Alzheimer’s Abstracts 1 - Hormones

© 2010

Sex, Hormones, and Alzheimer’s Disease

(Baum 2005) Download

More women than men have Alzheimer's disease (AD). Retrospective studies suggested that hormone replacement therapy (HRT) might counteract this disparity by reducing the risk of developing dementia. However, a recent, large, prospective study revealed the puzzling result that HRT increased dementia risk. A review of the literature was conducted to generate hypotheses that might explain why more women than men have AD, and how HRT may increase dementia risk. Longer life span of women than men may be the largest factor in the preponderance of women with AD. Longer duration of disease, less vascular dementia, and less testosterone in women than men may also contribute somewhat. HRT might increase dementia risk by several mechanisms: greater risk of strokes, leading to dementia; use of medroxyprogesterone acetate and estrone, which might have somewhat different possible effects on neuronal and cerebrovascular function than may progesterone and estradiol; decrease of free testosterone which might protect against AD; a dose or delivery method perhaps producing drug levels that might lie outside a hypothetical beneficial range; and down-regulation of estrogen receptors on cholinergic neurons, possibly reducing cholinergic activity. Further study is required to discern by which of several possible mechanisms HRT increases dementia risk.

Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer's disease

            (Brinton 2008) Download

Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis and citric acid cycle-driven oxidative phosphorylation and ATP generation. Data derived from experimental and clinical paradigms investigating estrogen intervention in healthy systems and prior to neurodegenerative insult indicate enhanced neural defense and survival through maintenance of calcium homeostasis, enhanced glycolysis coupled to the citric acid cycle (aerobic glycolysis), sustained and enhanced mitochondrial function, protection against free radical damage, efficient cholesterol trafficking and beta amyloid clearance. The convergence of E(2) mechanisms of action onto mitochondrial is also a potential point of vulnerability when activated in a degenerating neural system and could exacerbate the degenerative processes through increased load on dysregulated calcium homeostasis. The data indicate that as the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neuronal survival and neurological function. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the basic to clinical domains of scientific inquiry and on which to predict future applications of estrogen and hormone therapeutic interventions sustain neurological health and to prevent age-associated neurodegenerative diseases such as Alzheimer's. Overall, E(2) promotes the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism). The enhanced aerobic glycolysis in the aging brain would be predicted to prevent conversion of the brain to using alternative sources of fuel such as the ketone body pathway characteristic of Alzheimer's.

Long-term exposure to magnetic fields and the risks of Alzheimer's disease and breast cancer: Further biological research

            (Davanipour and Sobel 2009) Download

Objective: Extremely low frequency (ELF) and radio frequency (RF) magnetic fields (MFs) pervade our environment. Whether or not these magnetic fields are associated with increased risk of serious diseases, e.g., cancers and Alzheimer's disease, is thus important when developing a rational public policy. The Bioinitiative Report was an effort by internationally recognized scientists who have spent significant time investigating the biological consequences of exposures to these magnetic fields to address this question. Our objective was to provide an unbiased review of the current knowledge and to provide our general and specific conclusions. Results: The evidence indicates that long-term significant occupational exposure to ELF MF may certainly increase the risk of both Alzheimer's disease and breast cancer. There is now evidence that two relevant biological processes (increased production of amyloid beta and decreased production of melatonin) are influenced by high long-term ELF MF exposure that may lead to Alzheimer's disease. There is further evidence that one of these biological processes (decreased melatonin production) may also lead to breast cancer. Finally, there is evidence that exposures to RF MF and ELF MF have similar biological consequences. Conclusion: It is important to mitigate ELF and RF MF exposures through equipment design changes and environmental placement of electrical equipment, e.g., AC/DC transformers. Further research related to these proposed and other biological processes is required.

Estrogens, episodic memory, and Alzheimer's disease: a critical update

            (Henderson 2009) Download

Estrogen-containing hormone therapy initiated during late postmenopause does not improve episodic memory (an important early symptom of Alzheimer's disease), and it increases dementia risk. Cognitive consequences of exogenous estrogen exposures during midlife are less certain. Observational evidence implies that use of hormone therapy at a younger age close to the time of menopause may reduce risk of Alzheimer's disease later in life. However, there are concerns that observational findings may be systematically biased. Partial insight on this critical issue may be gleaned from results of ongoing clinical trials involving midlife postmenopausal women (Early versus Late Intervention Trial with Estrogen; Kronos Early Estrogen Prevention Study). The effects of exogenous midlife estrogen exposures and Alzheimer risk can also be approached through better animal models, through carefully designed cohort studies, and through use of surrogate outcomes in randomized controlled trials in midlife women. Selective estrogen receptor modulators have the potential to affect cognitive outcomes and also merit additional study.

Hormone replacement therapy to maintain cognitive function in women with dementia

            (Hogervorst, Yaffe et al. 2009) Download

BACKGROUND: As estrogens have been shown to have several potentially beneficial effects on the central nervous system, it is biologically plausible that maintaining high levels of estrogens in postmenopausal women by means of estrogen replacement therapy (ERT) could be protective against cognitive decline in women with Alzheimer's disease (AD) or other dementia syndromes. OBJECTIVES: To investigate the effects of ERT (estrogens only) or HRT (estrogens combined with a progestagen) compared with placebo in randomized controlled trials (RCTs) on cognitive function of postmenopausal women with dementia. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group Specialized Register, which contains records from many medical databases, The Cochrane Library, EMBASE, MEDLINE, CINAHL, PsycINFO and LILACS were searched on 7 November 2007 using the terms ORT, PORT, ERT, HRT, estrogen*, oestrogen* and progesterone*. SELECTION CRITERIA: All double-blind randomized controlled trials (RCTs) into the effect of ERT or HRT for cognitive function with a treatment period of at least two weeks in postmenopausal women with AD or other types of dementia. DATA COLLECTION AND ANALYSIS: Abstracts of the references retrieved by the searches were read by two reviewers (EH and KY) independently in order to discard those that were clearly not eligible for inclusion. The two reviewers studied the full text of the remaining references and independently selected studies for inclusion. Any disparity in the ensuing lists was resolved by discussion with all reviewers in order to arrive at the final list of included studies. The selection criteria ensured that the blinding and randomization of the included studies was adequate. The two reviewers also assessed the quality of other aspects of the included trials. One reviewer (EH) extracted the data from the studies, but was aided and checked by JB from Cochrane. MAIN RESULTS: A total of seven trials including 351 women with AD were analysed. Because different drugs were used at different studies it was not possible to combine more than two studies in any analysis.On a clinical global rating, clinicians scored patients taking CEE as significantly worse compared with the placebo group on the Clinical Dementia Rating scale after 12 months (overall WMD = 0.35, 95% CI = 0.01 to 0.69, z = 1.99, P < 0.05).Patients taking CEE had a worse performance on the delayed recall of the Paragraph Test (overall WMD = -0.45, 95% CI = -0.79 to -0.11, z = 2.60, P < 0.01) after one month than those taking placebo. They had a worse performance on Finger Tapping after 12 months (WMD = -3.90, 95% CI = -7.85 to 0.05, z = 1.93, P < 0.05).Limited positive effects were found for the lower dosage of CEE (0.625 mg/day) which showed a significant improvement in MMSE score only when assessed at two months, and disappeared after correction for multiple testing. No significant effects for MMSE were found at longer end points (3, 6 and 12 months of treatment). With a dosage of 1.25 mg/d CEE, short-term significant effects were found for Trial-Making test B at one month and Digit Span backward at four months. After two months of transdermal diestradiol (E2) treatment, a highly significant effect was observed for the word recall test (WMD = 6.50, 95% CI = 4.04 to 8.96, z = 5.19, P < 0.0001). No other significant effects were found for other outcomes measured. AUTHORS' CONCLUSIONS: Currently, HRT or ERT for cognitive improvement or maintenance is not indicated for women with AD.

Hormone replacement therapy for cognitive function in postmenopausal women

            (Lethaby, Hogervorst et al. 2008) Download

BACKGROUND: As estrogens have been found in animal models to be associated with the maintenance and protection of brain structures, it is biologically plausible that maintaining high levels of estrogens in postmenopausal women by medication could be protective against cognitive decline. OBJECTIVES: To investigate the effect of ERT (estrogens only) or HRT (estrogens combined with a progestagen) in comparison with placebo in RCTs on cognitive function in postmenopausal women. SEARCH STRATEGY: The CDCIG Specialized Register was searched 7 March 2006. Additional searches were made of MEDLINE (1966-2006/02); EMBASE (1985-2006/02); PsycINFO (1967-2006/02) and CINAHL (1982-2006/01). SELECTION CRITERIA: All double-blind RCTs trials of the effect of ERT or HRT on cognitive function over a treatment period of at least two weeks in postmenopausal women. DATA COLLECTION AND ANALYSIS: Selection of studies, assessment of quality and extraction of data were undertaken independently by three reviewers with disagreements resolved by discussion. MAIN RESULTS: In total, 24 trials were included, but only 16 (10,114 women) had analysable data. Meta-analyses showed no effects of either ERT or HRT on prevention of cognitive impairment after five and four years of treatment, respectively (odds ratio 1.34, 95% CI 0.95 to 1.9; odds ratio 1.05, 95% CI 0.72 to 1.54 respectively) (trend favouring control in both instances). Analyses assessing the effects of treatment over time found that both ERT and HRT did not maintain or improve cognitive function and may even adversely affect this outcome (WMD = -0.45, 95% CI -0.99 to 0.09; WMD = -0.16, 95% CI -0.58 to 0.26, respectively at maximum follow up). Negative effects were found for ERT after one year and HRT after three and four years of therapy. Results from smaller trials assessing effects on individual cognitive domains mostly reported no evidence of benefit. AUTHORS' CONCLUSIONS: There is good evidence that both ERT and HRT do not prevent cognitive decline in older postmenopausal women when given as short term or longer term (up to five years) therapy. It is not known whether either specific types of ERT or HRT have specific effects in subgroups of women, although there was evidence that combined hormone therapy in similarly aged women was associated with a decrement in a number of verbal memory tests and a small improvement in a test of figural memory. There is insufficient evidence to determine whether subgroups of women using specific types of hormone therapy could benefit from treatment. It remains to be determined whether factors such as younger age (< 60 years of age), type of menopause (surgical or natural) and type of treatment (type of estrogen with or without a progestagen), mode of delivery (transdermal, oral or intramuscular) and dosage have positive effects at a clinically relevant level. In addition, whether the absence or presence of menopausal symptoms can modify treatment effects should be investigated in more detail. Large RCTs currently underway in the USA may be able to provide answers to these uncertainties by the year 2010. In the meantime, based on the available evidence, ERT or HRT cannot be recommended for overall cognitive improvement or maintenance in older postmenopausal women without cognitive impairment.

Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease

            (Olcese, Cao et al. 2009) Download

The neurohormone melatonin has been reported to exert anti-beta-amyloid aggregation, antioxidant, and anti-inflammatory actions in various in vitro and animal models. To comprehensively determine the potential for long-term melatonin treatment to protect Alzheimer's transgenic mice against cognitive impairment and development of beta-amyloid (Abeta) neuropathology, we administered melatonin (100 mg/L drinking water) to APP + PS1 double transgenic (Tg) mice from 2-2.5 months of age to their killing at age 7.5 months. A comprehensive behavioral battery administered during the final 6 weeks of treatment revealed that Tg mice given melatonin were protected from cognitive impairment in a variety of tasks of working memory, spatial reference learning/memory, and basic mnemonic function; Tg control mice remained impaired in all of these cognitive tasks/domains. Immunoreactive Abeta deposition was significantly reduced in hippocampus (43%) and entorhinal cortex (37%) of melatonin-treated Tg mice. Although soluble and oligomeric forms of Abeta1-40 and 1-42 were unchanged in the hippocampus and cortex of the same melatonin-treated Tg mice, their plasma Abeta levels were elevated. These Abeta results, together with our concurrent demonstration that melatonin suppresses Abeta aggregation in brain homogenates, are consistent with a melatonin-facilitated removal of Abeta from the brain. Inflammatory cytokines such as tumor necrosis factor (TNF)-alpha were decreased in hippocampus (but not plasma) of Tg+ melatonin mice. Finally, the cortical mRNA expression of three antioxidant enzymes (SOD-1, glutathione peroxidase, and catalase) was significantly reduced to non-Tg levels by long-term melatonin treatment in Tg mice. Thus, melatonin's cognitive benefits could involve its anti-Abeta aggregation, anti-inflammatory, and/or antioxidant properties. Our findings provide support for long-term melatonin therapy as a primary or complementary strategy for abating the progression of Alzheimer disease.

Incidence of dementia in long-term hormone users

            (Petitti, Crooks et al. 2008) Download

Results from epidemiologic studies of postmenopausal hormone use and dementia have been conflicting. Investigators from the Women's Health Initiative Memory Study reported that the incidence of dementia in women aged >/=65 years assigned to hormone use was increased. Here the authors report results from a prospective cohort study of 2,906 dementia-free women (1,519 hormone users and 1,387 hormone nonusers) aged > or =75 years who were recruited from a Southern California health plan in 1999 and followed through 2003. Cognitive status was assessed annually using the Telephone Interview of Cognitive Status-modified, supplemented by the Telephone Dementia Questionnaire and medical record review. The mean self-reported age at initiation of hormone use was 48.3 years for users of estrogen alone (n = 1,072) and 54.9 years for users of estrogen plus progestin (n = 447); self-reported mean durations of hormone use were 30.5 years and 23.2 years, respectively. There were 283 incident dementia cases identified during follow-up. After adjustment for age, education, and medical history, hazard ratios for incident dementia were 1.34 (95% confidence interval: 0.95, 1.89) in estrogen/progestin users and 1.23 (95% confidence interval: 0.94, 1.59) in estrogen users. These findings do not provide support for an effect of estrogen or estrogen/progestin use in preventing dementia.

Protective actions of sex steroid hormones in Alzheimer’s disease

            (Pike, Carroll et al. 2009) Download

Risk for Alzheimer's disease (AD) is associated with age-related loss of sex steroid hormones in both women and men. In post-menopausal women, the precipitous depletion of estrogens and progestogens is hypothesized to increase susceptibility to AD pathogenesis, a concept largely supported by epidemiological evidence but refuted by some clinical findings. Experimental evidence suggests that estrogens have numerous neuroprotective actions relevant to prevention of AD, in particular promotion of neuron viability and reduction of beta-amyloid accumulation, a critical factor in the initiation and progression of AD. Recent findings suggest neural responsiveness to estrogen can diminish with age, reducing neuroprotective actions of estrogen and, consequently, potentially limiting the utility of hormone therapies in aged women. In addition, estrogen neuroprotective actions are also modulated by progestogens. Specifically, continuous progestogen exposure is associated with inhibition of estrogen actions whereas cyclic delivery of progestogens may enhance neural benefits of estrogen. In recent years, emerging literature has begun to elucidate a parallel relationship of sex steroid hormones and AD risk in men. Normal age-related testosterone loss in men is associated with increased risk to several diseases including AD. Like estrogen, testosterone has been established as an endogenous neuroprotective factor that not only increases neuronal resilience against AD-related insults, but also reduces beta-amyloid accumulation. Androgen neuroprotective effects are mediated both directly by activation of androgen pathways and indirectly by aromatization to estradiol and initiation of protective estrogen signaling mechanisms. The successful use of hormone therapies in aging men and women to delay, prevent, and or treat AD will require additional research to optimize key parameters of hormone therapy and may benefit from the continuing development of selective estrogen and androgen receptor modulators.

Characteristics of hormone therapy, cognitive function, and dementia: the prospective 3C Study

            (Ryan, Carriere et al. 2009) Download

OBJECTIVES: To examine the association between hormone therapy (HT) and cognitive performance or dementia, focusing on the duration and type of treatment used, as well as the timing of initiation of HT in relation to the menopause. METHODS: Women 65 years and older were recruited in France as part of the Three City Study. At baseline and 2- and 4-year follow-up, women were administered a short cognitive test battery and a clinical diagnosis of dementia was made. Detailed information was also gathered relating to current and past HT use. Analysis was adjusted for a number of sociodemographic, behavioral, physical, and mental health variables, as well as APOE epsilon4. RESULTS: Among 3,130 naturally postmenopausal women, current HT users performed significantly better than never users on verbal fluency, working memory, and psychomotor speed. These associations varied according to the type of treatment and a longer duration of HT appeared to be more beneficial. However, initiation of HT close to the menopause was not associated with better cognition. HT did not significantly reduce dementia risk over 4 years but current treatment diminished the negative effect associated with APOE epsilon4. CONCLUSIONS: Current hormone therapy (HT) was associated with better performance in certain cognitive domains but these associations are dependent on the duration and type of treatment used. We found no evidence that HT needs to be initiated close to the menopause to have a beneficial effect on cognitive function in later life. Current HT may decrease the risk of dementia associated with the APOE epsilon4 allele.

A multi-center, randomized, double blind placebo-controlled trial of estrogens to prevent Alzheimer's disease and loss of memory in women: design and baseline characteristics

            (Sano, Jacobs et al. 2008) Download

BACKGROUND: Observational studies and small clinical trials suggested that hormone replacement therapy (HRT) decreases risk of cognitive loss and Alzheimer's disease (AD) in postmenopausal women and may have value in primary prevention. PURPOSE: A clinical trial was designed to determine if HRT delays AD or memory loss. This report describes the rationale and original design of the trial and details extensive modifications that were required to respond to unanticipated findings that emerged from other studies during the course of the trial. METHODS: The trial was designed as a multi-center, placebo-controlled primary prevention trial for women 65 years of age or older with a family history of dementia. Recruitment from local sites was supplemented by centralized efforts to use names of Medicare beneficiaries. Inclusion criteria included good general health and intact memory functioning. Participants were randomized to HRT or placebo in a 1:1 ratio. Assignment was stratified by hysterectomy status and site. The primary outcomes were incident AD and memory decline on neuropsychological testing. RESULTS: Enrollment began in March 1998. In response to the Women's Health Initiative (WHI) May 2002 report of increased incidence of heart disease, stroke, pulmonary embolism, and breast cancer among women randomized to HRT, participants were re-consented with a revised consent form. Procedural modifications, including discontinuation of study medication and a modification of the planned primary outcome based on a final enrollment below the target enrollment (N = 477), were enacted in response to the subsequent WHI Memory Study report of increased risk of dementia and poorer cognitive function with HRT. The mean length of treatment exposure prior to discontinuation was 2.14 years. Participants' mean age at baseline was 72.8; mean education was 14.2 years. Minority participation was 19% and 34% had a hysterectomy. The study continues to follow these participants for a total of 5 years blind to the original medication assignment. LIMITATIONS: Results reported from the WHI during the course of this study mandated extensive procedural modifications, including discontinuing recruitment before completion and halting study medication. Alternative strategies for study redesign that were considered are discussed.

Melatonin in Alzheimer's disease and other neurodegenerative disorders

            (Srinivasan, Pandi-Perumal et al. 2006) Download

Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-beta toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and kynuric metabolites may have potential value in prevention and treatment of AD and other neurodegenerative disorders.

Hormone replacement therapy in postmenopausal women with Alzheimer's disease: a randomized, prospective study

            (Yoon, Kim et al. 2003) Download

OBJECTIVE: To compare the therapeutic efficacy of hormone replacement therapy (HRT) and tacrine in Alzheimer's disease. DESIGN: Six-month, randomized, open-label study. SETTING: University hospital. PATIENT(S): Fifty-five women with mild to moderate Alzheimer's disease were randomly assigned to tacrine (n = 26) or HRT (n = 29). INTERVENTION(S): In the tacrine group, an initial dose of 40 mg/day was increased up to 160 mg/day. In the HRT group, conjugated equine estrogen was given to patients without uteri (n = 3) or together with micronized progesterone to patients with uteri (n = 26). MAIN OUTCOME MEASURE(S): Mini-Mental State Examination (MMSE), Hopkins Verbal Learning Test, Boston Naming Test, Controlled Oral Word Association Test, Geriatric Depression Scale, Hamilton Depression Scale (HDS), and Instrumental Activities of Daily Living (IADL). RESULT(S): Thirty-three patients who completed the outcome measures (tacrine, 17; HRT, 16) were included in an intent-to-treat analysis. The results did not differ between groups except for IADL, which rated more highly after HRT. Apolipoprotein E genotype effects were assessed. MMSE and HDS scores were improved after tacrine treatment in epsilon 4-negative patients. CONCLUSION(S): Overall efficacy of estrogen plus progesterone combination was similar to tacrine for cognition and mood, but greater for ADL. In epsilon 4-negative patients, tacrine is preferable for cognition and mood.


References

Baum, L. W. (2005). "Sex, hormones, and Alzheimer's disease." J Gerontol A Biol Sci Med Sci 60(6): 736-43.

Brinton, R. D. (2008). "Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer's disease." Adv Drug Deliv Rev 60(13-14): 1504-11.

Davanipour, Z. and E. Sobel (2009). "Long-term exposure to magnetic fields and the risks of Alzheimer's disease and breast cancer: Further biological research." Pathophysiology 16(2-3): 149-56.

Henderson, V. W. (2009). "Estrogens, episodic memory, and Alzheimer's disease: a critical update." Semin Reprod Med 27(3): 283-93.

Hogervorst, E., K. Yaffe, et al. (2009). "Hormone replacement therapy to maintain cognitive function in women with dementia." Cochrane Database Syst Rev(1): CD003799.

Lethaby, A., E. Hogervorst, et al. (2008). "Hormone replacement therapy for cognitive function in postmenopausal women." Cochrane Database Syst Rev(1): CD003122.

Olcese, J. M., C. Cao, et al. (2009). "Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease." J Pineal Res 47(1): 82-96.

Petitti, D. B., V. C. Crooks, et al. (2008). "Incidence of dementia in long-term hormone users." Am J Epidemiol 167(6): 692-700.

Pike, C. J., J. C. Carroll, et al. (2009). "Protective actions of sex steroid hormones in Alzheimer's disease." Front Neuroendocrinol 30(2): 239-58.

Ryan, J., I. Carriere, et al. (2009). "Characteristics of hormone therapy, cognitive function, and dementia: the prospective 3C Study." Neurology 73(21): 1729-37.

Sano, M., D. Jacobs, et al. (2008). "A multi-center, randomized, double blind placebo-controlled trial of estrogens to prevent Alzheimer's disease and loss of memory in women: design and baseline characteristics." Clin Trials 5(5): 523-33.

Srinivasan, V., S. R. Pandi-Perumal, et al. (2006). "Melatonin in Alzheimer's disease and other neurodegenerative disorders." Behav Brain Funct 2: 15.

Yoon, B. K., D. K. Kim, et al. (2003). "Hormone replacement therapy in postmenopausal women with Alzheimer's disease: a randomized, prospective study." Fertil Steril 79(2): 274-80.