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Vol. 162 No. 17, September 23, 2002 |
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Review Article |
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The Role of Hormone Replacement Therapy in the Prevention of Alzheimer Disease
Howard M. Fillit, MD
Arch Intern Med. 2002;162:1934-1942.
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.
INTRODUCTION
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,1-2
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,3
with the prevalence of AD among women in the United States double that among
men.2 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.4 These data
suggest that low estrogen levels may be linked to the decline in cognitive
function associated with dementia of the Alzheimer type.5
Decreased estrogen levels after menopause is a risk factor for AD,6 and neurobiological studies have found a link between
estrogen and learning and memory functions.7-13
For example, low estrogen levels negatively affect the performance of rodents
on learning and memory tasks, whereas administration of estrogen reverses
this effect.14 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 women15-19;
the effect of ERT/HRT on the cognitive decline of elderly women, some of whom
have mild cognitive impairment20-24;
the link between ERT/HRT and the risk for development of AD25-29;
and the use of estrogen to treat AD.30-34
A recent meta-analysis35 found 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.35
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 AD
A 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.36 In addition, Panidis et al36
suggested 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 ( 2, 3,
and 4), the 4
allele is a known risk factor for AD.37-38
The 4 allele is responsible for the production
of the ApoE4 isoform, which can interact with amyloid  -protein (A)
to form AD-associated neuritic plaques.39 Autopsy
findings in patients with late-onset AD show increases in A deposition
in patients with ApoE 4.40
Early AD mainly affects brain regions involved in learning and memory,
such as the entorhinal cortex and the hippocampus.41-43
The 2 main signs of the pathologic changes of AD include neuritic plaques
mainly containing fibrillar A, and neurofibrillary tangles composed
of phosphorylated tau molecules that form paired helical filaments.36, 44-46 Amyloid -protein
is probably produced by the metabolism of the amyloid precursor protein (APP)
at the cleavage site.47 Mutations of
APP have been implicated in early-onset AD and can lead to aggregations of
A plaques early in the development of the disease.48
Neurofibrillary tangles, which are found in aging brains in general, may mark
a phase in neuronal degeneration, since they appear where neurons have died.44 Neurofibrillary tangles and A plaques can occur
independently.45 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,49-50 and glutamate,
the principal excitatory neurotransmitter, which may contribute to AD through
excitotoxicity.50
Patients with AD also exhibit profound, progressive loss of cholinergic
neurons in the nuclei of the basal forebrain,45, 51
which project to the hippocampus and the neocortex and are essential for learning
and memory.52-53 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.54-56
Whitehouse et al51 demonstrated 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.45
The best available marker for cholinergic neurons in the basal forebrain
is choline acetyltransferase (ChAT) activity.51
Choline acetyltransferase synthesizes the neurotransmitter acetylcholine (ACh),
which is involved in transmitting messages between the basal forebrain and
the cortex, hippocampus, and amygdala.36 Choline
acetyltransferase also inhibits the expression of acetylcholinesterase, an
enzyme that is involved in the metabolism of ACh.57
Several studies have reported a significant decrease in ChAT activity in the
postmortem brains of demented patients,56 and
levels of ACh are 90% lower in patients with AD.36
EFFECTS OF ESTROGEN ON BRAIN FUNCTION
There 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).12 New research supports
additional protective and regulatory activities of estrogen on the expression
of genes associated with AD.58, 65, 84-87
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Effects of Estrogen on Brain Regions Involved in Memory and Cognitive
Function*
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NEUROPROTECTIVE EFFECTS OF ESTROGEN
Although more research is needed on the specific mechanisms, recent
data from an in vitro study indicate that estrogen is highly neuroprotective
against a wide range of neurologic insults associated with AD.50
Experimental evidence further suggests that the antioxidant potency of estrogen
is inherent, independent of receptor binding.49, 94
The neuroprotective effects of estrogen against the oxidative damage and lipid
peroxidation caused by toxins could be a mechanism to explain the reduced
risk for AD seen in women using estrogen therapy.50
Estrogen is particularly effective against neuronal injury induced by
the toxins A49-50,59-62,64
and glutamate.10, 49-50
Using an animal model, Thomas and Rhodin64
recently found that low doses of conjugated equine estrogens prevented the
abnormal deposition of A in the cerebral vasculature and the adhesion
and transmigration of leukocytes that mark an inflammatory reaction, which
may have relevance for the chronic inflammation seen in AD. Estrogen has been
shown to attenuate elevated calcium levels induced by A and glutamate
and to suppress lipid peroxidation induced by iron and A.59
Xu et al63 recently found that 17-estradiol
reduced the generation of plaque-forming A by rodent and human neurons.
Estrogen may also protect neurons from A toxicity by stimulating
the proteolysis of APP.58 Jaffe and colleagues58 reported that estrogen promotes the metabolism of
APP into its nonamyloidogenic part. A more recent study of the effect of estrogen
on neuronal Swedish-mutated APP found that although estradiol increased nonamyloidogenic
APP secretion in primary cortical neurons, A production was undiminished,
possibly owing to the interference of astrocytes.65
Recent animal models of AD have also indicated a link between the excessive
expression of APP and the loss of cholinergic function seen in AD.95-97 Interactions among
estrogen, APP, and nerve growth factor have been suggested to protect against
the degeneration of cholinergic neurons,98
but more research is needed to determine the mechanisms by which estrogen
influences APP metabolism.
Estrogen also guards against intracellular hydrogen peroxide accumulation,
preventing the degeneration of primary neurons and hippocampal cells.49-50 It appears that 17-estradiol
acts directly on synapses to prevent oxidative impairment of sodium and potassium
ions in adenosine triphosphatase activity, glucose transport, and glutamate
transport.61
Finally, a recent report73 that used
magnetic resonance imaging to evaluate the effects of sex and estrogen use
on hippocampal volume in 13 elderly women taking ERT, 46 women not taking
any estrogen therapy, and 38 men found that the women taking ERT had significantly
larger right anterior hippocampal volumes than the other 2 groups. Sex did
not have a significant effect, supporting a neuroprotective effect of estrogen.
NEUROTROPHIC EFFECTS OF ESTROGEN
In addition to the neuroprotective properties, estrogen exerts trophic
and regulatory effects on basal forebrain cholinergic neurons.11
A number of studies have shown that the regulatory role of estrogen in the
basal forebrain influences hippocampal morphology and function. Luine and
colleagues70 have suggested that, in addition
to the direct effects of estrogen on the hippocampus, estrogen initiates hippocampal
effects that are mediated by areas projecting to the hippocampus. They found
that the performance of rats on spatial memory tasks, which are dependent
on hippocampal function, improved significantly after long-term estradiol
treatment; however, increases in monoaminergic and amino acid neurotransmitter
activity were seen in the frontal cortex and the basal forebrain rather than
in the hippocampus.70 These results are consistent
with those of other studies69, 71
in which administration of estradiol to ovariectomized rats improved their
performance on spatial memory tasks—in one study,71
after 3.5 and 12 months of continuous treatment—and reduced the cognitive-impairing
effects of scopolamine hydrochloride. These experimental studies were supported
by a recent randomized, placebo-controlled study72
among 15 postmenopausal women that showed that the effects of scopolamine
hydrochloride (2.5 µg/kg given as a one-time dose) were blunted in subjects
treated with 17-estradiol (1 mg/d) for 3 months. Long-term benefits
in hippocampal function may be due to the influence of short-term changes
in cholinergic activity, induced by estrogen, that project to the hippocampus,
and may help explain the reduction in the risk for and severity of AD in postmenopausal
women who have taken ERT.71
Dendritic spines, the principal loci of neuronal interactions and communication
in the central nervous system, are among the central targets of the mechanisms
of action of estrogen. A dramatic decrease in dendritic spine density has
been observed in the ventromedial hypothalamic neurons of ovariectomized rats
that was reversed by administering estrogen.99
This is consistent with findings that the density of synapses and synaptic
spines fluctuates during the estrous cycle, increasing in response to estrogen.7-8 More recent studies9, 13
on rat hippocampal neurons in culture have confirmed that estrogen plays a
critical role in a process that yields a 2-fold increase in dendritic spine
density. This process may be mediated by brain-derived neurotrophic factor;
however, the effects of estrogen on brain-derived neurotrophic factor regulation
in this brain region are not yet fully understood.13, 100
The functional consequence of increased dendritic spine density is reflected
in the improvement of rodent performance in behaviors related to hippocampal
function. Estrogen enhances the induction of long-term potentiation in awake
animals, a model of synaptic plasticity in the hippocampus with potential
relevance to learning and associative memory.101
Evidence of the local effects of estrogen in the hippocampus and the
neocortex has also been established. Estrogen appears to interact closely
with neurotrophins, which also promote neuronal growth and block apoptosis,
in the basal forebrain. In the 1980s, O'Malley and colleagues74
proposed that estrogen modulated the production, release, and uptake of ACh
by cholinergic neurons. Administering estrogen to ovariectomized rats induced
the potassium-evoked release of ACh,68 which
is inhibited by A,102 in the hippocampus
and the overlying cortex. The enhanced release of ACh in these areas is reflected
in direct, trophic effects of estrogen on hippocampal neurons. Brinton66 reported filopodial growth in hippocampal neurons
within 5 minutes of exposure to 17-estradiol, and has since demonstrated
with others significantly increased hippocampal and neocortical neurite outgrowth,
viability, and survival after exposure to 17-estradiol and conjugated
equine estrogens.50, 67 Effective
protection of rodent neuronal cells in vitro from toxic complexes formed by
the combination of acetylcholinesterase and A by 17-estradiol
has also been demonstrated.62
Estradiol was also found to increase ChAT activity in certain basal
forebrain cholinergic nuclei in female rats.57
A recent study, however, reported that although the administration of estradiol
increased ChAT expression and high-affinity choline uptake in the cholinergic
system of ovariectomized rats after 2 weeks, no changes were found after 4
weeks of continuous or repeated estrogen treatment.83
Furthermore, continuous estrogen therapy administered for 13 months led to
a decrease in high-affinity choline uptake, especially in the hippocampus.83 Although these findings indicate that enhancement
of cholinergic function by estrogen may be short-term, other data show that
4 weeks of estrogen treatment in rats produces consistent decreases in levels
of the low-affinity nerve growth factor receptor p75NGFR, an effect
of increased ChAT levels that plays a crucial role in regulating cholinergic
activity.80
Toran-Allerand and colleagues103 consider
estrogen to be a neuronal growth factor that shares many characteristics of
neurotrophins, enabling convergence of estrogen- and neurotrophin-signaling
pathways. The decline of gonadal steroid levels in both sexes with aging may
thus contribute to the loss of neuronal systems integral to cognitive function.103
EFFECTS OF ESTROGEN ON GENES ASSOCIATED WITH AD
Recent studies have investigated the effects of estrogen on the expression
of ApoE4. Estradiol up-regulated ApoE gene expression by increasing levels
of ApoE messenger RNA in an animal model of AD84;
in a similar animal model, estradiol enhanced synaptogenesis, possibly through
an ApoE-dependent mechanism.85 Teter and colleagues86 have recently confirmed these findings by studying
the interaction of ApoE and estrogen in mouse hippocampal slice cultures.
Neuronal sprouting increased in ApoE-dependent areas, possibly as a consequence
of the up-regulation by estrogen of ApoE expression to enable the recycling
of membrane lipids for use by sprouting neurons.86
A population-based case-control study investigating a possible link between
estrogen and early-onset AD, which included 53% ApoE 3/4 or ApoE 4/4 carriers, found a
stronger inverse correlation between estrogen use and early-onset AD in this
group (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.08-1.58) than
in women with the ApoE3 3/3 genotype
(OR, 0.60; 95% CI, 0.19-1.88).104 However,
another study found no reduction in the risk for cognitive decline among women
with the ApoE 4 allele who used ERT/HRT, although
hormone users without the ApoE 4 allele exhibited
less cognitive decline.38 Moreover, Lendon
and Lambert105 recently reported that estrogen
enhanced expression of the 4 allele. The possible
mechanisms involved in the interaction of estrogen and ApoE are the subject
of ongoing research.
Mattson et al87 have shown that 17-estradiol
blocks the expression of mutant presenilin-1, a proapoptotic gene linked to
early-onset AD that was found in a study of transgenic mice to have a synergistic
effect with mutated APP, leading to decreased cholinergic function.96 In conjunction with findings that 17-estradiol
protects neurons against nip-2, another gene that
promotes cell death,106 this research suggests
a direct, receptor-independent role for estrogen in preventing neuronal loss
associated with AD. More specifically, 17-estradiol delayed cellular
glucose deprivation induced by nip-2106
through a mechanism that may have relevance to AD, since glucose transport
and metabolism are diminished in the disease.107
In their study of the antiapoptotic action of estrogen, Mattson and colleagues87 found an additional protective capacity of 17-estradiol
to stabilize mitochondrial function.
OTHER EFFECTS OF ESTROGEN ON THE BRAIN
Studies of cognitive function in individuals have established that,
during memory processing, estrogen increases glucose transport88
and regional cerebral blood flow,89-91
which are decreased in AD. Recently, Maki and Resnick91
examined longitudinal changes in regional cerebral blood flow in 12 ERT/HRT
users and 16 nonusers during the performance of verbal and figural recognition
memory tasks. In addition to obtaining higher scores than nonusers on a battery
of standardized memory tests, the ERT/HRT users exhibited enhanced regional
cerebral blood flow in the hippocampus, the parahippocampal gyrus, and the
temporal lobe, regions fundamental to memory function that can reveal preclinical
abnormalities in individuals at risk for AD. These results were similar to
those found in 2 earlier studies,89-90
suggesting a key mechanism through which ERT/HRT may decrease the risk for
AD. In their recent comparison of the effect of estradiol on middle-aged and
young female rats, Dubal and Wise92 suggested
that estrogen achieves neuroprotective effects by modulating regional blood
flow, which may be maintained after menopause by ERT.
In summary, numerous studies confirm that estrogen exerts a wide range
of neuroprotective and neurotrophic influences on brain regions and neuronal
subtypes involved in memory and cognitive function that are negatively affected
by AD. These studies have provided the basis for investigations of the effects
of estrogen on cognitive impairment in the course of normal as well as pathologic
aging of postmenopausal women.
ERT/HRT AND THE RISK FOR AND ONSET OF AD
As mentioned earlier, AD is more likely to develop in women older than
65 years than in their male counterparts,3-4
possibly due to reduced estrogen levels.5 The
association between ERT/HRT and the risk for AD remains controversial, although
most investigations suggest that ERT/HRT reduces the risk for AD (Figure 1). A recent meta-analysis35 of 14 studies reported an OR of 0.56 (95% CI, 0.46-0.68)
for the relative risk for the development of AD. The results of the studies
analyzed were heterogeneous, and poor recall of ERT/HRT use may have confounded
the results. A major 1998 meta-analysis116
of the effect of ERT/HRT on the risk for the development of AD in postmenopausal
women, which examined 8 case-control studies6, 108-114
and 2 prospective cohort studies,26, 115
reported a summary OR of 0.71 (95% CI, 0.52-0.98) for the development of dementia
among estrogen users. Both prospective cohort studies and 1 case-control study113 reported a significantly lower risk for dementia
in women who had ever used estrogen. Of the remaining studies, 3 reported
no significant increase among estrogen users,6, 110, 114
2 reported no difference in risk,112-113
and 2 found no significant increased risk for dementia among estrogen users
compared with nonusers.108-109
Because of significant heterogeneity in the findings, which may be attributable
to study design, a separate analysis was performed of the 2 study types. The
summary OR for the case-control studies was 0.80 (95% CI, 0.56-1.16) for diagnosis
of AD; for the prospective studies, the summary OR was 0.48 (95% CI, 0.29-0.81).
The 3 studies that investigated the relationship between the duration of estrogen
use and protection against dementia found inconsistent results,6, 26, 115
although in a follow-up investigation of their earlier study, Paganini-Hill
and Henderson25 found a decreased risk among
long-term users of ERT.
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Odds ratios (squares) and 95% confidence intervals (horizontal lines)
from studies of the risk for the development of Alzheimer disease among postmenopausal
women using estrogen therapy. Adapted with permission from Yaffe et al.116
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As the authors point out, observational studies are prone to confounding
and compliance bias, which may influence their assessment for the risk of
development of AD. In addition, despite the fact that HRT is prescribed more
commonly than unopposed ERT in the United States, none of these studies included
a significant proportion of HRT users. Two studies from the meta-analysis,
however, merit more detailed consideration. The population-based investigations
of Paganini-Hill and Henderson,6, 25
which show a decreased risk for AD with estrogen treatment, included a cohort
of 8877 women and the completion of health surveys by the individuals rather
than by proxy informants, an approach that provides more accurate data about
the use of estrogen. The risk for AD was found to be 35% lower in estrogen
users.25 Tang and colleagues26
followed up 1124 older women for 1 to 5 years and identified 167 incident
cases of AD. The risk for AD was reduced by 50% among subjects who had used
estrogen (OR adjusted for education, ethnicity, and ApoE genotype). A direct
relationship between the duration of hormone treatment and the risk for AD
was also reported; the risk was lower among women who had used estrogen for
1 to 5 years than among subjects who had used estrogen for 1 year or less.
When demented patients who had used and those who had never used estrogen
were compared, the age of AD onset was significantly delayed among estrogen
users.
One of the 2 case-control studies in the 1998 meta-analysis116 that reported no difference in risk111-112
raised the possibility that the route of administration may influence whether
estrogen protects against AD. Brenner and colleagues112
compared the use of estrogen in 107 cases with AD and 120 age-matched control
subjects and found no association between the use of estrogen and the risk
for AD. However, the point estimate for AD was decreased by 30% when the results
were analyzed for intake of oral estrogen alone. In contrast to these findings,
the decrease in the risk for AD did not depend on the route of estrogen intake
in the study by Paganini-Hill and Henderson.6
Two population-based, case-control studies published after the 1998
meta-analysis report conflicting findings. Results from a study by Waring
and colleagues28 regarding the use of ERT/HRT
and the risk for development of AD are consistent with the findings from Tang
and associates.26 Among 222 women from the
Rochester Epidemiology Project records-linkage system who were diagnosed as
having AD from 1980 to 1984, the frequency of estrogen use was half that of
the age-matched control group (n = 222) at 10% vs 5% (OR, 0.42; 95% CI, 0.18-0.96).
In contrast, a nested case-control study by Seshadri et al29
found no reduced risk for development of AD among current ERT/HRT users. Starting
with a large base cohort (n = 221 406) from the General Practice Research
Database in the United Kingdom, 59 women were verified as having a new diagnosis
of AD from 1992 to 1998 and matched to 221 controls. Fifteen (25%) of the
59 cases and 53 (24%) of the 221 controls were current hormone users, yielding
an OR of 1.18 (95% CI, 0.59-2.37) for the risk for development of AD among
current ERT/HRT users. The inconsistency in findings between these 2 studies
indicates that this issue remains unresolved pending results from further
studies.
Two recent studies suggest that ERT/HRT use is associated with a reduced
risk for development of AD, but both have limitations due to study methods.
Baldereschi and colleagues27 used results of
the Mini-Mental State Examination for an initial screen in 2816 Italian women
aged 65 to 84 years; those with positive findings underwent clinical assessment
for dementia and AD. The frequency of hormone use was significantly higher
among nondemented patients than those with AD after adjustment for age, education,
age at menarche, age at menopause, cigarette and alcohol use, body weight
at 50 years of age, and number of children (OR 0.28; 95% CI, 0.08-0.98). These
findings were prone to recall bias regarding the elderly subjects' use of
estrogen, especially among those who were cognitively impaired, although next
of kin were questioned in these cases. In a longitudinal study of 3128 women
who were outpatients at the California State Alzheimer's Disease Diagnostic
and Treatment Centers, hormone users had significantly lower rates of diagnosis
of AD at baseline and after 1 year, compared with nonusers.117
Moreover, patients who had not used estrogen showed increased cognitive deterioration
from baseline to follow-up, whereas no significant change in cognitive function
occurred among the estrogen users during this period. However, no significant
difference was found between the performance of estrogen users and nonusers
who had been diagnosed as having AD at baseline. Complete follow-up data were
available for only a very small number (n = 16) of hormone users; nevertheless,
these data suggest that estrogen may protect against cognitive decline in
the earlier stages.
A recent population-based study in the Netherlands was, to our knowledge,
the first to examine the effect of estrogen use on the risk for early-onset
AD. In comparing patients with AD (n = 109) with age- and residence-matched
controls (n = 119), Slooter and colleagues104
found a significant inverse correlation between estrogen treatment and early-onset
AD (adjusted OR, 0.34; 95% CI, 0.12-0.94), suggesting that more research is
needed in this specific area.
TREATMENT OF AD WITH ESTROGEN
Despite the significant neuroprotective and neurotrophic effect of estrogen,
particularly in vitro, described already, human studies of the effect of estrogen
as therapy for AD have been equivocal.5, 30-35
Some studies, primarily short-term ones, have suggested that estrogen use
results in short-term improvements in cognition.30-33,118-119
In contrast, 3 recent randomized, double-blind clinical trials analyzing the
effects of estrogen on the clinical course of AD found no significant benefit
with estrogen treatment.34, 120-121
These findings may be surprising in view of the increasing evidence showing
protective benefits of estrogen on neurons involved in learning and memory
and studies showing a significantly reduced risk for AD among women using
ERT or HRT. However, an agent that reduces the risk for AD will not necessarily
influence the clinical course of the disease once it is established, since
the mechanisms involved may be different. The administration of estrogen after
neuronal injury has been initiated or has progressed (eg, after AD is expressed)
may have no benefit, but estrogen may protect neurons at the initial phases
or before the onset of the disease.
Thus, the initial timing of hormone treatment may be crucial. In the
study by Mulnard and colleagues,34 ERT was
not initiated immediately after hysterectomy, and the subjects were older
than 60 years. The mean ages were 77 years for the estrogen group and 78 years
for the placebo group in the study by Henderson et al120
and 73 years for the estrogen group and 71 years for the placebo group in
the study by Wang et al.121 Estrogen may be
most effective as a preventive agent immediately or shortly after menopause.
Using an animal model, Gibbs122 determined
that estrogen treatment initiated immediately after or 3 months after ovariectomy—but
not after 10 months—improved performance on a spatial memory task. This
research suggests that a key window of opportunity for the initiation of hormone
treatment in the prevention of cognitive decline in humans may exist, a hypothesis
that warrants further investigation. This situation is somewhat analogous
to the prevention of osteoporosis, ie, the earlier estrogen treatment is initiated
after menopause, the more beneficial its effect, since bone that is already
lost cannot be replaced to any significant degree.123
Because the prevalence of osteoporosis rises dramatically with age, early
intervention is necessary to forestall bone loss as long as possible.
CONCLUSIONS
Evidence supports a central role for estrogen in brain regions involved
in memory and other cognitive tasks and in protection from AD-associated toxins
and genes. A number of observational studies have suggested a significantly
reduced risk for development of AD among women who have used ERT/HRT. The
Women's Health Initiative Study of Cognitive Aging, a randomized, placebo-controlled
trial among 2900 women that will assess cognitive outcomes with ERT/HRT use,
is expected to provide substantial evidence regarding the influence of estrogen-based
therapy on cognition and AD. That study is ancillary to the Women's Health
Initiative Memory Study, which in turn is an arm of the Women's Health Initiative
that is sponsored by the National Institutes of Health, Bethesda, Md. The
Women's Health Initiative Memory Study will investigate the effect of conjugated
equine estrogens on cognitive function and on the risk for the development
of AD and other dementia among more than 8000 postmenopausal women, with a
minimum follow-up of 6 years.50, 124
The Women's International Study of Long-Duration Oestrogen After the Menopause,
also under way, is not due to report results until 2010.125
These large clinical studies will provide valuable information regarding the
potential effects of ERT/HRT on preserving cognitive function in postmenopausal
women.
At present, most observational evidence, which is supported by neurobiological
research findings on the action of estrogen, indicates that ERT/HRT mitigates
the degeneration that may lead to AD. The lack of evidence of a role of estrogen
in the treatment of AD suggests that ERT/HRT should be initiated as early
as possible after menopause, before the onset or the progression of the disease.
Thus, the relationship of postmenopausal hormone therapy to AD is somewhat
parallel to its relationship to osteoporosis in that, in both cases, ERT/HRT
seems to have a role in primary prevention.
AUTHOR INFORMATION
Accepted for publication February 6, 2002.
Corresponding author and reprints: Howard M. Fillit, MD, The Institute
for the Study of Aging, Inc, 767 Fifth Ave, Suite 4600, New York, NY 10153
(e-mail: hfillit{at}rslmgmt.com).
From The Institute for the Study of Aging, Inc, New York, NY.
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Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women
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Copper Perturbation in 2 Monozygotic Twins Discordant for Degree of Cognitive Impairment
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Changes in endometrial blood vessels in the endometrium of women with hormone replacement therapy-related irregular bleeding
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Management of Alzheimer's Disease
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