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Postmenopausal Estrogen Replacement Therapy and the Risk of Alzheimer Disease
Sudha Seshadri, MD;
Gwen L. Zornberg, MD, ScD;
Laura E. Derby, DSc;
Marian W. Myers, MPH;
Hershel Jick, MD;
David A. Drachman, MD
Arch Neurol. 2001;58:435-440.
ABSTRACT
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Background Previous studies have examined the relation between postmenopausal estrogen
replacement therapy (ERT) and the risk of Alzheimer disease (AD). The findings
have been inconsistent, since some studies have been interpreted as showing
a protective effect while others have reported no effect.
Objective To determine whether exposure to ERT is associated with a reduced risk
of AD.
Design Population-based nested case-control study.
Setting The United Kingdom–based General Practice Research Database.
Patients The base cohort consisted of women who were recipients of ERT (n = 112 481)
and a similar cohort of women who did not use estrogens (n = 108 925).
The 2 cohorts were restricted to women born on or before January 1, 1950.
From the 2 cohorts, we identified and verified 59 newly diagnosed cases of
AD and 221 matched control subjects.
Main Outcome Measure Prior and current use of ERT in cases compared with controls.
Results Among the 59 newly diagnosed cases of AD, 15 (25%) were current estrogen
users, while among the controls, 53 (24%) were current users. The adjusted
odds ratio comparing all current estrogen recipients with nonrecipients was
1.18 (95% confidence interval, 0.59-2.37). In estrogen users who took the
drug for 5 years or longer compared with nonusers, the odds ratio was 1.05
(95% confidence interval, 0.32-3.44). Odds ratios were similar for estrogen
recipients who received estrogens alone and recipients who received combined
estrogen-progestin treatment.
Conclusion The use of ERT in women after the onset of menopause was not associated
with a reduced risk of developing AD.
INTRODUCTION
AN ESTIMATED 15% of older women will develop Alzheimer disease (AD)
during their lifetimes,1 and treatments that
might reduce this risk are of great interest. A sharp decline in estrogen
levels characterizes aging and menopause; the risks of developing osteoporosis
and coronary artery disease—2 other conditions that affect women in
their postmenopausal years—appear to be decreased by postmenopausal
estrogen replacement therapy (ERT). Many basic neural mechanisms suggest that
estrogen could beneficially affect the brain areas and processes involved
in AD. Estrogen can enhance neuronal survival, inhibit apoptosis, and promote
synaptogenesis and synaptic plasticity2, 3
alone and synergistically with nerve growth factor. It increases levels of
acetylcholine in the basal forebrain and hippocampus, serves as an antioxidant
protecting neurons from the toxic effects of ß-amyloid and glutamate,
enhances repair of neuronal injury via apolipoprotein E–dependent mechanisms,
and improves cerebral blood flow.4, 5, 6
However, biological plausibility alone does not establish a beneficial effect.
Some recent studies7, 8, 9, 10, 11, 12, 13, 14
have suggested that ERT may be associated with a reduced risk or delayed age
at onset of AD, while several other studies have found no apparent protective15, 16, 17 or palliative18, 19, 20 effect on the course
of the illness. Many studies had significant methodologic drawbacks, including
the unreliability and incompleteness of the ERT exposure history7, 8, 9, 10, 11, 12, 13, 15, 16
and the use of prevalent cases.7, 8, 11, 12, 13, 15, 16
The final results of 2 ongoing randomized trials21, 22
of ERT for preventing dementia are unlikely to be available for a decade.
In the interim, evaluation of the question in valid observational studies
can serve as a guidepost to the value of ERT in preventing AD.
To investigate the relation between postmenopausal ERT and the risk
of developing AD, we conducted a population-based nested case-control study,
comparing the risks of newly diagnosed AD in a large cohort of postmenopausal
women without dementia who were documented to have used ERT with a similar
group of women who had not used ERT.
PATIENTS AND METHODS
Information from the General Practice Research Database (GPRD) was used
in the study. Since 1987, more than 3 million residents of the United Kingdom
have been enrolled by selected general practitioners who use office computers
and have agreed to provide data made anonymous for research purposes to the
GPRD. Recorded information includes patient characteristics, diagnoses, drugs
dispensed, referrals to consultants, and hospitalizations. Prescriptions are
written directly on the computer, and the details are automatically transcribed
into the patients' computer records. Information on referrals and hospitalizations
in the general practitioners' manual medical files has been shown to be recorded
in the computerized database more than 90% of the time.23, 24
A modification of the Oxford Medical Information System is used to classify
medical diagnoses, and a coded dictionary based on the Prescription Pricing
Authority's dictionary is used for prescriptions.
The GPRD provides full contemporaneous longitudinal information on patients
who attended some 300 general practices for as long as 11 years and allows
retrospective evaluation of drug effects. More than 70 studies using the GPRD
have been published in peer-reviewed journals.
STUDY POPULATION
We identified all women in the population born on or before January
1, 1950, who had received at least 1 prescription for a systemic (oral or
transdermal) estrogen preparation between January 1, 1990, and October 31,
1998. For comparison with the ERT-exposed cohort, a cohort of women also born
on or before January 1, 1950, who had not received estrogens at any recorded
time, were matched to the ERT users based on age within 5 years, physician's
practice, and date of registration. The 2 cohorts represent the base population
from which the nested case-control evaluation was conducted. Estrogen replacement
therapy–exposed and ERT-unexposed women diagnosed as having alcoholism,
other drug addiction, psychotic disorders, Parkinson disease, stroke, motor
neuron disease, deep vein thrombosis, pulmonary emboli, or cancer (except
nonmelanoma skin cancers) recorded in the database before a diagnosis of AD
were excluded from the study population.
In the base population, 83% of the women were aged 59 years or younger,
14% were between the ages of 60 and 69 years, and only 3% were older than
70 years. Among the women who used ERT in the underlying cohorts, only 0.4%
were aged 80 years or older. Among all ERT users in the base population, 1
to 2 prescriptions were recorded for 20%, 3 to 10 for 37.5%, and 11 or more
for 42.5%. Each prescription typically covered a period of 3 months.
NESTED CASE-CONTROL ANALYSIS
Identification and Validation of AD Cases
We identified all women who had a first-time computer diagnosis of AD,
senile dementia, or presenile dementia between January 1, 1992, and October
31, 1998, from the base cohorts of ERT users and nonusers, without knowledge
of their use of ERT. For each woman identified as a case, the general practitioner
was sent a request for depersonalized copies of all referral letters, diagnostic
tests, and clinical notes concerning the diagnosis of dementia. To determine
the final case status, the computerized and clinical records of potential
patients with AD were reviewed by 2 neurologists specializing in AD (S.S.
and D.A.D.) without knowledge of the subject's ERT exposure. Subjects were
considered to have developed incident AD if (1) they had no prior evidence
of dementia based on information in the clinical records and (2) there was
evidence of the development of dementia and a first-time diagnosis of AD after
the date of study initiation.
The diagnosis of AD was based on National Institute of Neurologic and
Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders
Association (NINCDS-ADRDA) criteria for probable AD.25
Subjects were required to have evidence of dementia
(defined as impairment of memory with deficits in at least 2 other domains
of cognitive function) by history and clinical examination, and documented
progression for at least 6 months. The likely cause of established dementia
was based on historical information and clinical examination data (including
neuropsychological testing) and on the results of laboratory investigations
(hematological and biochemical variables, serum vitamin B12 and
thyroid hormone levels, neuroimaging [computed tomography, magnetic resonance
imaging, single photon emission computed tomography, and, when available,
cerebrospinal fluid and electroencephalographic recordings]). The presumptive
diagnosis of the 2 reviewing neurologists (S.S. and D.A.D.) was compared with
the diagnosis made by the consulting specialist (neurologist, psychiatrist,
or consultant geriatrician). Only when the reviewing and treating physicians
concurred on a diagnosis of AD was the subject included as a case.
From the computer records, we initially identified 128 women with a
new diagnosis of dementia or possible AD for review of manual records. Based
on this review, we classified 62 women as meeting NINCDS-ADRDA criteria for
probable (n = 49) or possible (n = 13) AD. Sixty-six potential cases of dementia,
AD, or both were excluded (Table 1)
after review of the case histories. Of those with a GPRD diagnosis of AD,
for whom adequate data were available, 84% (43/51) were considered to have
probable or possible AD, using NINCDS-ADRDA criteria. To simplify the interpretation
of the findings, we restricted the primary analysis to current ERT users.
(Three exposed cases whose last prescription for estrogen was >1 year before
the date of diagnosis were defined as past users.)
There remained 59 cases of AD that we included in the primary analysis. These
subjects had been in a GPRD practice for the entire study period (or until
death) and had medical information for at least 2 years before diagnosis.
The date of diagnosis in each case was used as the index date from which the
initiation of current ERT use was determined for matched control subjects.
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Table 1. Reasons for Exclusion of Potential Cases of Incident Alzheimer
Disease
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Control Selection
For each of the 62 cases, we randomly selected up to 4 women as controls
from the 2 base cohorts, matched to the cases on age within 5 years, physician's
practice, index date, and date of first prescription in the database. The
same exclusion criteria that were applied to the cases were applied to the
controls.
Exposure to Estrogens
Women who had received estrogen for at least 1 year and had their last
prescription within 1 year before the index date of the diagnosis of AD and
the same date in controls were classified as current users. Women who used
estrogen were characterized according to the presence or absence of combined
treatment with progestin and oral or transdermal formulations.
The duration of treatment with ERT was determined from the prescriptions
recorded in the computer files of the GPRD. We made an a priori decision to
define a biologically meaningful ERT exposure as use for at least a year.
Consequently, of the 15 cases and 53 controls who had "ever" received ERT,
2 cases (13%) and 6 controls (11%) were categorized as nonusers based on minimal
use. Of these minimal users, 88% (7/8) had been prescribed only a single prescription
for 3 months or less. We categorized the ERT users further by duration of
use.
Data Analysis
We conducted a matched analysis using conditional logistic regression
to calculate the relative risk estimates (odds ratios [ORs]) and 95% confidence
intervals (CIs) of developing AD, adjusting for smoking and body mass index
(BMI) (calculated as weight in kilograms divided by the square of height in
meters). The analyses were performed with the SAS statistical software package,
version 6.12 (SAS Institute Inc, Cary, NC).
RESULTS
The primary nested case-control analysis included 59 women considered
to be newly diagnosed cases of AD and 221 controls matched on age, physician's
practice, index date, and date of first prescription according to information
in the database. The length of recorded follow-up before the diagnosis of
AD averaged 5.34 years (range, 2.04-7.79 years). The characteristics of the
patients with AD and the control subjects are given in Table 2. The women who were diagnosed as having AD were slightly
older than the controls.
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Table 2. Characteristics of Subjects Included in the Primary Nested
Case-Control Analysis According to Case Status*
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Women who used ERT for at least 1 year were at equal risk of developing
AD compared with nonusers: 25.4% of the cases and 24.0% of the controls used
ERT, yielding a relative risk estimate (OR) of 1.18 (95% CI, 0.59-2.37) after
adjusting for BMI and smoking (Table 3).
When past ERT recipients were combined with current users, the risk of developing
AD did not change substantially, resulting in a relative risk estimate of
1.19 (95% CI, 0.62-2.27) comparing any use with no use. Similarly, the risk
of developing new-onset AD among current users of estrogen combined with progestin,
or without progestin, did not differ materially compared with nonusers (Table 4).
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Table 3. Relative Risk of Incident Alzheimer Disease Associated With
the Duration of Use of Current ERT in Postmenopausal Women*
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Table 4. Women Taking Different Formulations of Postmenopausal Hormones
and Relative Risk of Incident Alzheimer Disease Compared With Nonusers
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Further stratification of women who used ERT by duration of use produced
no substantial differences in effect (Table
3). Compared with nonusers, ERT use for less than 3 years or for
3 to 4 years resulted in adjusted relative risk estimates (ORs) of 1.68 and
0.89, respectively (Table 3).
Comparing ERT users for 5 or more years with nonusers yielded a relative risk
estimate adjusted for BMI and smoking of 1.05. Adjustment of the regression
model for additional variables, such as hypercholesterolemia, diabetes mellitus,
and ischemic heart disease, did not change the results.
Current and past smoking (vs nonsmoking) was not an independent risk
factor for AD. On the other hand, BMI was an independent risk factor for AD.
Of the measures used for BMI calculations, 90% were made more than 4 years
before the index date. The OR estimates adjusted for estrogen use and smoking
for subjects with a BMI of 23 to 26.9 and 27 and greater compared with subjects
with a BMI of less than 23 were 0.82 (95% CI, 0.36-1.88) and 0.29 (95% CI,
0.09-0.87), respectively.
COMMENT
In this cohort-based study with an average follow-up of more than 5
years, we found no material evidence that current ERT use in postmenopausal
women reduced the risk of developing AD. The risk estimate comparing all current
ERT users with nonusers was 1.18 (95% CI, 0.59-2.37). For ERT users who received
the drug for 5 years or more compared with nonusers, it was 1.05 (95% CI,
0.32-3.44). Odds ratio estimates were similar in women who used unopposed
estrogens and for those who also used progestins.
The study design used is highly unusual and can only be applied to a
data resource with comprehensive and well-documented information on drugs
prescribed and clinical diagnoses over a long period.23, 24, 26
It allowed us to identify all women who were prescribed systemic estrogen
preparations and a comparable cohort of women who were not, and to identify
those women in both cohorts who developed a clinical diagnosis of dementia.
Extensive paper clinical records were available, which allowed for an appraisal
of the validity of the diagnosis and the time of first diagnosis. Such a design
is highly efficient because it provides long-term follow-up information on
a large group of all ERT users and a comparable sample of nonusers. While
the design yields fewer cases of the illness of interest (in this case, AD)
than a study based on the total population of menopausal women, it nevertheless
provides sufficient valid information to provide a reasonably precise comparison
of risks among women in the 2 cohorts. Furthermore, an efficient case-control
analysis can be performed that allows for more precise control of relevant
risk factors.27
We examined the incidence of newly diagnosed AD among unselected community-based
individuals who were not noted to be cognitively impaired on clinical assessment
for at least 2 years while under general practice physician care. The study
of incident cases limits the number of cases of AD compared with studies of
patients with prevalent AD,7, 8, 11, 12, 13, 15, 16
as does the relatively young age of the base population. However, requiring
that all subjects not have dementia for at least 2 years of observation helps
to reduce the misclassification of incident cases. While physicians may miss
mild or early cognitive impairment, the duration of observation, the matching
of control subjects from the same practice, and the stringent criteria used
for the positive diagnosis of AD minimize the impact of such uncertainties.
Major strengths of this study relate to the high quality and completeness
of the information on ERT use23, 24, 26
and the rigorous diagnostic criteria used to identify cases of AD. We were
able to evaluate the effect of well-defined durations of ERT use. While prescription
records cannot ensure compliance, the inclusion of those subjects who had
continuously renewed their prescriptions for at least a year reduced the possibility
of important misclassification of exposure. Furthermore, since estrogen could
act differentially on vascular dementia and AD, we included only those incident
cases of AD that met stringent, standardized criteria for the diagnosis.
Previously published observational studies of ERT and the risk of AD
used highly relevant major differences in study design. For example, in the
case-control study of Brenner et al,17 newly
diagnosed cases (n = 107) of AD (average age, 77 years) were identified from
an Alzheimer's Disease Registry based on an extensive evaluation of physical
and laboratory tests for this diagnosis. Exposure to estrogens was derived
from fully documented complete and accurate pharmacy files.17
This study yielded relative risk estimates carefully controlled for age, comparing
ERT users with nonusers, of 1.1 (95% CI, 0.6-1.8), a result that was virtually
identical to the estimate found in our study.
By contrast, Tang et al9 reported a follow-up
study of 1124 elderly women (mean age, 74.2 years) in whom the diagnosis of
AD was based on a series of standardized tests for AD. The history of exposure
to estrogen at any time was obtained by patient interview only at the start
of follow-up. Fourteen percent of the women gave a history of any estrogen
use at the start of follow-up, but only 2% were current users at the start
of follow-up. No further information was obtained on ERT use after the initial
interview. Women who reported ever use of ERT for less than 1 year (average,
4 months) were reported to have a substantially reduced risk of AD (OR, 0.47).
The finding of a reduced risk in women who had ever used ERT for less than
1 year (in whom an effect on AD seems unlikely) suggests that substantial
misclassification of ERT use may have been present. The lack of an accurate,
well-documented, continuous history of drug use is an important limitation
of the study by Tang et al.
To our knowledge, only 1 prior published observational study17 used previously recorded computerized prescription
information; the remainder required patient or surrogate interviews7, 8, 9, 10, 11, 12, 13, 15, 16
or record abstraction14 to obtain a history
of drug use. Some studies7, 8, 11, 12, 13, 15, 16
evaluated prevalent cases of AD, where information on drug exposure and onset
of disease is likely to be of limited validity. Design problems are likely
to explain, at least in part, the conflicting results.27
We considered the possibility that our negative results were due to
selection bias, whereby subjects with early memory loss were prescribed ERT
as a prophylactic measure against the development of AD, but this is unlikely
because the suggestion that ERT might protect against AD was not well-known
at the time that most of the information on ERT use was recorded. In addition,
there was no effect when women who used ERT for 5 or more years were compared
with nonusers.
Correspondingly, the data from 3 recent randomized placebo-controlled
trials18, 19, 20 of
ERT treatment in women diagnosed as having AD at enrollment indicated that
short-term ( 1 year) ERT use does not alter the progression of the established
illness, or materially improve the symptoms of AD. In our analyses, we focused
deliberately on reduction of risk (delaying the onset or preventing AD), and
found no substantial effect.
This report is not a direct study of the association between BMI and
AD, but subjects in the highest BMI category showed an independent, lower
risk for AD. Modest amounts of confounding by BMI were present, since the
frequency of estrogen use was highest in the largest BMI group, and women
in that category were less likely to be diagnosed as having AD. Previous research28 on women with AD also showed that cases tended to
be thinner than comparison subjects.
The findings from this study need to be interpreted with care for the
following reasons. First, the number of recorded past ERT users was small,
and our primary analysis was restricted to current estrogen users. However,
the analysis of combined past and current ERT use on the risk of AD did not
differ materially from current use alone. It remains possible that extensive
distant past use, or use at a critical perimenopausal period, may be more
effective in lowering the risk for AD. This seems unlikely since we found
no effect in subjects who were long-term users. In this study, we chose not
to include historically derived data on past estrogen use (before establishment
of the computerized database in 1987), since introducing retrospective undocumented
estimates of ERT use would have diminished the quality of our information
on ERT exposure.
Second, we did not examine other risk factors for AD, such as level
of education, APOE genotype, or familial risk. To
reduce the degree of confounding by educational level, we matched cases to
controls within the same physician's practice, the local practice serving
as a surrogate for educational and socioeconomic levels.
Third, our study is limited in size because of restriction of the study
population to incident rather than prevalent cases and, most important, because
of the relative youth and health of ERT users in our population. It is possible
that genetic influences are more likely to determine the development of AD
at this age, whereas environmental exposures such as estrogen replacement
may be more relevant at older ages. Because of secular trends in estrogen
use in the United Kingdom, women aged 80 years and older—the women at
highest risk for AD—rarely used estrogens, reducing the quantity of
information on a possible ERT effect in the most elderly age groups. In a
population in which only a small percentage have been exposed to ERT, the
matched cohort design, as previously noted, maximized efficiency by enabling
us to detect all incident cases of AD occurring among ERT users and a comparable
group of nonusers. Despite this, the proportion of included women who were
exposed to ERT in this study is larger than in several recent studies9, 10, 14 that have found a
protective effect.
The possibility exists that chance, residual confounding, or unknown
biases may explain the null findings of this observational study. By careful
matching of all newly diagnosed cases of AD to controls, and using prospectively
collected data on exposure and outcome, we attempted to minimize this possibility.
In summary, our findings indicate that ERT use in postmenopausal women
is not associated with a substantially reduced risk of AD, and highlight the
need for restraint in advocating postmenopausal ERT for this purpose.
AUTHOR INFORMATION
Accepted for publication September 29, 2000.
This study was supported in part by grant AG08122 from the National
Institute on Aging, National Institutes of Health, Bethesda, Md (Dr Seshadri);
grant NS17950 from the National Institutes of Health, NINCDS (Dr Seshadri);
grant AG05134 from the National Institute on Aging, National Institutes of
Health (Dr Drachman); the Sterling Morton Charitable Trust (Dr Drachman);
and the Stanley and Harriet Friedman Research Fund (Dr Drachman). The Boston
Collaborative Drug Surveillance Program is supported in part by grants from
AstraZeneca, Moindal, Sweden; Berlex Laboratories, Inc, Wayne, NJ; Boehringer
Ingelheim Pharmaceuticals, Inc, Ridgefield, Conn; Boots Healthcare International,
Nottingham, United Kingdom; Bristol-Myers Squibb Pharmaceutical Research Institute,
Wallingford, Conn; Glaxo Wellcome Inc, Research Triangle Park, NC; Hoffmann–La
Roche Ltd, Basel, Switzerland; Janssen Pharmaceutica Products, LP, Titusville,
NJ; RW Johnson Pharmaceutical Research Institute, Raritan, NJ; McNeil Consumer
Products Co, Fort Washington, Pa; and Novartis Farmacéutica SA, Barcelona,
Spain; and by cooperative agreement FD-U-001639-01 from the Food and Drug
Administration, Rockville, Md.
This article contains the views of the authors and is not necessarily
an official position of the Food and Drug Administration. This study was not
specifically supported by the above grantors to the Boston Collaborative Drug
Surveillance Program (Dr Seshadri).
From the Framingham Heart Study and the Department of Neurology, Boston
University School of Medicine, Boston, Mass (Dr Seshadri); the Boston Collaborative
Drug Surveillance Program, Boston University School of Medicine, Lexington,
Mass (Drs Zornberg, Derby, and Jick and Ms Myers); and the Department of Neurology,
University of Massachusetts Medical Center, Worcester (Dr Drachman).
Corresponding author and reprints: David A. Drachman, MD, Department
of Neurology, University of Massachusetts Medical Center, 55 Lake Ave N, Worcester,
MA 01655 (e-mail: david.drachman{at}umassmed.edu).
REFERENCES
| |
1. Seshadri S, Wolf PA, Beiser A, et al. Lifetime risk of dementia and Alzheimer's disease: the impact of mortality
on risk estimates in the Framingham study. Neurology. 1997;49:1498-1504.
FREE FULL TEXT
2. McEwen BS. Clinical review 108: the molecular and neuroanatomical basis for estrogen
effects in the central nervous system. J Clin Endocrinol Metab. 1999;84:1790-1797.
FREE FULL TEXT
3. Gibbs RB. Estrogen and nerve growth factor–related systems in brain: effects
on basal forebrain cholinergic neurons and implications for learning and memory
processes and aging. Ann N Y Acad Sci. 1994;743:165-196.
ISI
| PUBMED
4. Jaffe AB, Toran-Allerand C, Greengard P, Gancy SE. Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J Biol Chem. 1994;269:13065-13068.
FREE FULL TEXT
5. Stone DJ, Rozovsky I, Morgan TE, Anderson CP, Finch CE. Increased synaptic sprouting in response to estrogen via an apolipoprotein
E–dependent mechanism: implications for Alzheimer's disease. J Neurosci. 1998;18:3180-3185.
FREE FULL TEXT
6. Funk JL, Mortel KKF, Meyer JS. Effects of estrogen replacement therapy on cerebral perfusion and cognition
among postmenopausal women. Dementia. 1991;2:268-272.
7. Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter G. Estrogen replacement therapy in older women. Arch Neurol. 1994;51:896-900.
FREE FULL TEXT
8. Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer's disease in women. Am J Epidemiol. 1994;140:256-261.
FREE FULL TEXT
9. Tang M, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's
disease. Lancet. 1996;348:429-432.
FULL TEXT
|
ISI
| PUBMED
10. Kawas C, Resnick S, Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of
developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology. 1997;48:1517-1521.
FREE FULL TEXT
11. Lerner A, Koss E, Debanne S, et al. Smoking and oestrogen-replacement therapy as protective factors for
Alzheimer's disease. Lancet. 1997;349:403-404.
ISI
| PUBMED
12. Baldereschi M, Di-Carlo A, Lepore V, et al. Estrogen-replacement therapy and Alzheimer's disease in the Italian
Longitudinal Study on Aging. Neurology. 1998;50:996-1002.
FREE FULL TEXT
13. Slooter AJC, Bronzova J, Witteman JCM, Van Broeckhoven C, Hofman A, van Duijn CM. Estrogen use and early onset Alzheimer's disease: a population-based
study. J Neurol Neurosurg Psychiatry. 1999;67:779-781.
FREE FULL TEXT
14. Waring SC, Rocca WA, Petersen RC, O'Brien PC, Tangalos EG, Kokmen E. Postmenopausal estrogen replacement therapy and risk of AD. Neurology. 1999;52:965-970.
FREE FULL TEXT
15. Broe GA, Henderson AS, Creasey H, et al. A case-control study of Alzheimer's disease in Australia. Neurology. 1990;40:1698-1707.
FREE FULL TEXT
16. Barrett-Connor E, Kritz-Silverstein D. Estrogen replacement therapy and cognitive function in older women. JAMA. 1993;269:2637-2641.
FREE FULL TEXT
17. Brenner DE, Kukull WA, Stergachis A, et al. Postmenopausal estrogen therapy and the risk of Alzheimer's disease:
a population-based case-control study. Am J Epidemiol. 1994;140:262-267.
FREE FULL TEXT
18. Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer's disease in women. Neurology. 2000;54:295-301.
FREE FULL TEXT
19. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer
disease. JAMA. 2000;283:1007-1015.
FREE FULL TEXT
20. Wang PN, Liao SQ, Liu RS, et al. Effects of estrogen on cognition, mood, and cerebral blood flow in
AD: a controlled study. Neurology. 2000;54:2061-2066.
FREE FULL TEXT
21. Shumaker SA, Melton BA, Espeland MA, et al. The Women's Health Initiative Memory Study (WHIMS): a trial of the
effect of estrogen therapy in preventing and slowing the progression of dementia. Control Clin Trials. 1998;19:604-621.
FULL TEXT
|
ISI
| PUBMED
22. Marder K, Sano M. Estrogen to treat Alzheimer's disease: too little, too late? Neurology. 2000;54:2035-2037.
FREE FULL TEXT
23. Jick H, Jick SS, Derby LE. Validation of information recorded on general practitioner based computerised
data resource in the United Kingdom. BMJ. 1991;302:766-768.
24. Jick H, Terris BZ, Derby LE, Jick SS. Further validation of information recorded on a general practitioner–based
computerized data resource in the United Kingdom. Pharmacoepidemiol Drug Safety. 1992;1:347-349.
FULL TEXT
25. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 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;34:939-944.
FREE FULL TEXT
26. Jick H, Jick SS, Derby LE, Vasilakis C, Myers MW, Meier CR. Calcium channel blockers and risk of cancer. Lancet. 1997;349:525-528.
FULL TEXT
|
ISI
| PUBMED
27. Jick H, García Rodríguez LA, Pérez Gutthann S. Principles of epidemiologic research on adverse and beneficial drug
effects. Lancet. 1998;352:1767-1770.
FULL TEXT
|
ISI
| PUBMED
28. Berlinger WG, Potter JF. Low body mass index in demented outpatients. J Am Geriatr Soc. 1991;39:973-978.
ISI
| PUBMED
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J. Med. Genet. 2004;41:104-112.
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Hormone Replacement Therapy and Incidence of Alzheimer Disease in Older Women: The Cache County Study
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Hormone Therapy and Risk of Alzheimer Disease: A Critical Time
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