Estrogen use and early onset Alzheimer's disease: a population-based study

Slooter, Arjen J. C.; Bronzova, Juliana; Witteman, J.C.M.; Broeckhoven, Christine Van; Hofman, Albert; Duijn, C.M. van

doi:10.1136/jnnp.67.6.779

Cited by 117 publications

(68 citation statements)

References 28 publications

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“…Reports that post-menopausal estrogen replacement therapy (ERT) 1 is clinically efficacious in delaying the onset of Alzheimer's disease (AD) (1) or improving cognition (2) in post-menopausal women have been corroborated by numerous studies (3)(4)(5). Reports questioning the validity of these retrospective studies (6) demonstrated that women with clinically defined AD have no improvement on specific cognitive tasks following short (2-15-month) trials of estrogen treatment.…”

mentioning

confidence: 99%

Estrogen Lowers Alzheimer β-Amyloid Generation by Stimulating trans-Golgi Network Vesicle Biogenesis

Greenfield

Leung

Cai

et al. 2002

Journal of Biological Chemistry

122

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Estrogen reduces the risk of Alzheimer's disease in post-menopausal women, ␤-amyloid (A␤) burden in animal models of Alzheimer's disease, and secretion of A␤ from neuronal cultures. The biological basis for these effects remains unknown. Here, utilizing cell-free systems derived from both neuroblastoma cells and primary neurons, we demonstrate that 17␤-estradiol (17␤-E2) stimulates formation of vesicles containing the ␤-amyloid precursor protein (␤APP) from the transGolgi network (TGN). Accelerated ␤APP trafficking precludes maximal A␤ generation within the TGN. 17␤-E2 appears to modulate TGN phospholipid levels, particularly those of phosphatidylinositol, and to recruit soluble trafficking factors, such as Rab11, to the TGN. Together, these results suggest that estrogen may exert its anti-A␤ effects by regulating ␤APP trafficking within the late secretory pathway. These results suggest a novel mechanism through which 17␤-E2 may act in estrogen-responsive tissues and illustrate how altering the kinetics of the transport of a protein can influence its metabolic fate.Reports that post-menopausal estrogen replacement therapy (ERT) 1 is clinically efficacious in delaying the onset of Alzheimer's disease (AD) (1) or improving cognition (2) in post-menopausal women have been corroborated by numerous studies (3-5). Reports questioning the validity of these retrospective studies (6) demonstrated that women with clinically defined AD have no improvement on specific cognitive tasks following short (2-15-month) trials of estrogen treatment. However, the neuroprotective effects of estrogen are hypothesized to safeguard against the development of AD and not to aid in recovering lost function. The biological mechanism(s) through which estrogen exerts its neuroprotective effects remain largely unknown; hypotheses have included modulation of basal forebrain cholinergic activity, dendritic plasticity, N-methyl-D-aspartic acid (NMDA) receptor density, and regulation of neurotrophin signaling pathways (7).ERT may slow AD progression by reducing the release of A␤, the primary constituent of amyloid plaques, into brain parenchyma. This phenomenon was first described in non-neuronal (8) and neuronal (9) cell culture. It has now received support from animal models demonstrating that ovariectomized guinea pigs (10) and transgenic mutant ␤APP/PS1-expressing mice (11) develop increased levels of parenchymal A␤ compared with intact littermates. This A␤ burden is reversible with postsurgical estrogen replacement. In addition, a recent study (12) demonstrates an inverse relationship between the levels of 17␤-E2 and A␤42, the more amyloidogenic A␤ variant, in the cerebrospinal fluid of female patients with AD. In summary, results from retrospective clinical trials, recent and on-going animal studies, and corroborating cell culture data all support the hypothesis that post-menopausal cessation of estrogen production may facilitate A␤ deposition and that the clinical efficacy of ERT may be due, in part, to a direct A␤-lowering effect.A␤ is p...

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mentioning

confidence: 99%

Estrogen Lowers Alzheimer β-Amyloid Generation by Stimulating trans-Golgi Network Vesicle Biogenesis

Greenfield

Leung

Cai

et al. 2002

Journal of Biological Chemistry

122

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“…There was insufficient information in the studies to assess the effect of estrogen or progestogen with regard to formulation, dosage, duration, or time since last use. Results of three subsequent epidemiologic studies are conflicting but do not change the overall estimate of risk reduction in a meaningful way (31)(32)(33).…”

Section: Senile Dementia and Cognitive Impairmentmentioning

confidence: 92%

Estrogen and progestogen therapy in postmenopausal women

2008

Fertility and Sterility

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This Educational Bulletin discusses the effectiveness of hormone therapy (HT) for relieving vasomotor and urogenital symptoms and the side effects associated with such treatment; considers the evidence concerning the effects of HT on the risk of osteoporosis and related fractures and on the risks of coronary artery disease, dementia, and colorectal cancer; and considers the longer term effects of HT on the risks of stroke, venous thromboembolism, and cancer of the breast, endometrium, and ovary.

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“…The epidemiologic trials that revealed the protective effects of hormone replacement therapy against Alzheimer's disease included those of Tang et al (1996), Paganini-Hill and Henderson (1996), Kawas et al (1997), Baldereschi et al (1998), Waring et al (1999, Slooter et al (1999), Zandi et al (2002), Henderson et al (2005), Shao et al (2012), Imtiaz et al (2017a) and Imtiaz et al (2017b). In all the trials, the relative risks of developing Alzheimer's disease in the study participants subjected to hormone replacement therapy were less than one (<1) which indicated protective effects (these findings are presented in Table 1).…”

Section: Protective Association Between Hrt and Alzheimer's Diseasementioning

confidence: 99%

“…Other studies such as the Baltimore Longitudinal study (Kawas et al, 1997), Rochester population-based (Waring et al, 1999), Rotterdam population-based (Slooter et al, 1999), and the Multi-Institutional Research on Alzheimer's disease (Henderson et al, 2005) all revealed the protective effects of estrogen in AD after adjusting for other covariates such as age and educational status. This 'estrogen effect' could be attributed to Cholinergic mechanisms and other neuroprotective effects (Henderson, 1997).…”

Section: Protective Association Between Hrt and Alzheimer's Diseasementioning

confidence: 99%

Hormone replacement therapy and Alzheimers disease in older women: A systematic review of literature

Ibrahim¹,

Sodipo²,

Mshelia³

et al. 2018

J. Neurosci. Behav. Health

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The relationships between estrogen and cognitive functions have been explored in many experimental and observational studies with rather inconsistent outcomes. This study explored the relationship between hormone replacement therapy (estrogen-based) and Alzheimer's disease in postmenopausal women based on existing literature. A comprehensive search was conducted for relevant articles written in English language from 1990. PubMed, Medline search, Science direct and SCOPUS databases with keywords such as: 'Alzheimer's disease', 'hormone replacement therapy', 'pathogenesis of AD', 'epidemiology of AD in older women', 'biological role of oestrogen in neuroprotection', 'menopause and hormonal changes', and 'effects of HRT on cognitive functioning' were used for the search. The search strategy was based on Cochrane review recommendations and the relative risk was used to indicate the degree of relationship. A total of 898 citations were initially identified, of which 15 met the inclusion criteria for this study. Ten of the fifteen articles revealed that Estrogen Replacement Therapy (ERT) has a protective effect against Alzheimer's Disease (AD) in postmenopausal women with relative risks ranging from 0.28 -0.95 (95% C.I. = 0.08 -0.99), while the remaining five studies showed increased risk of AD in postmenopausal women exposed to ERT with relative risks ranging from 1.10 to 2.10 (95% C.I. = 0.60 -3.50). Conclusively, longstanding commencement of HRT prior to the onset of menopause might be protective against the development of Alzheimer's disease on empirical basis, but does not seem to have any therapeutic value after the onset of the disease.

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Estrogen use and early onset Alzheimer's disease: a population-based study

Cited by 117 publications

References 28 publications

Estrogen Lowers Alzheimer β-Amyloid Generation by Stimulating trans-Golgi Network Vesicle Biogenesis

Estrogen Lowers Alzheimer β-Amyloid Generation by Stimulating trans-Golgi Network Vesicle Biogenesis

Estrogen and progestogen therapy in postmenopausal women

Hormone replacement therapy and Alzheimers disease in older women: A systematic review of literature

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