 |
|
JAMA-EXPRESS
Estrogen Replacement Therapy for Treatment of Mild to Moderate Alzheimer Disease
A Randomized Controlled Trial
Ruth A. Mulnard, RN, DNSc;
Carl W. Cotman, PhD;
Claudia Kawas, MD;
Christopher H. van Dyck, MD;
Mary Sano, PhD;
Rachelle Doody, MD, PhD;
Elizabeth Koss, PhD;
Eric Pfeiffer, MD;
Shelia Jin, MD, MPH;
Anthony Gamst, PhD;
Michael Grundman, MD, MPH;
Ronald Thomas, PhD;
Leon J. Thal, MD;
for the Alzheimer's Disease Cooperative Study
JAMA. 2000;283:1007-1015.
ABSTRACT
| |
Context Several reports from small clinical trials have suggested that estrogen replacement therapy may be useful for the treatment of Alzheimer disease (AD) in women.
Objective To determine whether estrogen replacement therapy affects global, cognitive, or functional decline in women with mild to moderate AD.
Design The Alzheimer's Disease Cooperative Study, a randomized, double-blind, placebo-controlled clinical trial conducted between October 1995 and January 1999.
Setting Thirty-two study sites in the United States.
Participants A total of 120 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 28 who had had a hysterectomy.
Interventions Participants were randomized to estrogen, 0.625 mg/d (n = 42), or 1.25 mg/d (n = 39), or to identically appearing placebo (n = 39). One subject withdrew after randomization but before receiving medication; 97 subjects completed the trial.
Main Outcome Measures The primary outcome measure was change on the Clinical Global Impression of Change (CGIC) 7-point scale, analyzed by intent to treat; secondary outcome measures included other global measures as well as measures of mood, specific cognitive domains (memory, attention, and language), motor function, and activities of daily living; compared by the combined estrogen groups vs the placebo group at 2, 6, 12, and 15 months of follow-up.
Results The CGIC score for estrogen vs placebo was 5.1 vs 5.0 (P = .43); 80% of participants taking estrogen vs 74% of participants taking placebo worsened (P = .48). Secondary outcome measures also showed no significant differences, with the exception of the Clinical Dementia Rating Scale, which suggested worsening among patients taking estrogen (mean posttreatment change in score for estrogen, 0.5 vs 0.2 for placebo; P = .01).
Conclusions Estrogen replacement therapy for 1 year did not slow disease progression nor did it improve global, cognitive, or functional outcomes in women with mild to moderate AD. The study does not support the role of estrogen for the treatment of this disease. The potential role of estrogen in the prevention of AD, however, requires further research.
INTRODUCTION
Alzheimer disease (AD) affects more than 4 million Americans and is one of the most frequent obstacles to healthy aging in this country. Women appear to be at higher risk for developing AD, only in part due to increased longevity.1 Because women with AD also live longer than men with AD, there are approximately twice as many women as men in the population with this disorder. It has been suggested that the abrupt decline of estrogen production in postmenopausal women may be associated with a vulnerability of women to develop AD. Men, in contrast, have an intrinsic supply of estrogen by having the ability to aromatize testosterone into estrogen in the brain.
Considerable evidence has emerged from neuropathological studies,2-4 animal behavioral studies,5-6 and human investigations7-8 to suggest that estrogen may be beneficial in improving cognition and mood in AD. Several open-label clinical trials9-11 and 1 randomized clinical trial12 reported selective cognitive improvement in women with dementia who received estrogen replacement therapy (ERT). However, these studies have all been relatively brief, generally ranging from 6 to 8 weeks of treatment with estrogen. Similarly, the number of subjects taking the drug in these trials has been small, ranging from 7 to 12, and most have not used standardized diagnostic criteria. Thus, the evidence for using estrogen as treatment for clinically diagnosed AD is modest at best. Since the potential role of estrogen for the treatment of AD is of public health significance, this intervention, if scientifically supported, could become a routine part of the management regimen for women with AD.
We conducted this study to provide a definitive, placebo-controlled, double-blind, randomized clinical trial of adequate duration and size to determine the benefit of ERT for the treatment of women with mild to moderate AD. We chose to study unopposed estrogens because previous investigations have suggested that progesterone may mitigate some of estrogen's beneficial effects in the central nervous system.
METHODS
Objectives
The specific aims of the study were to (1) determine if women with AD treated with unopposed estrogens would experience improvement or stability in cognition and other parameters during or after 12 months of therapy; (2) determine which components of the psychometric assessment were improved or stabilized by treatment; (3) determine whether there was a differential response to 2 dosages of estrogen; and (4) establish the safety and tolerability of estrogen in elderly women with AD.
Participants
Participants for this study were recruited from participating sites of the Alzheimer's Disease Cooperative Study (ADCS; a consortium supported by the National Institute on Aging), with enrollment of 120 women with hysterectomies between October 1995 and January 1999. Selection of women with hysterectomies allowed for the subjects' long-term exposure (1 year) to unopposed estrogen therapy while eliminating the risk and safety concern of endometrial hyperplasia, which occurs in prolonged unopposed estrogen administration in women with an intact uterus. Thirty-two sites (designated as AD centers by the National Institute on Aging and/or selected sites of the ADCS) participated in the recruitment of these subjects. General inclusion criteria included a diagnosis of probable AD according to National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria13 in the mild to moderate stage (the study protocol specified a Mini-Mental State Examination [MMSE]14 score of 14-28; several exceptions were made by the project director to allow for participants with MMSE scores as low as 12); female sex; previous hysterectomy (oophorectomy not required); age older than 60 years; absence of major clinical depressive disorder (as measured by scores of <17 on the Hamilton Depression Rating Scale [Ham-D]15); and normal gynecological, breast, and mammography examination results.
Exclusion criteria were myocardial infarction within 1 year, history of thromboembolic disease or hypercoagulable state, hyperlipidemia, or use of excluded medications (ie, estrogens within 3 months; current use of antipsychotics, anticonvulsants, anticoagulants,  -blockers, narcotics, methyldopa, clonidine, or prescription cognitive-enhancing or antiparkinson medications, including experimental medications within 60 days prior to baseline. Stable dosages of neuroleptics, antidepressants, anxiolytics, sedatives, and hypnotics were allowed). At the initiation of the protocol, individuals treated with donepezil or tacrine were excluded, but a protocol amendment after 20 months of enrollment allowed the stable use (minimum of 4 weeks) of these medications before screening for the study.
Intervention
This study used a 12-month, randomized, double-blind, placebo-controlled, parallel-group design, in which 120 women were enrolled and randomized to receive a single daily dose of placebo, Premarin (conjugated equine estrogens [CEEs], Wyeth-Ayerst Pharmaceuticals, St Davids, Pa), 0.625 mg, or Premarin, 1.25 mg, followed by a 3-month, single-blind placebo washout phase for all women. Conjugated equine estrogens were chosen for this trial because this formulation is the most commonly prescribed form of ERT. Additionally, CEEs include multiple components, some of which have been shown to have neurotrophic properties, which could be beneficial to brain function.
Participants were randomly allocated to 1 of the 3 treatment arms (Figure 1). Treatments were assigned in randomized permuted blocks of 6 and shipped to each site at the start of the study. The ADCS biostatistical division generated and archived the randomization list. Boxes containing 7-day blister cards of study medication were packaged and shipped by the manufacturer according to instructions provided by the ADCS. Patients were instructed to take 2 identically appearing tablets of study medication each morning. Subjects assigned to estrogen, 1.25 mg/d, received 2 estrogen 0.625-mg tablets; those assigned to estrogen, 0.625 mg/d, received 1 placebo tablet and 1 estrogen 0.625-mg tablet; those assigned to placebo received 2 placebo tablets. Hereafter, the 0.625-mg/d and 1.25-mg/d estrogen dosages are referred to as low and high dosages, respectively. All subjects in this study were required to have a caregiver who administered the investigational agent during the trial. Compliance monitoring was done through plasma estradiol level evaluation at each visit and pill count.
|
|
|
|
Figure 1. Participant Flow Diagram
|
|
|
Cognitive, global, and other outcome measures were evaluated at screening, baseline, and 2, 6, 12, and 15 months. A telephone check was performed at the 4-month interval to verify ongoing administration of the experimental medication and the status of concurrent medications and to address any issues or concerns, and a brief safety visit was conducted at the 9-month interval. The study was reviewed and approved by the institutional review board at each site. Written informed consent was obtained from all participants.
Outcome Measures
The ADCS version of the Clinical Global Impression of Change (CGIC) scale, developed as a semistructured interview from the traditional CGIC scale,16 was the primary outcome measure used to assess change from baseline. On this scale, scores of 1, 2, and 3 represent marked, moderate, and mild improvement, respectively; 4 represents no change; and 5, 6, and 7 represent mild, moderate, and marked worsening, respectively.
The MMSE (range, 0-30) and the Clinical Dementia Rating Scale17 (CDR; range, 0-5) also were used as global staging instruments. Through the judicious choice of other secondary outcome measures, this study also aimed to address several unanswered questions: (1) independent of mood enhancement, does estrogen therapy improve cognition in AD; (2) by what mechanism is memory improved; and (3) what other clinically relevant benefit does estrogen have in AD?
The first goal was to determine to what degree observed cognitive benefit was associated with improved mood. To this end, it was proposed that the evaluation of estrogen include a traditional measure of depression (Ham-D) and an index of mood state (Multiple Affect Adjective Checklist–Revised [MAACL-R]18) conducted concurrently with other cognitive assessments. To elucidate possible mechanisms for estrogen's effect on memory that are separate from specific mood alteration, the assessment of memory included measurement of (1) explicit verbal learning (Alzheimer's Disease Assessment Scale–Cognitive [ADAS-Cog]19), (2) mood-congruent memory (Emotional Face Recognition Test; unpublished data, Elizabeth Koss, PhD, 1995), and (3) visual delayed nonmatched to sample recognition (New Dot Test20). We investigated other cognitive benefits that could be associated with estrogen by testing the subjects on measures of attention (Letter Cancellation,21 Trail-Making Test A,22 and Digit Symbol23), language (Category Fluency24 and Letter Fluency25), and motor behavior (Grooved Pegboard Test26 and Finger Tapping Test27). Another goal in the choice of secondary measures was to assess the effect of estrogen on activities of daily living abilities in AD, as measured by the Blessed Dementia Rating Scale28 and the Dependency Scale.29
Safety Monitoring
To reduce risk associated with estrogen administration, screening measures before enrollment included a baseline gynecological and breast examination within the 3 preceding months, a mammogram within the 6 preceding months, and a Papanicolaou test within the previous 3 years. As an additional safety measure, the mammogram was repeated at the end of the 12-month double-blind phase of the study to monitor for any breast complications. At each visit, blood pressure, body weight, and fluid retention (ankle swelling) were monitored. An additional lipid profile was performed at the 2-month visit to detect the complication of hyperlipidemia as a rare reaction to estrogen compounds. Adverse event reports were reviewed quarterly by the independent ADCS safety monitoring committee, who found no necessity to break the blind or interrupt the trial at any time.
Patient Populations
For purposes of analysis, 3 patient populations were defined. These included traditional intent-to-treat (based on a last observation carried forward imputation scheme) and completers populations (12-month visit completed) as well as a compliers population (defined as all individuals who completed the study and ingested at least 80% of the randomized agent by pill count). Of the 120 randomized subjects, 119 were exposed to the investigational agent (1 subject dropped out because of medical problems before starting the medication). Figure 1 shows the subject flow and disposition through the course of the trial. Of the 120 randomized subjects, 97 completed the trial. There was no attempt to balance the use of donepezil across treatment groups. Table 1 shows that more patients in the ERT groups took donepezil during the course of the trial compared with the placebo group.
|
|
|
|
Table 1. Baseline Demographic and Clinical Characteristics*
|
|
|
Statistical Analyses
Power calculations were performed using data from a clinical trial with a similar design that included only women aged at least 60 years with baseline MMSE scores of 16 to 28. Based on the data from this similar trial, with 40 subjects receiving placebo and 80 subjects receiving estrogen, the design power was 81% to detect a 29% difference in the proportion of subjects who worsen in the 2 groups (60% worse in the placebo group vs 31% worse in the estrogen group) using a 2-tailed  = .05. Since this was a dosage-finding study, a large effect size was sought to ensure clinical meaningfulness and to estimate the signal size for a possible follow-up trial, if the findings were positive.
In all analyses, a set of predefined covariates was assessed as potential confounders (subject age, apolipoprotein e4 allele frequency, subject education). Any variables unbalanced at baseline (P .15) and significantly associated with response (P.10) were included in the statistical model. In the 2-group analysis (combined estrogen groups vs placebo group), there was no significant imbalance of the covariates at baseline, negating the inclusion of these prestated potential confounders to the statistical models. In the 3-group analysis (differential dosage response vs placebo), subject age at baseline was marginally unbalanced (P = .07) in the low-dosage estrogen group, and was significantly associated with 3 outcome variables. Therefore, age was included as a covariate in the statistical analysis models for the ADAS-Cog (P = .07), Dependency Scale (P = .07), and Grooved Pegboard (P = .06).
The primary end point used to evaluate the differential effect of estrogen on progression of AD was the ADCS-CGIC. For this analysis, the 7-point scale was collapsed to 5 points because of lack of subjects in the marked or moderately improved categories and was analyzed using ordinal logistic regression. Other primary and secondary end-point treatment differences were analyzed as follows: for continuous measures, linear regression adjusting for baseline values (analysis of covariance) was applied. For categorical measures, logistic regression adjusting for baseline values was used. Confirmatory analyses were conducted using linear regression on changes in scores with no baseline adjustment and  2 tests (with Mantel-Haenszel adjustment if necessary) for categorical measures. No interim analyses were performed.
RESULTS
The demographic and clinical characteristics of each group at baseline are illustrated in Table 1. No significant group differences were seen on any characteristic at baseline (all P values >.05).
Two-Group Comparison
To assess the overall efficacy of estrogen, the low- and high-dosage estrogen groups were combined into a single group of 81 women with AD and hysterectomies who took estrogen. These 81 women were compared with the 39 placebo subjects regarding performance on the ADCS-CGIC, MMSE, ADAS-Cog, and the CDR at 12 months to assess change. The primary intent-to-treat analysis comparing the combined estrogen groups with the placebo group showed no difference between groups for the percentage of patients who worsened on the ADCS-CGIC (P = .48), the ADCS-CGIC score (P = .43), the MMSE score (P = .51), or the ADAS-Cog score (P = .13). However, a significant difference was seen on the CDR (P = .01) favoring the placebo group (Table 2 and Figure 2). Repeated completers and compliers analyses on the primary outcome measure likewise did not reveal any differential treatment effects on the ADCS-CGIC (data available from the authors on request).
|
|
|
|
Table 2. Intent-to-Treat Analysis of Combined Estrogen Groups vs Placebo Group: Mean Change in Scores at 12 Months*
|
|
|
|
|
|
|
Figure 2. Two-Group Intent-to-Treat Analysis
Data are the mean changes from baseline for the Alzheimer's Disease Cooperative Study version of the Clinical Global Impression of Change scale (ADCS-CGIC), Alzheimer's Disease Assessment Scale–Cognitive (ADAS-Cog), Mini-Mental State Examination (MMSE), and Clinical Dementia Rating Scale (CDR). Plotted values for the CDR scores are computed to 2 decimal places. Error bars represent 95% confidence intervals around the mean values; gray lines indicate baseline. See footnote to Table 1 for explanation of treatment groups.
|
|
|
Analysis of secondary outcomes with sensitivity to changes in mood (Ham-D), memory (Emotional Face Recognition Test and New Dot Test), attention (Letter Cancellation, Trail-Making Test A, and Digit Symbol) and activities of daily living (Blessed Dementia Rating Scale and Dependency Scale) showed no significant differences between treatment and placebo groups (Table 2). Among the language measures, Category Fluency favored the placebo group (P = .05), yet there were no group differences on Letter Fluency. Of the 2 motor measures, the Grooved Pegboard Test did not detect group differences, but the Finger Tapping Test favored the placebo group (P = .05). Similar analyses on completer and complier populations showed consistent results (data available on request).
Three-Group Comparison
A separate analysis addressed treatment effect differences between each of the 2 dosages of estrogen compared with placebo. Again, the 12-month intent-to-treat analysis showed no difference between groups for the proportion who worsened on the ADCS-CGIC (P = .73 for both low and high dosages), the ADCS-CGIC score (low dosage, P = .66; high dosage, P = .36), the MMSE score (low dosage, P = .48; high dosage, P = .64), or the ADAS-Cog score (low dosage, P = .09; high dosage, P = .32). However, a significant difference was seen on the CDR at 12 months (low dosage, P = .03; high dosage, P = .01), again favoring the placebo group (Table 3 and Figure 3). In addition, we found a benefit of low-dosage estrogen on the MMSE change in score after 2 months of exposure (low dosage = -0.36; placebo = -1.64; P = .05), but the benefit did not persist with continued treatment. There was no evidence of improvement in global functioning at any point in the trial. Repeated completers and compliers analyses on the primary outcome measure likewise did not reveal any differential treatment effects on the ADCS-CGIC (data available from the authors on request).
|
|
|
|
Table 3. Differential Dose-Response Intent-to-Treat Analysis: Mean Change in Scores at 12 Months by Treatment Arm*
|
|
|
|
|
|
|
Figure 3. Three-Group Intent-to-Treat Analysis
Data are the mean changes from baseline for the Alzheimer's Disease Cooperative Study version of the cognitive tests (see legend to Figure 2 for explanation of abbreviations). Plotted values for the CDR scores are computed to 2 decimal places. Error bars represent 95% confidence intervals around the mean values; gray lines indicate baseline. See footnote to Table 1 for explanation of treatment groups.
|
|
|
Analysis of the remaining secondary outcome variables showed either nonsignificant differences between groups or results that favored the placebo group (Table 3). The Ham-D, a measure of mood, did not differ between groups. The subscale factors of the MAACL-R also did not differ between groups (data available from the authors on request). There were no detectable group differences in memory, attention, or language measures. Among the motor measures, the Grooved Pegboard Test did not detect group differences, but the Finger Tapping Test again favored placebo, but only in the low-dosage group (P = .04). Measures of activities of daily living were not significantly different between groups. Repeated analyses on completer and complier populations showed the same results (data available from the authors).
Two additional analyses were performed to compare results on the primary outcome measures among women with prior estrogen exposure and then among women with prior donepezil treatment. Within each treatment group (placebo, low-dosage and high-dosage estrogen), the participants with a history of estrogen use were compared with the participants who had no history of estrogen use prior to the present trial on four 12-month outcome variables, the CGIC, CDR, MMSE and ADAS). As reflected in Table 1, years of prior estrogen exposure were comparable between the placebo and high-dosage estrogen groups (5.4 vs 6.4 mean years). For the placebo group, mean differences on the outcome measures were not significant for prior estrogen use vs nonuse, respectively, (CGIC, 5.0 vs 5.1, P = .32; CDR, 1.3 vs 1.2, P = .42; MMSE, 18.3 vs 17.5, P = .90;ADAS-Cog, 27.9 vs 25.8, P = .41). For the high-dosage group, mean differences were likewise not significant (CGIC, 5.4 vs 5.0, P = .07; CDR, 1.7 vs 1.5, P = .24;MMSE, 16.0 vs 19.4, P = .21; ADAS-Cog, 31.4 vs 26.2, P = .97). However, participants in the low-dosage estrogen group with a longer period of prior estrogen exposure (16.8 mean years) had significantly better mean CGIC scores at 12 months (4.8 vs 5.5; P = .04), but no significant impact on the CDR (mean, 1.4 vs 1.8; P = .71), the MMSE (mean, 18.8 vs 16.4; P = .61), and the ADAS-Cog (mean, 26.6 vs 34.1; P = .86). A similar analysis of donepezil users vs nonusers showed no significant differences in performance on the CGIC, CDR, MMSE, or the ADAS-Cog outcome variables.
Treatment-emergent adverse events, grouped categorically, were not significantly different between placebo and estrogen-treated groups. However, 2 clinically important issues arose during the trial: 4 episodes of vaginal bleeding occurred, representing protocol violations because these 4 women had not had prior hysterectomies, despite confirmatory gynecological examinations before randomization into the protocol; and 4 episodes of deep vein thrombosis occurred, 2 in the low-dosage and 2 in the high-dosage estrogen groups. Two patients died, 1 in each of the estrogen groups. Both deaths were sudden but neither death was believed to be related to treatment medication.
COMMENT
Estrogen failed to improve cognitive or functional outcomes in this 1-year study of women with mild to moderate AD and hysterectomies. Similar to previous reports, we found a benefit of low-dosage estrogen on the MMSE after brief exposure (2 months; P = .05), but the benefit did not persist with continued treatment. In fact, patients receiving estrogen appeared to decline more than those receiving placebo on 1 global clinical measure, the CDR, despite the greater use of donepezil in the estrogen-treated patients. Overall, the results of this study do not support the role of estrogen in the treatment of AD.
To date, this study is the largest and the longest study to examine estrogen as a treatment for women with AD. Given that patients receiving estrogen did no better or worse than patients receiving placebo, the use of a larger sample size would not have changed this result.
There are several plausible explanations for the difference between the results of this study and previous studies. Animal studies indicate that in the neural tissue, estrogen modulates cholinergic,3 serotonergic,30 and catecholaminergic31 neurotransmitter systems; regulates synaptogenesis during the estrous cycle; regulates neurogenesis32; and is neuroprotective,33 reducing the brain damage associated with ischemic insult.34-35 It is possible that short-term improvements that have been seen in some clinical trials were due to gene-dependent regulation of neurotransmitter systems such as the up-regulation of cholinergic activity.36 A second mechanism of estrogen action could involve surface receptor–associated signaling via ion channels, modulating electrical properties of neurons and transmitter release processes.37-38 Such mechanisms are palliative, however, and insufficient to prevent decline over the long term.
In basic studies on the mechanisms underlying neurodegeneration, it has been suggested that there are at least 2 phases in the process, an initiation phase and a propagation phase.39 It is hypothesized that estrogen can delay the initiation phase but is insufficient to slow the propagation phase. Thus, for example, cell culture studies on primary hippocampal neurons show that estrogen is only partially protective against a variety of insults.33 Estrogen appears to operate in part through a gene-dependent up-regulation of antiapoptotic proteins in the bcl-2 family in vitro and in vivo.33-34 In the AD brain, these genes are already up-regulated and, thus, further benefit may not be gained.40 Estrogen also has antioxidant properties, though they are relatively weak compared with vitamin E. The present data suggest that the antioxidant capacity of estrogen is evidently insufficient to slow progression. In addition, the anatomical organization of estrogen receptors may favor a role in early stages. Estrogen receptors are most concentrated in brain regions involved with the initial stages of the disease (eg, the limbic system). As degeneration spreads to other regions, estrogen might be unable to regulate gene-dependent defense mechanisms. Other mechanisms also show selectivity for the initiation and propagation phases. For example, apolipoprotein e4 appears to accelerate disease onset, but most studies agree that it does not slow the rate of progression,39, 41-42 although there have been exceptions.43 While the mechanisms underlying the present results are as yet unknown, the data suggest that some therapeutic interventions may only act during selective phases of the disease process.
Thus, in the intact healthy brain, estrogen could play a key neuroprotective role by delaying the initiation phase of neurodegenerative disease onset, thereby supporting the finding of reduced risk of dementia from several published epidemiological studies.44-47 Two multicenter prevention trials are currently under way to answer this question prospectively.
Of public health concern is the tendency for experimental treatments to become standard of care before the rigorous scientific evidence is thoroughly gathered. Such is the concern with estrogen administration for women with AD. Numerous publications with broad-based distribution48-49 are now supporting the addition of ERT to the armamentarium of treatments for women with AD as a means to enhance cognitive function and delay progression of the disease. Such clinical practice, begun in advance of rigorous clinical trials, could prove to be detrimental to patient outcome. While other ongoing investigations (Women's Health Initiative–Memory Study, Women's International Study of Long Duration Oestrogen for Menopause, and Preventing Postmenopausal Memory Loss and Alzheimer's with Replacement Estrogens study) will provide needed data on hormone replacement therapy in the primary prevention of AD, this study does not support the role of estrogen for treatment of established AD. However, there remains a possibility that estrogen could have an important role as an adjuvant treatment, or as a means of delaying onset of disease. Further investigation of ERT in these areas is still warranted.
AUTHOR INFORMATION
Members of the Alzheimer's Disease Cooperative Study (NIA AG-10483): Martha G. MacAvoy, Lauren M. Half, Yale University, New Haven, Conn; Lynn Hoffman, Paul Schulz, Jamie Sims, Baylor College of Medicine, Houston, Tex; Karen Bell, Arlene Lawton, Evelyn Dominguez, Karen Anderson, Christine Weber, Columbia Presbyterian Medical Center, New York, NY; Brian R. Ott, Margaret C. Lannon, Brown University, Providence, RI; Dorothy Baxter, Barbara Luhn, University of South Florida College of Medicine, Tampa; John C. Morris, Mary Coats, Eugene H. Rubin, Washington University, St Louis, Mo; Marwan Sabbagh, Deborah Olasin Fontaine, Valerie Rice, Don Connor, University of California, San Diego, La Jolla; John H. Growdon, Michael C. Irizarry, Marsha Tennis, Massachusetts General Hospital, Boston; Alan J. Lenner, Nancy A. Strick, Kathleen Fedor, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio; Frederick A. Schmitt, J. Wesson Ashford, J. Eileen Tekrony, University of Kentucky, Lexington; Neill R. Graff-Radford, Francine Parfitt, Dawn Epstein, Mayo Clinic Jacksonville, Jacksonville, Fla; Cora Tasaki, Catherine McAdams-Ortiz, University of California, Irvine; Myron F. Weiner, University of Texas, Dallas; Steven T. DeKosky, University of Pittsburgh, Pittsburgh, Pa; Ronald C. Petersen, Kris Johnson, Mayo Clinic, Rochester, Minn; Murray Raskind, Elaine Peskind, University of Washington, Seattle; Ann S. Morrison, Helen Karagiozis, Johns Hopkins University, Baltimore, Md; Martin Farlow, Nicki Coleman, Indiana University, Indianapolis; Steven H. Ferris, Thomas McRae, Isabel Monteiro, Istvan Boksay, New York University, New York, NY; Allan Levey, Janet Cellar, Joan M. Harrison, Emory University, Atlanta, Ga; Charles DeCarli, Michael White, University of Kansas, Kansas City; David Bennett, Neelum Aggarwal, Concetta Forchetti, Rush Alzheimer's Disease Center, Chicago, Ill; Ranjan Duara, Shawn Saunders, Vivian Garcia, Mount Sinai Medical Center, Miami, Fla; Rachel J. Schindler, State University of New York, Stony Brook; David Knopman, Margaret Prod'Homme, June LaValleur, University of Minnesota, Minneapolis; Sandra Vicari, Frances Schaefer, Southern Illinois University, Carbondale; Christopher Clark, University of Pennsylvania, Philadelphia; William Jagust, Bruce Reed, University of California, Davis, Martinez; John P. Blass, Rosanna T. Cirio, Nancy E. Scott, Burke Medical Research Institute, White Plains, NY. Clinical Monitors: Kimberly Schafer, Rebecca E. Ryan-Jones, University of California, San Diego, La Jolla; Mario Schittini, Columbia Presbyterian Medical Center, New York, NY; Joan Mackell, New York University, New York, NY; Angela L. Berry, Washington University, St Louis, Mo. Safety Monitoring Committee: Karl Kieburtz, Pierre Tariot, University of Rochester, Rochester, NY; Trey Sunderland, National Institute of Mental Health, Bethesda, Md; Arlene Morales, Charles C. Berry, University of California, San Diego, La Jolla.
Funding/Support: This study was supported by grant U01-AG10483 from the National Institute on Aging, National Institutes of Health. We thank Wyeth-Ayerst Pharmaceuticals for providing the study drug for this investigation.
Financial Disclosure: Dr Sano participates in an unrestricted educational grant to Columbia University from Wyeth Ayerst Pharmaceuticals, the manufacturer of the estrogen replacement therapy drug used in this study.
Corresponding Author and Reprints: Ruth A. Mulnard, RN, DNSc, Institute for Brain Aging and Dementia, University of California, Irvine, 1113 Gillespie Neuroscience Research Facility, Irvine, CA 92697-4540 (e-mail: ramulnar{at}uci.edu).
Author Affiliations: University of California, Irvine (Drs Mulnard and Cotman); Johns Hopkins University, Baltimore, Md (Dr Kawas); Yale University, New Haven, Conn (Dr van Dyck); Columbia University, New York, NY (Dr Sano); Baylor College of Medicine, Houston, Tex (Dr Doody); Case Western Reserve University, Cleveland, Ohio (Dr Koss); University of South Florida, Tampa (Dr Pfeiffer); and the University of California, San Diego (Drs Jin, Gamst, Grundman, Thomas, and Thal).
REFERENCES
| |
1. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand. 1987;76:465-479.
ISI
| PUBMED
2. Gould E, Woolly CS, Frankfurt M, McEwen BS. Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. J Neurosci. 1990;10:1286-1291.
ABSTRACT
3. Luine VN. Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats. Exp Neurol. 1985;89:484-490.
FULL TEXT
|
ISI
| PUBMED
4. Toran-Allerand CD, Miranda RC, Bentham WDL, et al. Estrogen receptors co-localize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain. Proc Natl Acad Sci U S A. 1992;89:4668-4672.
FREE FULL TEXT
5. Joseph JA, Kochman K, Roth GS. Reduction of motor behavioral deficits in senescence via chronic prolactin or estrogen administration: time course and putative mechanisms of action. Brain Res. 1989;505:195-202.
FULL TEXT
|
ISI
| PUBMED
6. McDermott JL, Kreutzberg JD, Liu B, Dluzen DE. Effects of estrogen treatment on sensorimotor task performance and brain dopamine concentrations in gonadectomized male and female CD-1 mice. Horm Behav. 1994;28:16-28.
FULL TEXT
| PUBMED
7. Ditkoff EC, Crary WG, Cristo M, Lobo RA. Estrogen improves psychological function in asymptomatic postmenopausal women. Obstet Gynecol. 1991;78:991-995.
ISI
| PUBMED
8. Sherwin B. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology. 1988;13:345-357.
FULL TEXT
|
ISI
| PUBMED
9. Fillit H, Weinreb H, Cholst I, et al. Observations in a preliminary open trial of estradiol therapy for senile dementia—Alzheimer's type. Psychoneuroendocrinology. 1986;11:337-345.
FULL TEXT
|
ISI
| PUBMED
10. Honjo H, Ogino Y, Naitoh K, et al. In vivo effects by estrone sulfate on the central nervous system-senile dementia (Alzheimer's type). J Steroid Biochem. 1989;34:521-525.
FULL TEXT
|
ISI
| PUBMED
11. Ohkura T, Isse K, Akazawa K, Hamamoto M, Yaio Y, Hagino N. Evaluation of estrogen in female patients with dementia of the Alzheimer type. Endocr J. 1994;41:361-371.
ISI
| PUBMED
12. Asthana S, Craft S, Baker LD, et al. Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer's disease: results of a placebo-controlled, double-blind, pilot study. Psychoneuroendocrinology. 1999;24:657-677.
FULL TEXT
|
ISI
| PUBMED
13. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology. 1984;34:939-944.
FREE FULL TEXT
14. Folstein MF, Folstein SE, McHugh PR. Mini-Mental State: a practical method for grading the cognitive state of the patient for the clinician. J Psychiatr Res. 1975;12:189-198.
FULL TEXT
|
ISI
| PUBMED
15. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62.
FREE FULL TEXT
16. Schneider LS, Olin JT, Doody RS, et al. Validity and reliability of the Alzheimer's Disease Cooperative Study: Clinical Global Impression of Change. Alzheimer Dis Assoc Disord. 1997;11:S22-S31.
17. Morris JC. The Clinical Dementia Rating Scale: current version and scoring rules. Neurology. 1993;43:2412-2414.
FREE FULL TEXT
18. Zuckerman M, Lubin B, Robins S. Validation of the Multiple Affect Adjective Checklist in clinical situations. J Consult Psychol. 1965;29:594.
FULL TEXT
|
ISI
| PUBMED
19. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141:1356-1364.
FREE FULL TEXT
20. Moss MB, Albert MS, Butters N, Payne M. Differential patterns of memory loss among patients with Alzheimer's disease, Huntington's disease, and alcoholic Korsakoff's syndrome. Arch Neurol. 1986;43:239-246.
FREE FULL TEXT
21. Mohs R, Knopman D, Petersen R, et al for the Alzheimer's Disease Cooperative Study. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broadens its scope. Alzheimer Dis Assoc Disord. 1997;11:S13-S21.
22. Army Individual Test Battery: Manual of Directions and Scoring. Washington, DC: War Department Adjutant General's Office; 1944.
23. Wechsler D. Wechsler Adult Intelligence Scale—Revised. New York, NY: Psychological Corp; 1981.
24. Morris JC, Heyman A, Mohs RC, et al. The consortium to establish a registry for Alzheimer's disease (CERAD), I: clinical and neuropsychological assessment of Alzheimer's disease. Neurology. 1989;39:1159-1165.
FREE FULL TEXT
25. Benton AL, Hamsher K. Multilingual Aphasia Examination Manual. Iowa City: University of Iowa; 1978.
26. Mathews CG, Klove W. Instruction Manual for the Adult Neuropsychological Test Battery. Madison: University of Wisconsin Medical Center; 1964.
27. Reitan RM, Wolfson D. The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation. Tucson, Ariz: Neuropsychology Press; 1990.
28. Blessed G, Tomlinson BE, Roth M. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry. 1968;114:797-811.
FREE FULL TEXT
29. Stern Y, Albert SM, Sano M, et al. Assessing patient dependence in Alzheimer's disease. J Gerontol. 1994;49:M216-M222.
30. Frankfurt M, McKittrick CR, Mendelson SD, McEwen BS. Effect of 5,7-dihydroxytryptamine, ovariectomy and gonadal steroids on serotonin receptor binding in rat brain. Neuroendocrinology. 1994;59:245-250.
ISI
| PUBMED
31. Kritzer MF, Kohama SG. Ovarian hormones differentially influence immunoreactivity for dopamine beta-hydroxylase, choline acetyltransferase, and serotonin in the dorsolateral prefrontal cortex of adult rhesus monkeys. J Comp Neurol. 1999;409:438-451.
FULL TEXT
|
ISI
| PUBMED
32. Hidalgo A, Barami K, Iversen K, Goldman SA. Estrogens and non-estrogenic ovarian influences combine to promote the recruitment and decrease the turnover of new neurons in the adult female canary brain. J Neurobiol. 1995;27:470-487.
FULL TEXT
|
ISI
| PUBMED
33. Pike CJ. Estrogen modulates neuronal bcl-xL expression and beta-amyloid-induced apoptosis: relevance to Alzheimer's disease. J Neurochem. 1999;72:1552-1563.
FULL TEXT
|
ISI
| PUBMED
34. Dubal DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM. Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. J Neurosci. 1999;19:6385-6393.
FREE FULL TEXT
35. Toung TJ, Traystman RJ, Hurn PD. Estrogen-mediated neuroprotection after experimental stroke in male rats. Stroke. 1998;29:1666-1670.
FREE FULL TEXT
36. Simpkins JW, Green PS, Gridley KE, Singh M, de Fiebre NC, Rajakumar G. Role of estrogen replacement therapy and the prevention of neuronal loss associated with Alzheimer's disease. Am J Med. 1997;103:19S-25S.
37. Paul SM, Purdy RH. Neuroactive steroids. FASEB J. 1992;6:2311-2322.
ABSTRACT
38. Razandi M, Pedram A, Greene GL, Levin ER. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ER-alpha and ER-beta expressed in Chinese hamster ovary cells. Mol Endocrinol. 1999;13:307-319.
FREE FULL TEXT
39. Johnson JK, McCleary R, Oshita MH, Cotman CW. Initiation and propagation stages of beta-amyloid are associated with distinctive apolipoprotein E, age, and gender profiles. Brain Res. 1998;798:18-24.
FULL TEXT
|
ISI
| PUBMED
40. Su JH, Satou T, Anderson AJ, Cotman CW. Up-regulation of bcl-2 is associated with neuronal damage in Alzheimer's disease brain. Neuroreport. 1996;7:437-440.
ISI
| PUBMED
41. Corder EH, Saunders AM, Strittmatter WJ, et al. Apolipoprotein E, survival in Alzheimer's disease patients, and the competing risks of death and Alzheimer's disease. Neurology. 1995;45:1323-1328.
FREE FULL TEXT
42. Dal Forno G, Rasmusson DX, Brandt JA, et al. Apolipoprotein E genotype and rate of decline in probable Alzheimer's disease. Arch Neurol. 1996;53:345-350.
FREE FULL TEXT
43. Craft S, Teri L, Edland SD, et al. Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease. Neurology. 1998;51:149-153.
FREE FULL TEXT
44. 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
45. 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
46. Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med. 1996;156:2213-2217.
FREE FULL TEXT
47. Tang MX, 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
48. Rodriguez MM, Grossberg GT. Estrogen as a psychotherapeutic agent. Clin Geriatr Med. 1998;14:177-189.
ISI
| PUBMED
49. Sloane PD. Advances in the treatment of Alzheimer's disease. Am Fam Physician. 1998;58:1577-1586.
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED LETTERS
Estrogen as a Treatment for Alzheimer Disease
Daniel Cosgrove, C. Dominique Toran-Allerand, and Ruth A. Mulnard
JAMA. 2000;284(3):307-308.
EXTRACT
| FULL TEXT
Effects of Estrogen Plus Progestin on Risk of Dementia—Reply
Sally A. Shumaker, Stephen R. Rapp, Mark A. Espeland, Robert B. Wallace, Susan L. Hendrix, Victor W. Henderson, Margery L. Gass, and Leon Thal
JAMA. 2003;290(13):1707-1708.
EXTRACT
| FULL TEXT
RELATED ARTICLES
Estrogen and Alzheimer Disease: Plausible Theory, Negative Clinical Trial
Bennett A. Shaywitz and Sally E. Shaywitz
JAMA. 2000;283(8):1055-1056.
EXTRACT
| FULL TEXT
February 23, 2000
JAMA. 2000;283(8):1079-1080.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
The Potential for Estrogens in Preventing Alzheimer's Disease.
Simpkins et al.
Therapeutic Advances in Neurological Disorders 2009;2:31-49.
ABSTRACT
Reassessing Benefits and Risks of Hormone Therapy
Gass et al.
AMERICAN JOURNAL OF LIFESTYLE MEDICINE 2009;3:29-43.
ABSTRACT
Incidence of Dementia in Long-term Hormone Users
Petitti et al.
Am J Epidemiol 2008;167:692-700.
ABSTRACT
| FULL TEXT
The Contribution of Luteinizing Hormone to Alzheimer Disease Pathogenesis
Webber et al.
Clin Med Res 2007;5:177-183.
ABSTRACT
| FULL TEXT
Hormone therapy in menopausal women with cognitive complaints: A randomized, double-blind trial
Maki et al.
Neurology 2007;69:1322-1330.
ABSTRACT
| FULL TEXT
Should surgical menopausal women be treated with estrogens to decrease the risk of dementia?
Hogervorst and Bandelow
Neurology 2007;69:1070-1071.
FULL TEXT
The Complex Role of Estrogens in Inflammation
Straub
Endocr. Rev. 2007;28:521-574.
ABSTRACT
| FULL TEXT
Estrogen Receptors: How Do They Signal and What Are Their Targets
Heldring et al.
Physiol. Rev. 2007;87:905-931.
ABSTRACT
| FULL TEXT
Neurocognitive Outcomes Are Not Improved by 17{beta}-Estradiol in Postmenopausal Women Undergoing Cardiac Surgery
Hogue et al.
Stroke 2007;38:2048-2054.
ABSTRACT
| FULL TEXT
Brain Infusion of Lipopolysaccharide Increases Uterine Growth as a Function of Estrogen Replacement Regimen: Suppression of Uterine Estrogen Receptor-{alpha} by Constant, But Not Pulsed, Estrogen Replacement
Marriott et al.
Endocrinology 2007;148:232-240.
ABSTRACT
| FULL TEXT
Clinical practice with anti-dementia drugs: a consensus statement from British Association for Psychopharmacology
Burns and O'Brien
J Psychopharmacol 2006;20:732-755.
ABSTRACT
Estrogen, Menopause, and the Aging Brain: How Basic Neuroscience Can Inform Hormone Therapy in Women
Morrison et al.
J. Neurosci. 2006;26:10332-10348.
FULL TEXT
Complex Actions of Sex Steroids in Adipose Tissue, the Cardiovascular System, and Brain: Insights from Basic Science and Clinical Studies
Turgeon et al.
Endocr. Rev. 2006;27:575-605.
ABSTRACT
| FULL TEXT
Effects of ultra-low-dose transdermal estradiol on cognition and health-related quality of life.
Yaffe et al.
Arch Neurol 2006;63:945-950.
ABSTRACT
| FULL TEXT
Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis.
Morales et al.
J. Neurosci. 2006;26:6823-6833.
ABSTRACT
| FULL TEXT
Estrogen Alters Spine Number and Morphology in Prefrontal Cortex of Aged Female Rhesus Monkeys
Hao et al.
J. Neurosci. 2006;26:2571-2578.
ABSTRACT
| FULL TEXT
Effects of Testosterone on Cognition and Mood in Male Patients With Mild Alzheimer Disease and Healthy Elderly Men
Lu et al.
Arch Neurol 2006;63:177-185.
ABSTRACT
| FULL TEXT
Familial Alzheimer disease in Latinos: Interaction between APOE, stroke, and estrogen replacement
Rippon et al.
Neurology 2006;66:35-40.
ABSTRACT
| FULL TEXT
Role of Protein Phosphatases in Estrogen-Mediated Neuroprotection
Yi et al.
J. Neurosci. 2005;25:7191-7198.
ABSTRACT
| FULL TEXT
Sex, Hormones, and Alzheimer's Disease
Baum
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2005;60:736-743.
ABSTRACT
| FULL TEXT
Estrogen Therapy Fails to Alter Amyloid Deposition in the PDAPP Model of Alzheimer's Disease
Green et al.
Endocrinology 2005;146:2774-2781.
ABSTRACT
| FULL TEXT
Postmenopausal hormone therapy: from monkey glands to transdermal patches
Davis et al.
J Endocrinol 2005;185:207-222.
ABSTRACT
| FULL TEXT
Are Estrogens Protective or Risk Factors in Brain Injury and Neurodegeneration? Reevaluation after the Women's Health Initiative
Wise et al.
Endocr. Rev. 2005;26:308-312.
ABSTRACT
| FULL TEXT
Molecular Endocrinology and Physiology of the Aging Central Nervous System
Smith et al.
Endocr. Rev. 2005;26:203-250.
ABSTRACT
| FULL TEXT
The role of aromatization in testosterone supplementation: Effects on cognition in older men
Cherrier et al.
Neurology 2005;64:290-296.
ABSTRACT
| FULL TEXT
17{beta}-Estradiol Differentially Regulates Blood-Brain Barrier Permeability in Young and Aging Female Rats
Bake and Sohrabji
Endocrinology 2004;145:5471-5475.
ABSTRACT
| FULL TEXT
Estrogen Modulates Microglial Inflammatory Mediator Production via Interactions with Estrogen Receptor {beta}
Baker et al.
Endocrinology 2004;145:5021-5032.
ABSTRACT
| FULL TEXT
Alzheimer's Disease
Cummings
NEJM 2004;351:56-67.
FULL TEXT
Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women: Women's Health Initiative Memory Study
Shumaker et al.
JAMA 2004;291:2947-2958.
ABSTRACT
| FULL TEXT
Estrogen and Dementia: Insights From the Women's Health Initiative Memory Study
Schneider
JAMA 2004;291:3005-3007.
FULL TEXT
Postmenopausal Estrogen Use Affects Risk for Parkinson Disease
Currie et al.
Arch Neurol 2004;61:886-888.
ABSTRACT
| FULL TEXT
Idebenone treatment fails to slow cognitive decline in Alzheimer's disease
Thal et al.
Neurology 2003;61:1498-1502.
ABSTRACT
| FULL TEXT
Postmenopausal Hormone Therapy and Its Association With Cognitive Impairment
Mitchell et al.
Arch Intern Med 2003;163:2485-2490.
ABSTRACT
| FULL TEXT
Detangling Alzheimer's Disease
Helmuth
Sci Aging Knowl Environ 2003;2003:oa2-2.
ABSTRACT
| FULL TEXT
Effects of Estrogen Plus Progestin on Risk of Dementia--Reply
Shumaker et al.
JAMA 2003;290:1707-1708.
FULL TEXT
Early Alzheimer's Disease
Kawas
NEJM 2003;349:1056-1063.
FULL TEXT
Managing Alzheimer Dementia Tomorrow
Rosenthal and Khotianov
J Am Board Fam Med 2003;16:423-434.
ABSTRACT
| FULL TEXT
Oestrogen, brain function, and neuropsychiatric disorders
Cutter et al.
J. Neurol. Neurosurg. Psychiatry 2003;74:837-840.
FULL TEXT
Screening for Dementia in Primary Care: A Summary of the Evidence for the U.S. Preventive Services Task Force
Boustani et al.
ANN INTERN MED 2003;138:927-937.
ABSTRACT
| FULL TEXT
Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women: The Women's Health Initiative Memory Study: A Randomized Controlled Trial
Shumaker et al.
JAMA 2003;289:2651-2662.
ABSTRACT
| FULL TEXT
Nulliparity and Late Menopause Are Associated With Decreased Cognitive Decline
McLay et al.
J. Neuropsychiatry Clin. Neurosi. 2003;15:161-167.
ABSTRACT
| FULL TEXT
Estrogen and Cognitive Functioning in Women
Sherwin
Endocr. Rev. 2003;24:133-151.
ABSTRACT
| FULL TEXT
Estrogen and Cognition: The Story So Far
Asthana
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2003;58:M322-323.
FULL TEXT
Hormone Replacement Therapy and Cognitive Performance: The Role of Homocysteine
Whitmer et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2003;58:M324-330.
ABSTRACT
| FULL TEXT
Management of Alzheimer's Disease
Grossberg and Desai
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2003;58:M331-353.
FULL TEXT
Alzheimer Disease: Current Concepts and Emerging Diagnostic and Therapeutic Strategies
Clark and Karlawish
ANN INTERN MED 2003;138:400-410.
ABSTRACT
| FULL TEXT
Long-term cholinesterase inhibitor therapy for Alzheimer's disease: Implications for long-term care
Brangman
AM J ALZHEIMERS DIS OTHER DEMEN 2003;18:79-84.
ABSTRACT
Selective Estrogen-Receptor Modulators -- Mechanisms of Action and Application to Clinical Practice
Riggs and Hartmann
NEJM 2003;348:618-629.
FULL TEXT
Estrogen Levels Do Not Correlate With Improvement in Cognition
Thal et al.
Arch Neurol 2003;60:209-212.
ABSTRACT
| FULL TEXT
Higher Estrogen Levels Are Not Associated With Larger Hippocampi and Better Memory Performance
den Heijer et al.
Arch Neurol 2003;60:213-220.
ABSTRACT
| FULL TEXT
Effectiveness of Estrogen Replacement in Restoration of Cognitive Function after Long-Term Estrogen Withdrawal in Aging Rats
Markowska and Savonenko
J. Neurosci. 2002;22:10985-10995.
ABSTRACT
| FULL TEXT
Pharmacologic Agents Associated with a Preventive Effect on Alzheimer's Disease: A Review of the Epidemiologic Evidence
in 't Veld et al.
Epidemiol Rev 2002;24:248-268.
FULL TEXT
Hormone Replacement Therapy and Incidence of Alzheimer Disease in Older Women: The Cache County Study
Zandi et al.
JAMA 2002;288:2123-2129.
ABSTRACT
| FULL TEXT
Hormone Therapy and Risk of Alzheimer Disease: A Critical Time
Resnick and Henderson
JAMA 2002;288:2170-2172.
FULL TEXT
Message about hormone replacement therapy is unclear
Dixon
BMJ 2002;325:1036-1036.
FULL TEXT
The Role of Hormone Replacement Therapy in the Prevention of Alzheimer Disease
Fillit
Arch Intern Med 2002;162:1934-1942.
ABSTRACT
| FULL TEXT
Cognitive Decline Among Female Estrogen Users in Nursing Homes
Ott et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2002;57:M594-598.
ABSTRACT
| FULL TEXT
Prevalence of Dementia in Users of Hormone Replacement Therapy as Defined by Prescription Data
Petitti et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2002;57:M532-538.
ABSTRACT
| FULL TEXT
American Society of Clinical Oncology Technology Assessment of Pharmacologic Interventions for Breast Cancer Risk Reduction Including Tamoxifen, Raloxifene, and Aromatase Inhibition
Chlebowski et al.
JCO 2002;20:3328-3343.
ABSTRACT
| FULL TEXT
Longitudinal Assessment of Patient Dependence in Alzheimer Disease
Brickman et al.
Arch Neurol 2002;59:1304-1308.
ABSTRACT
| FULL TEXT
Hormone Replacement Therapy for Prevention: More Evidence, More Pessimism
Petitti
JAMA 2002;288:99-101.
FULL TEXT
Achieving and Maintaining Cognitive Vitality With Aging
Fillit et al.
Mayo Clin Proc. 2002;77:681-696.
ABSTRACT
Frontiers in Neuropharmacotherapy Part I: Alzheimer's Disease and Epilepsy
Chappell and Cohen
Journal of Pharmacy Practice 2002;15:195-220.
ABSTRACT
Alzheimer Disease
Cummings and Cole
JAMA 2002;287:2335-2338.
FULL TEXT
Genetic and host factors for dementia in Down's syndrome
SCHUPF and Sergievsky
Br. J. Psychiatry 2002;180:405-410.
ABSTRACT
| FULL TEXT
Estrogen Lowers Alzheimer beta -Amyloid Generation by Stimulating trans-Golgi Network Vesicle Biogenesis
Greenfield et al.
J. Biol. Chem. 2002;277:12128-12136.
ABSTRACT
| FULL TEXT
Endogenous Estradiol in Elderly Individuals: Cognitive and Noncognitive Associations
Senanarong et al.
Arch Neurol 2002;59:385-389.
ABSTRACT
| FULL TEXT
Antiresorptive Treatment of Postmenopausal Osteoporosis: Comparison of Study Designs and Outcomes in Large Clinical Trials with Fracture as an Endpoint
Marcus et al.
Endocr. Rev. 2002;23:16-37.
ABSTRACT
| FULL TEXT
Use of Lipid-Lowering Agents, Indication Bias, and the Risk of Dementia in Community-Dwelling Elderly People
Rockwood et al.
Arch Neurol 2002;59:223-227.
ABSTRACT
| FULL TEXT
New drugs for Alzheimer's disease and other dementias
BULLOCK
Br. J. Psychiatry 2002;180:135-139.
ABSTRACT
| FULL TEXT
Production and Actions of Estrogens
Gruber et al.
NEJM 2002;346:340-352.
FULL TEXT
Hormone replacement therapy and reduced cognitive decline in older women: The Cache County Study
Carlson et al.
Neurology 2001;57:2210-2216.
ABSTRACT
| FULL TEXT
Genome and Hormones: Gender Differences in Physiology: Invited Review: Estrogens effects on the brain: multiple sites and molecular mechanisms
McEwen
J. Appl. Physiol. 2001;91:2785-2801.
ABSTRACT
| FULL TEXT
Prospective Assessment of Estrogen Replacement Therapy and Cognitive Functioning: Atherosclerosis Risk in Communities Study
de Moraes et al.
Am J Epidemiol 2001;154:733-739.
ABSTRACT
| FULL TEXT
Detangling Alzheimer's Disease
Helmuth
Sci Aging Knowl Environ 2001;2001:oa2-2.
ABSTRACT
| FULL TEXT
High-dose estradiol improves cognition for women with AD: Results of a randomized study
Asthana et al.
Neurology 2001;57:605-612.
ABSTRACT
| FULL TEXT
Hormone Replacement in Women with a History of Breast Cancer
Pritchard
The Oncologist 2001;6:353-362.
ABSTRACT
| FULL TEXT
Testosterone supplementation improves spatial and verbal memory in healthy older men
Cherrier et al.
Neurology 2001;57:80-88.
ABSTRACT
| FULL TEXT
Postmenopausal Hormone-Replacement Therapy
Manson and Martin
NEJM 2001;345:34-40.
FULL TEXT
Hormone Replacement Therapy and Prevention of Nonvertebral Fractures: A Meta-analysis of Randomized Trials
Torgerson and Bell-Syer
JAMA 2001;285:2891-2897.
ABSTRACT
| FULL TEXT
Hormone replacement therapy (HRT)-- risks and benefits
Barrett-Connor and Stuenkel
Int J Epidemiol 2001;30:423-426.
FULL TEXT
Practice parameter: Management of dementia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology
Doody et al.
Neurology 2001;56:1154-1166.
ABSTRACT
| FULL TEXT
Cellular and Molecular Mechanisms of Estrogen Regulation of Memory Function and Neuroprotection Against Alzheimer's Disease: Recent Insights and Remaining Challenges
Brinton
Learn. Mem. 2001;8:121-133.
ABSTRACT
| FULL TEXT
Can Estrogen or Selective Estrogen-Receptor Modulators Preserve Cognitive Function in Elderly Women?
Mayeux
NEJM 2001;344:1242-1244.
FULL TEXT
Differential Mechanisms of Neuroprotection by 17 {beta}-Estradiol in Apoptotic versus Necrotic Neurodegeneration
Harms et al.
J. Neurosci. 2001;21:2600-2609.
ABSTRACT
| FULL TEXT
Reproductive Period and Risk of Dementia in Postmenopausal Women
Geerlings et al.
JAMA 2001;285:1475-1481.
ABSTRACT
| FULL TEXT
Hormone Replacement Therapy and Cognition: Systematic Review and Meta-analysis
LeBlanc et al.
JAMA 2001;285:1489-1499.
ABSTRACT
| FULL TEXT
Estrogen Prevents the Lipopolysaccharide-Induced Inflammatory Response in Microglia
Vegeto et al.
J. Neurosci. 2001;21:1809-1818.
ABSTRACT
| FULL TEXT
Endogenous Sex Hormone Levels in Postmenopausal Women with Alzheimer's Disease
Cunningham et al.
J. Clin. Endocrinol. Metab. 2001;86:1099-1103.
ABSTRACT
| FULL TEXT
Exogenous estrogen in systemic lupus erythematosus: oral contraceptives and hormone replacement therapy
Petri
Lupus 2001;10:222-226.
ABSTRACT
Postmenopausal Estrogen Replacement Therapy and the Risk of Alzheimer Disease
Seshadri et al.
Arch Neurol 2001;58:435-440.
ABSTRACT
| FULL TEXT
Physical Activity and Risk of Cognitive Impairment and Dementia in Elderly Persons
Laurin et al.
Arch Neurol 2001;58:498-504.
ABSTRACT
| FULL TEXT
Alzheimer's Disease in Man and Transgenic Mice : Females at Higher Risk
Turner
Am. J. Pathol. 2001;158:797-801.
FULL TEXT
Augmented Senile Plaque Load in Aged Female {beta}-Amyloid Precursor Protein-Transgenic Mice
Callahan et al.
Am. J. Pathol. 2001;158:1173-1177.
ABSTRACT
| FULL TEXT
Effects of Long-Term Hormone Therapy on Cholinergic Synaptic Concentrations in Healthy Postmenopausal Women
Smith et al.
J. Clin. Endocrinol. Metab. 2001;86:679-684.
ABSTRACT
| FULL TEXT
Impact of Estrogen Use on Decline in Cognitive Function in a Representative Sample of Older Community-resident Women
Fillenbaum et al.
Am J Epidemiol 2001;153:137-144.
ABSTRACT
| FULL TEXT
Risk factors for dementia
McCullagh et al.
Adv. Psychiatr. Treat. 2001;7:24-31.
FULL TEXT
|
