Full Text PDF PubMed Scopus (151) Google Scholar, 23Singh M Meyer EM Simpkins JW The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats.Endocrinology. 1995; 136: 2320-2324Crossref PubMed Google Scholar, 24Singh M Meyer EM Huang FS Millard WJ Simpkins JW Ovariectomy reduces ChAT activity and NGF mRNA levels in the frontal cortex and hippocampus of the female Sprague Dawley rat.Abstr Soc Neurosci. 1993; 19: 1254Google ScholarOestrogen protects hippocampal neurons in culture exposed to excitotoxins, oxidative stress, or amyloid p1Bush TL Cowan LD Barrett-Connor E et al.Estrogen use and all-cause mortality: preliminary results from the Lipid Research Clinics Program Follow-Up Study.JAMA. 1983; 249: 903-906Crossref PubMed Scopus (234) Google Scholar.25Goodman Y Bruce AJ Cheng B Mattson MP Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury and amyloid p-peptide toxicity of hippocampal neurons.J Neurochem. 1996; 66: 1836-1844Crossref PubMed Scopus (785) Google Scholar Cells cultured with 17β-oestradiol accumulate a soluble form of the amyloid precursor protein by enhancing the amount or activity of a-secretase.10Jaffe AB Toran-Allerand CD Greengard P Gandy SE Estrogen regulates metabolism of Alzheimer's amyloid beta precursor protein.J Biol Chem. 1994; 269: 13065-13068Summary Full Text PDF PubMed Google Scholar An exogenous source of oestrogen in postmenopausal women, even for a limited time, might foster the survival of neurons and limit the amount of amyloid β deposition, thus delaying the onset of overt manifestations of Alzheimer's disease.The association between APOEεA and Alzheimer's disease has been extensively investigated,26Saunders AM Strittmatter WJ Schmechel D et al.Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer's disease.Neurology. 1993; 43: 1467-1472Crossref PubMed Google Scholar, 27Roses AD Strittmatter WJ Pericak-Vance MA Corder EH Saunders AM Schmechel DE Clinical application of apolipoprotein E genotyping to Alzheimer's disease.Lancet. 1994; 343: 1564-1565Abstract PubMed Scopus (102) Google Scholar and our results are similar to other population estimates.28Henderson AS Easteal S Jorm AF et al.Apolipoprotein E allele e4, dementia, and cognitive decline in a population sample.Lancet. 1995; 346: 1387-1390PubMed Scopus (255) Google Scholar Oestrogen use was associated with a reduction in the risk of Alzheimer's disease among women heterozygous for ε4 and among women with other APOE genotypes, but we were unable to assess the effect of oestrogen among women homozygous for ε4.This study has limitations because the design was observational. Oestrogen use was assessed by history. Oestrogen use was less common among African-American women and more likely among better-educated women. Although we adjusted for some of these factors in our analyses, we cannot exclude the possibility that oestrogen use reflects a lifestyle characteristic or an as yet unidentified exposure or bias that accounts for the effect observed. We believe that a prospective trial of oestrogen in perimenopausal women to delay the onset of Alzheimer's disease is justified, once more data on the safety, dosage, and duration of oestrogen treatment required become available.We thank David Wilder and Rafael Lantigua (Stroud Center for the Study of Quality of Life and Center for Geriatrics and Gerontology at Columbia University) for their help in the design and conduct of the registry and Medicare survey; John Shinin, Maria Gonzales, Harold Brown, and Roseann Costa for technical assistance; interview team from the Sergievsky Center and the Center for Geriatrics and Gerontology at Columbia University; and Nicole Schupf, Wei-Yen Tsai, Allen Hauser, and Dominique Toran-Allerand for review of this work.This study was supported by federal grants AG07232, AG10963, AG08702, and RR00645 and the Charles S Robertson Memorial Gift for Alzheimer's disease research from the Banbury Fund. M-XT is supported by a Faculty Scholar Award (95–045) from the Alzheimer's Disease and Related Disorders Association. IntroductionUse of oestrogen by postmenopausal women has many health benefits.1Bush TL Cowan LD Barrett-Connor E et al.Estrogen use and all-cause mortality: preliminary results from the Lipid Research Clinics Program Follow-Up Study.JAMA. 1983; 249: 903-906Crossref PubMed Scopus (234) Google" @default.
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• W2098533587 title "Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease" @default.
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