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The Role of Hormone Replacement Therapy in the Prevention of Alzheimer Disease

The Role of Hormone Replacement Therapy in the Prevention of Alzheimer Disease Alzheimer disease (AD) is the most common form of dementia among the elderly. A higher prevalence of AD in women than in men suggests a link between gonadal hormone levels and AD. Increasing evidence supports a role for estrogen in brain regions involved in learning and memory and in the protection and regulation of cholinergic neurons, which degenerate in AD. Despite the lack of consensus, many studies indicate that hormone replacement therapy may decrease the risk for or delay the onset of AD in postmenopausal women. Recent trials have suggested that estrogen treatment may have no significant effect on the clinical course of AD in elderly women with the disease. Thus, the role of estrogen therapy seems to be confined to primary rather than secondary prevention of AD. Ongoing clinical studies may help to determine the role of estrogen in the cognitive function of postmenopausal women and in the prevention of AD.Alzheimer disease (AD) is a neurodegenerative disorder that progressively affects intellectual functions. Alzheimer disease is manifested primarily in the impairment of cognitive functions such as memory and language. In 2000, AD affected an estimated 2.5 million to 4.5 million Americans,resulting in a profound emotional, social, and economic burden. As life expectancy continues to increase in the United States, the delay or the prevention of this degenerative disorder will become even more pressing.Alzheimer disease is more common in women,with the prevalence of AD among women in the United States double that among men.A recent meta-analysis of 7 sex-specific studies of incidence rates for AD concluded that AD is 1.5 times more likely to develop in women than in men.These data suggest that low estrogen levels may be linked to the decline in cognitive function associated with dementia of the Alzheimer type.Decreased estrogen levels after menopause is a risk factor for AD,and neurobiological studies have found a link between estrogen and learning and memory functions.For example, low estrogen levels negatively affect the performance of rodents on learning and memory tasks, whereas administration of estrogen reverses this effect.Clinical research has focused on various roles for estrogen replacement therapy (ERT) (consisting of unopposed estrogens) and hormone replacement therapy (HRT) (consisting of estrogens in combination with a progestin): ERT/HRT in the cognitive function of healthy postmenopausal women; the effect of ERT/HRT on the cognitive decline of elderly women, some of whom have mild cognitive impairment; the link between ERT/HRT and the risk for development of AD; and the use of estrogen to treat AD.A recent meta-analysisfound that, according to most studies, ERT/HRT has beneficial effects on learning and memory in postmenopausal women and is associated with a reduced risk for AD; a handful of studies, however, did not show significant effects.In the absence of large randomized studies, no definitive evidence or consensus exists regarding the use of estrogen to prevent or to delay AD. It is also unclear whether any beneficial effects of estrogen on cognitive function occur immediately after menopause or later in life, and whether estrogen is effective in preventing the cognitive decline observed in normal aging and/or in pathological conditions. Inconsistent findings in these areas may be attributed to variations among any of the following variables: the size of the study population; the participants' ages, lifestyles, and educational levels; demographic features; the method of obtaining information about estrogen use, which may depend on participant recall; the route of administration of the hormone; the duration of the treatment; and the approach used to evaluate cognitive decline. More multicenter studies with a larger number of participants and standardized methods of diagnosis and evaluation are necessary to settle these issues.This article reviews the neuroprotective and neurotrophic effects of estrogen, focusing on brain regions involved in learning and memory. It then discusses evidence regarding the effectiveness of ERT/HRT in preventing or delaying the onset of AD and surveys the nascent research on the use of estrogen to treat the disease.MECHANISMS OF ADA number of underlying causes for the neuronal damage seen in AD have been proposed, including oxidative stress caused by free radicals, hormonal insufficiency, loss of trophic support, hypoxia, and trauma. Vascular disease, which diminishes regional cerebral blood flow, may also be a risk factor for AD.In addition, Panidis et alsuggested that nearly 30% of cases of AD are attributable to genetic factors, particularly polymorphism of apolipoprotein E (ApoE). Of the 3 types of genes for ApoE (ε2, ε3, and ε4), the ε4allele is a known risk factor for AD.The ε4allele is responsible for the production of the ApoE4 isoform, which can interact with amyloid β-protein (Aβ) to form AD-associated neuritic plaques.Autopsy findings in patients with late-onset AD show increases in Aβ deposition in patients with ApoE ε4.Early AD mainly affects brain regions involved in learning and memory, such as the entorhinal cortex and the hippocampus.The 2 main signs of the pathologic changes of AD include neuritic plaques mainly containing fibrillar Aβ, and neurofibrillary tangles composed of phosphorylated tau molecules that form paired helical filaments.Amyloid β-protein is probably produced by the metabolism of the amyloid precursor protein (APP) at the β cleavage site.Mutations of APP have been implicated in early-onset AD and can lead to aggregations of Aβ plaques early in the development of the disease.Neurofibrillary tangles, which are found in aging brains in general, may mark a phase in neuronal degeneration, since they appear where neurons have died.Neurofibrillary tangles and Aβ plaques can occur independently.Other neurotoxic agents that may play a role in the degeneration associated with AD are hydrogen peroxide, a precursor for free radicals that have also been associated with the neuronal damage seen in AD,and glutamate, the principal excitatory neurotransmitter, which may contribute to AD through excitotoxicity.Patients with AD also exhibit profound, progressive loss of cholinergic neurons in the nuclei of the basal forebrain,which project to the hippocampus and the neocortex and are essential for learning and memory.The loss of these neurons in the nuclei of the basal forebrain, and a corresponding decrease in cholinergic innervation of the hippocampal formation and the neocortex, are hallmarks of AD.Whitehouse et aldemonstrated that neurons in the nucleus basalis of Meynert, which project directly to the cerebral cortex, are decreased by as much as 80% in the brains of patients with AD or dementia of the Alzheimer type. The cortical neuronal atrophy and decline of synaptic density in the cortex and hippocampus are likely correlates of dementia.The best available marker for cholinergic neurons in the basal forebrain is choline acetyltransferase (ChAT) activity.Choline acetyltransferase synthesizes the neurotransmitter acetylcholine (ACh), which is involved in transmitting messages between the basal forebrain and the cortex, hippocampus, and amygdala.Choline acetyltransferase also inhibits the expression of acetylcholinesterase, an enzyme that is involved in the metabolism of ACh.Several studies have reported a significant decrease in ChAT activity in the postmortem brains of demented patients,and levels of ACh are 90% lower in patients with AD.EFFECTS OF ESTROGEN ON BRAIN FUNCTIONThere are multiple pathways to neuronal injury, dysfunction, and ultimately death in AD, many of which are potentially modified by estrogen. Evidence suggests that estrogen protects against various neurotoxic events and has a neurotrophic, regulatory role in the cholinergic system (Table 1).New research supports additional protective and regulatory activities of estrogen on the expression of genes associated with AD.Effects of Estrogen on Brain Regions Involved in Memory and Cognitive Function*EffectsReferences (Year)Neuroprotective effects against injuryAmyloid β-proteinJaffe et al(1994); Goodman et al(1996); Behl et al(1997); Gridley et al(1997); Keller et al(1997); Bonnefont et al(1998); Xu et al(1998); Brinton et al(2000); Thomas and Rhodin(2000); Vincent and Smith(2000)GlutamateGoodman et al(1996); Singer et al(1996); Behl et al(1997); Brinton et al(2000)Hydrogen peroxideBehl et al(1997); Brinton et al(2000)Neurotrophic effects in the basal forebrain cholinergic systemEnhances hippocampal functioningBrinton(1993); Brinton et al(1997); Gibbs et al(1997); Fader et al(1998); Luine et al(1998); Gibbs(1999); Brinton et al(2000); Newhouse et al(2001); Eberling et al(2001)Increases neuronal outgrowth and dendritic spine density in the hippocampusWoolley et al(1990); Woolley and McEwen(1993); Murphy and Segal(1996); Murphy et al(1998)Regulates cholinergic neurons in the basal forebrainLuine(1985); O'Malley et al(1987); Gibbs and Pfaff(1992); Toran-Allerand et al(1992); Miranda et al(1993); Gibbs et al(1994); McMillan et al(1996); Gibbs(1997); Gibbs(1998); Gibbs and Aggarwal(1998); Blurton-Jones et al(1999); Gibbs(2000)Effects on genes associated with ADRegulates expression of apolipoprotein ESrivastava et al(1997); Stone et al(1998); Teter et al(1999)Inhibits expression of mutant presenilin-7Mattson et al(1997)Other effectsIncreases glucose transportBishop and Simpkins(1995)Enhances regional cerebral blood flowOhkura et al(1995); Resnick et al(1998); Maki and Resnick(2000); Dubal and Wise(2001)Down-regulates the serotonin1Areceptor within the serotonin systemÖsterlund et al(2000)*AD indicates Alzheimer disease.NEUROPRO http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Internal Medicine American Medical Association

The Role of Hormone Replacement Therapy in the Prevention of Alzheimer Disease

Fillit, Howard M.
JAMA Internal Medicine , Volume 162 (17) – Sep 23, 2002
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American Medical Association
Copyright
Copyright 2002 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
ISSN
2168-6106
eISSN
2168-6114
DOI
10.1001/archinte.162.17.1934
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Abstract

Alzheimer disease (AD) is the most common form of dementia among the elderly. A higher prevalence of AD in women than in men suggests a link between gonadal hormone levels and AD. Increasing evidence supports a role for estrogen in brain regions involved in learning and memory and in the protection and regulation of cholinergic neurons, which degenerate in AD. Despite the lack of consensus, many studies indicate that hormone replacement therapy may decrease the risk for or delay the onset of AD in postmenopausal women. Recent trials have suggested that estrogen treatment may have no significant effect on the clinical course of AD in elderly women with the disease. Thus, the role of estrogen therapy seems to be confined to primary rather than secondary prevention of AD. Ongoing clinical studies may help to determine the role of estrogen in the cognitive function of postmenopausal women and in the prevention of AD.Alzheimer disease (AD) is a neurodegenerative disorder that progressively affects intellectual functions. Alzheimer disease is manifested primarily in the impairment of cognitive functions such as memory and language. In 2000, AD affected an estimated 2.5 million to 4.5 million Americans,resulting in a profound emotional, social, and economic burden. As life expectancy continues to increase in the United States, the delay or the prevention of this degenerative disorder will become even more pressing.Alzheimer disease is more common in women,with the prevalence of AD among women in the United States double that among men.A recent meta-analysis of 7 sex-specific studies of incidence rates for AD concluded that AD is 1.5 times more likely to develop in women than in men.These data suggest that low estrogen levels may be linked to the decline in cognitive function associated with dementia of the Alzheimer type.Decreased estrogen levels after menopause is a risk factor for AD,and neurobiological studies have found a link between estrogen and learning and memory functions.For example, low estrogen levels negatively affect the performance of rodents on learning and memory tasks, whereas administration of estrogen reverses this effect.Clinical research has focused on various roles for estrogen replacement therapy (ERT) (consisting of unopposed estrogens) and hormone replacement therapy (HRT) (consisting of estrogens in combination with a progestin): ERT/HRT in the cognitive function of healthy postmenopausal women; the effect of ERT/HRT on the cognitive decline of elderly women, some of whom have mild cognitive impairment; the link between ERT/HRT and the risk for development of AD; and the use of estrogen to treat AD.A recent meta-analysisfound that, according to most studies, ERT/HRT has beneficial effects on learning and memory in postmenopausal women and is associated with a reduced risk for AD; a handful of studies, however, did not show significant effects.In the absence of large randomized studies, no definitive evidence or consensus exists regarding the use of estrogen to prevent or to delay AD. It is also unclear whether any beneficial effects of estrogen on cognitive function occur immediately after menopause or later in life, and whether estrogen is effective in preventing the cognitive decline observed in normal aging and/or in pathological conditions. Inconsistent findings in these areas may be attributed to variations among any of the following variables: the size of the study population; the participants' ages, lifestyles, and educational levels; demographic features; the method of obtaining information about estrogen use, which may depend on participant recall; the route of administration of the hormone; the duration of the treatment; and the approach used to evaluate cognitive decline. More multicenter studies with a larger number of participants and standardized methods of diagnosis and evaluation are necessary to settle these issues.This article reviews the neuroprotective and neurotrophic effects of estrogen, focusing on brain regions involved in learning and memory. It then discusses evidence regarding the effectiveness of ERT/HRT in preventing or delaying the onset of AD and surveys the nascent research on the use of estrogen to treat the disease.MECHANISMS OF ADA number of underlying causes for the neuronal damage seen in AD have been proposed, including oxidative stress caused by free radicals, hormonal insufficiency, loss of trophic support, hypoxia, and trauma. Vascular disease, which diminishes regional cerebral blood flow, may also be a risk factor for AD.In addition, Panidis et alsuggested that nearly 30% of cases of AD are attributable to genetic factors, particularly polymorphism of apolipoprotein E (ApoE). Of the 3 types of genes for ApoE (ε2, ε3, and ε4), the ε4allele is a known risk factor for AD.The ε4allele is responsible for the production of the ApoE4 isoform, which can interact with amyloid β-protein (Aβ) to form AD-associated neuritic plaques.Autopsy findings in patients with late-onset AD show increases in Aβ deposition in patients with ApoE ε4.Early AD mainly affects brain regions involved in learning and memory, such as the entorhinal cortex and the hippocampus.The 2 main signs of the pathologic changes of AD include neuritic plaques mainly containing fibrillar Aβ, and neurofibrillary tangles composed of phosphorylated tau molecules that form paired helical filaments.Amyloid β-protein is probably produced by the metabolism of the amyloid precursor protein (APP) at the β cleavage site.Mutations of APP have been implicated in early-onset AD and can lead to aggregations of Aβ plaques early in the development of the disease.Neurofibrillary tangles, which are found in aging brains in general, may mark a phase in neuronal degeneration, since they appear where neurons have died.Neurofibrillary tangles and Aβ plaques can occur independently.Other neurotoxic agents that may play a role in the degeneration associated with AD are hydrogen peroxide, a precursor for free radicals that have also been associated with the neuronal damage seen in AD,and glutamate, the principal excitatory neurotransmitter, which may contribute to AD through excitotoxicity.Patients with AD also exhibit profound, progressive loss of cholinergic neurons in the nuclei of the basal forebrain,which project to the hippocampus and the neocortex and are essential for learning and memory.The loss of these neurons in the nuclei of the basal forebrain, and a corresponding decrease in cholinergic innervation of the hippocampal formation and the neocortex, are hallmarks of AD.Whitehouse et aldemonstrated that neurons in the nucleus basalis of Meynert, which project directly to the cerebral cortex, are decreased by as much as 80% in the brains of patients with AD or dementia of the Alzheimer type. The cortical neuronal atrophy and decline of synaptic density in the cortex and hippocampus are likely correlates of dementia.The best available marker for cholinergic neurons in the basal forebrain is choline acetyltransferase (ChAT) activity.Choline acetyltransferase synthesizes the neurotransmitter acetylcholine (ACh), which is involved in transmitting messages between the basal forebrain and the cortex, hippocampus, and amygdala.Choline acetyltransferase also inhibits the expression of acetylcholinesterase, an enzyme that is involved in the metabolism of ACh.Several studies have reported a significant decrease in ChAT activity in the postmortem brains of demented patients,and levels of ACh are 90% lower in patients with AD.EFFECTS OF ESTROGEN ON BRAIN FUNCTIONThere are multiple pathways to neuronal injury, dysfunction, and ultimately death in AD, many of which are potentially modified by estrogen. Evidence suggests that estrogen protects against various neurotoxic events and has a neurotrophic, regulatory role in the cholinergic system (Table 1).New research supports additional protective and regulatory activities of estrogen on the expression of genes associated with AD.Effects of Estrogen on Brain Regions Involved in Memory and Cognitive Function*EffectsReferences (Year)Neuroprotective effects against injuryAmyloid β-proteinJaffe et al(1994); Goodman et al(1996); Behl et al(1997); Gridley et al(1997); Keller et al(1997); Bonnefont et al(1998); Xu et al(1998); Brinton et al(2000); Thomas and Rhodin(2000); Vincent and Smith(2000)GlutamateGoodman et al(1996); Singer et al(1996); Behl et al(1997); Brinton et al(2000)Hydrogen peroxideBehl et al(1997); Brinton et al(2000)Neurotrophic effects in the basal forebrain cholinergic systemEnhances hippocampal functioningBrinton(1993); Brinton et al(1997); Gibbs et al(1997); Fader et al(1998); Luine et al(1998); Gibbs(1999); Brinton et al(2000); Newhouse et al(2001); Eberling et al(2001)Increases neuronal outgrowth and dendritic spine density in the hippocampusWoolley et al(1990); Woolley and McEwen(1993); Murphy and Segal(1996); Murphy et al(1998)Regulates cholinergic neurons in the basal forebrainLuine(1985); O'Malley et al(1987); Gibbs and Pfaff(1992); Toran-Allerand et al(1992); Miranda et al(1993); Gibbs et al(1994); McMillan et al(1996); Gibbs(1997); Gibbs(1998); Gibbs and Aggarwal(1998); Blurton-Jones et al(1999); Gibbs(2000)Effects on genes associated with ADRegulates expression of apolipoprotein ESrivastava et al(1997); Stone et al(1998); Teter et al(1999)Inhibits expression of mutant presenilin-7Mattson et al(1997)Other effectsIncreases glucose transportBishop and Simpkins(1995)Enhances regional cerebral blood flowOhkura et al(1995); Resnick et al(1998); Maki and Resnick(2000); Dubal and Wise(2001)Down-regulates the serotonin1Areceptor within the serotonin systemÖsterlund et al(2000)*AD indicates Alzheimer disease.NEUROPRO

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JAMA Internal Medicine – American Medical Association

Published: Sep 23, 2002

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