Context Previous studies have shown a sex-specific increased risk of Alzheimer
disease (AD) in women older than 80 years. Basic neuroscience findings suggest
that hormone replacement therapy (HRT) could reduce a woman's risk of AD.
Epidemiologic findings on AD and HRT are mixed.
Objective To examine the relationship between use of HRT and risk of AD among
Design, Setting, and Participants Prospective study of incident dementia among 1357 men (mean age, 73.2
years) and 1889 women (mean age, 74.5 years) residing in a single county in
Utah. Participants were first assessed in 1995-1997, with follow-up conducted
in 1998-2000. History of women's current and former use of HRT, as well as
of calcium and multivitamin supplements, was ascertained at the initial contact.
Main Outcome Measure Diagnosis of incident AD.
Results Thirty-five men (2.6%) and 88 women (4.7%) developed AD between the
initial interview and time of the follow-up (3 years). Incidence among women
increased after age 80 years and exceeded the risk among men of similar age
(adjusted hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.22-3.86).
Women who used HRT had a reduced risk of AD (26 cases among 1066 women) compared
with non-HRT users (58 cases among 800 women) (adjusted HR, 0.59; 95% CI,
0.36-0.96). Risk varied with duration of HRT use, so that a woman's sex-specific
increase in risk disappeared entirely with more than 10 years of treatment
(7 cases among 427 women). Adjusted HRs were 0.41 (95% CI, 0.17-0.86) for
HRT users compared with nonusers and 0.77 (95% CI, 0.31-1.67) compared with
men. No similar effect was seen with calcium or multivitamin use. Almost all
of the HRT-related reduction in incidence reflected former use of HRT (9 cases
among 490 women; adjusted HR, 0.33 [95% CI, 0.15-0.65]). There was no effect
with current HRT use (17 cases among 576 women; adjusted HR, 1.08 [95% CI,
0.59-1.91]) unless duration of treatment exceeded 10 years (6 cases among
344 women; adjusted HR, 0.55 [95% CI, 0.21-1.23]).
Conclusions Prior HRT use is associated with reduced risk of AD, but there is no
apparent benefit with current HRT use unless such use has exceeded 10 years.
Compared with men, women appear to be at increased risk of Alzheimer
disease (AD) after ages 80 to 85 years.1-3 Postmenopausal
depletion of endogenous estrogens may contribute to this risk. Estrogens may
exert several neuroprotective effects on the aging brain, including inhibition
of β-amyloid formation, stimulation of cholinergic activity, reduction
of oxidative stress-related cell damage, and protection against vascular risks.4
Several studies have examined whether hormone replacement therapy (HRT)
is associated with reduced risk of AD in older women. Early case-control study
results of this association were mixed.5-13 One
such study reported no relation of AD and HRT ascertained from pharmacy records
within a 10-year period of observation.14 Another
study using prescription records showed an inverse relation of AD with lifetime
HRT use.15 Two prospective studies16,17 suggested a benefit of lifetime HRT
use, but the most recent study,18 conducted
using the UK General Practice Research Database, showed no relation of AD
to HRT prescriptions within a 10-year period of observation. Thus, the relationship
of HRT and AD remains uncertain.
In the large Cache County cohort,3 we
analyzed prospective data on the association of HRT and AD in elderly women.
We examined whether a reduction in risk with HRT, if any, varied with the
number of ∊4 alleles at APOE, the polymorphic
genetic locus for apolipoprotein E. Finally, we assessed whether apparent
benefits with HRT varied in relation to duration and recency of exposure.
The Cache County Study is a longitudinal investigation of the prevalence
and incidence of AD and other dementias in relation to genetic and environmental
risk factors. Details of the study protocol have been published previously.3,19 Briefly, between 1995-1997 we used
a multistage screening and assessment protocol (wave I) to diagnose cases
of dementia among 5677 elderly residents of Cache County, Utah. More than
97% of the 5092 initial participants (90% of those aged ≥65 years, including
2928 women) provided buccal DNA for genotyping at APOE.
Three years later, between 1998-2000, we used similar procedures to diagnose
new cases of dementia (wave II) among the surviving at-risk population of
4119 (2401 women).3 Essentials of the screening
procedures and study protocol are shown in Figure 1.
Participants were screened with the Modified Mini-Mental State examination
(3MS)20 or, for those unable to participate,
an informant questionnarie21 followed by the
Dementia Questionnaire (DQ)22 administered
to collateral informants (spouses, companions, or others knowledgeable about
the respondents). Participants with screening results suggesting a cognitive
disturbance then underwent a clinical assessment. Collateral informants provided
a medical history, a dementia symptom checklist, and a chronological history
of cognitive symptoms; specially trained nurses conducted a structured neurological
examination; and psychometric technicians administered a 1-hour battery of
neuropsychological tests. A geriatric psychiatrist and neuropsychologist then
reviewed the results and assigned working diagnoses of dementia (Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria) or other cognitive syndromes; 83.9% of these subjects still
living were then examined by a board-certified geriatric psychiatrist, and
among these, 65.9% underwent routine laboratory diagnostic testing for differential
diagnosis. All this information was then considered by a panel of experts,
who identified dementia and assigned diagnoses of AD23 and
other disorders using standard criteria.
Among all study participants, we identified 152 individuals (98 women,
54 men) with incident dementia. To these we added 33 individuals (25 women,
8 men) who had an onset of dementia detected in the later stages of wave I
(before the start of wave II), yielding a total of 185 incident cases (123
women, 62 men). The estimated sensitivity of the screening protocol for detection
of incident dementia was 89% (K. Hayden et al, unpublished data, 2002). Of
the women with incident dementia, 88 had diagnoses of definite, probable,
or possible AD.23 A second diagnosis of another
dementing illness was entered for 12 of these AD cases. Of the 62 men with
incident dementia, 35 had an AD diagnosis, 8 of these with another dementing
illness. A comparison with neuropathological findings in 54 individuals suggested
that the accuracy of our AD diagnoses is similar to typical rates reported
from university AD clinics (eg, positive predictive value, 90%; B. Plassman
et al, unpublished data, 2002). Another 1801 women completed the wave II study
procedures sufficiently to assess their cognitive status and were found to
be free of dementia. Of these, 298 underwent all stages of evaluation, including
clinical assessment; the other 1503 showed no evidence of dementia on screening
measures and were not further evaluated. Unaffected men numbered 1322, of
whom 249 completed a clinical assessment.
The initial wave I interview provided 2 sources of information on HRT.
Women were asked if they had ever taken HRT and, if so, for how long. They
were also asked about use over the prior 2 weeks of any medicines, including
HRT. Interviewers then viewed these current medications and recorded the name,
dose, and usage indication for each. Although 18 women developed incident
AD within 30 months of their wave I interviews, none appeared to have substantial
cognitive impairment when interviewed, and all therefore provided their own
We first classified HRT according to report of lifetime use, categorizing
participants as "exposed" if they endorsed ever having taken HRT or if HRT
was among their current medicines. Complete data for HRT exposure were available
from 1866 (98.8%) of the 1889 women. Omitting 10 HRT users (1%) who did not
report their duration of use, we classified exposures into duration strata
of less than 3 years, 3 to 10 years, and more than 10 years. Finally, we classified
exposed women as current vs former users, the latter being individuals who
endorsed HRT exposure at some point but did not have HRT among their current
medicines. Among the current HRT users, 72% were taking an unopposed oral
We compared characteristics of HRT users and nonusers using χ2 tests for categorical variables and 2-sample t tests
for continuous measures. We then used discrete-time survival analysis24 to compare risks of incident AD among HRT users and
reference groups of nonusers and of men. We considered each year under observation
as a discrete time interval. Participants entered the analytic pool at the
age of their wave I interview and were then considered year by year until
they either developed AD or underwent wave II screening. Hazard ratios (HRs)
were estimated by odds ratios in logistic models that accommodated multiple
We fit a series of models that were built on a "base model" for AD incidence
that had previously yielded a good fit to the data for both men and women.3 That model included terms for age, age-squared, and
years of education, as well as dummy-coded terms for the presence of 1 or
2 APOE ∊4 alleles, and interactions between
age and the APOE ∊4 terms. It also included
terms for sex and its statistical interaction with age, but the current analyses
that considered only women omitted those terms. We fit the discrete-time logistic
models using SAS version 8 software (SAS Institute Inc, Cary, NC) and report
parameter estimates with 95% profile likelihood confidence intervals (CIs).
Table 1 presents the characteristics
of the current analytic sample of men and women, the latter categorized by
HRT use. Missing data on HRT use were relatively rare; women who did not provide
this information tended to be older and slightly less educated than women
who did. There were 411 living women who did not participate in the initial
assessment of wave II; they were less likely to report HRT use (P<.001) and had lower 3MS scores (P<.001)
at baseline than participating women. Among the remainder, 1066 women (56.4%)
reported use of HRT at any time, with a mean exposure duration of 11.6 years.
These users were significantly younger and more educated than nonusers.
Between the initial interview and the follow-up procedures (3 years),
35 men (2.6%) and 88 women (4.7%) developed AD. Univariate analyses suggested
that AD was significantly more common for women than for men (χ21 = 9.37, P = .002), but less common
among women with a history of HRT compared with nonusers (χ21 = 24.62, P<.001). Similarly, unadjusted
estimates of the hazard for AD (Table 2, models 1 and 2) were significantly higher for women than for men,
but were lower among women who reported HRT use than a reference group of
We next constructed a series of multiple discrete-time logistic models
that included the covariates of the base model3 (Figure 2A and the remainder of Table 2 and Table 3). Figure 2A shows AD incidence modeled for
men and women with 13 years of education (the sample median) and no ∊4
alleles at APOE (the most numerous group). The hazard
for men and for women appears roughly equal until age 80 years, but the base
model's significant sex-by-age interaction term3 implies
a substantial added risk for women after this age. This risk is indicated
by an adjusted HR of 2.11 (95% CI, 1.22-3.86) among women vs men older than
We next estimated the modification in women's risk with HRT after controlling
for the covariate terms of the base model (Table 2, model 3). Comparing this adjusted estimate with the unadjusted
figure (model 2) showed only a slight shift of the HR toward the null. The
adjusted estimate did not change appreciably (results not shown) when we added
terms separately for co-morbid conditions including diabetes mellitus, cardiovascular
disease, and depression, as well as for the use of nonsteroidal anti-inflammatory
drugs (NSAIDs).25 To investigate whether the
apparent reduction in AD risk among HRT users might simply reflect their tendency
toward a healthy lifestyle, we also added terms post hoc for use of multivitamins
and of calcium supplements (both obtained at the initial wave I interview)
as plausible indicators of such a tendency. Model 4 shows that neither of
these terms was significantly associated with risk of AD. Their inclusion
as covariates also yielded no appreciable change in the point estimate of
the relative hazard among HRT users. To examine whether the HRT effect varied
with age or with number of APOE ∊4 alleles,
we added terms to model 3 for interactions between HRT and these covariates.
Lack of an apparent interaction between HRT and age (model 5) suggested that
the effect with HRT did not vary over the life span. The interactions between
HRT and presence of 1 or 2 APOE ∊4 alleles also
failed to reach statistical significance (model 6), although there was some
suggestion that risk reduction with HRT may be greater in women with 2 ∊4
alleles (P = .19).
Table 3 shows variation
in the apparent HRT effect with duration and recency of exposure. We first
examined risk estimates among the 3 categories of usage duration (model 7).
Longer duration was associated with greater reduction in risk of AD. Figure 2B shows this graphically, depicting
the age-specific hazards modeled for women with no APOE ∊4 alleles and 13 years of education; Figure 2B also shows the risk for men with these same characteristics.
The increased hazard of AD among women vs men in late old age is again apparent.
The added risk for women appears greatest for those with no reported use of
HRT. This sex-specific risk was attenuated, however, with increasing years
of HRT exposure. The estimated hazard for women who had used HRT for more
than 10 years was similar to that for men (vs men, adjusted HR, 0.77; 95%
Model 8 shows risk estimates for women with HRT use after separation
of current and former users. Compared with nonusers, only former users showed
significantly reduced risk. Partitioning as before into 3 categories of usage
duration (model 9), we observed an incremental reduction in apparent risk
for former users with longer history of use. Former users with more than 10
years of exposure had an estimated 5-fold lower risk of AD. Among current
users, however, there was no suggestion of reduced risk with 10 or fewer years
of exposure, and only a modest reduction thereafter among 344 women.
These findings extend those of 2 previous prospective studies16,17 and provide new evidence to suggest
a protective effect of HRT. As in the previous studies, the adjusted risk
of incident AD among lifetime HRT users was reduced to little more than half
that among nonusers. This effect appeared to be stronger among women with
2 ∊4 alleles at APOE, but given the small numbers
available, the interpretation of this finding is uncertain. One previous prospective
study examined the effects with HRT across APOE genotypes,
suggesting a slightly greater apparent effect with HRT in women who had 1
∊4 allele.16 Only half the sample in that
study had been genotyped at APOE, however, and none
of the 9 women with 2 ∊4 alleles in that study had ever used HRT.
We observed a distinct relation between AD risk and duration of HRT
use. Two previous studies reported a similar result on dichotomizing duration
at 1 year of use.10,16 We observed
considerably stronger effects with longer duration of usage. Compared with
nonusers, Cache County women who had used HRT for more than 10 years experienced
2.5-fold lower incidence, comparable with the risk observed in men. Others
have speculated that the lower rates in older men may reflect their greater
availability of circulating testosterone, which may be converted in the central
nervous system by aromatase to estradiol.26 Taken
to their logical conclusion, our findings suggest that if women were to use
long-term postmenopausal HRT, their excess risk of AD over that of men in
late old age might disappear.
A new finding in this study is an apparent limited window of time during
which sustained HRT exposure seems to reduce the risk of AD. We found that,
in contrast with earlier use, HRT exposures within 10 years of AD onset yielded
little, if any, apparent benefit. These results are in accord with prior findings
of reduced cognitive decline in elderly women who initiated HRT at menopause,
but not in those with more recent exposures.27 In
fact, our results and those of all prior observational studies are consonant
with a loss of HRT effect from exposures near the onset of dementia. A similar
finding was reported recently for NSAIDs.28 The
results with both HRT and NSAIDs suggest that potentially neuroprotective
agents may be useful only in the latent pathogenetic stages of AD, before
there is extensive damage to the integrity of the brain. Limitation of the
benefit of HRT to the latent stages of AD is also consistent with recent randomized
treatment trials that suggest HRT is not effective in mitigating the progression
of cognitive decline in women with established AD.29-31
Some have suggested that HRT may be most beneficial at menopause, when
a precipitous depletion of endogenous estrogens may have greatest deleterious
effect on neurons.30 We were unable to test
this hypothesis directly, but our findings are consistent with it: many women
who had used HRT for more than 10 years before our wave I interview would
likely have been exposed many years prior to the time when they became vulnerable
to the onset of dementia. Furthermore, we found a reduced risk with HRT among
former users but not among current users unless the latter had used HRT for
more than 10 years. This last observation may explain the contrast in the
findings of the 2 prior prospective studies16,17 with
those of 2 well-designed case-control studies that evaluated the relation
of AD onset to prescription records within a 10-year interval.14,18
Our study capitalized on several characteristics of the Cache County
population. Its residents are well educated and relatively homogeneous in
their sociodemographic characteristics, including their tendency toward healthy
lifestyles. They offer high response rates in research, and they enjoy remarkably
long lives. Consequently, the current study may be less susceptible than some
to response or healthy user biases. Further, we attempted to control for the
latter bias in our analyses by testing a model with terms for multivitamin
and calcium supplement use. Only those who took HRT showed a significantly
reduced risk of AD.
Among potential limitations, the unusual sociocultural attributes of
the Cache County sample may suggest a lack of generalizability of our findings
to other populations, although this is less worrisome with biological measures
than with social or cultural ones. Another potential limitation is that we
observed a relatively short period of follow-up between wave I and wave II.
A common difficulty in pharmaco-epidemiologic studies is incomplete
recall of drug exposures. Faulty recall that is not related to the later occurrence
of incident AD (nondifferential exposure misclassification) would reduce the observed strength of any real association between
HRT and incident AD. Of greater concern is biased recall, in which exposures
are underreported by women who are destined subsequently to develop AD (differential exposure misclassification). This form of
bias may be of particular concern for the 18 women whose AD was detected in
the later stages of wave I. However, the threat of incomplete recall should
be lower with HRT than with most other medicines, because the use of HRT after
menopause is a major life decision for most women, almost always made in consultation
with a physician. Furthermore, because HRT is typically used for several years,
it is less likely to be forgotten than other, more transient drug exposures.
Also, regarding possible differential or biased recall, we found no relationship
between AD incidence and recollection of several other control exposures,
including calcium and multivitamin supplements. It seems unlikely that women
who later develop dementia would selectively forget their carefully considered
decision to use HRT, but would accurately recall their use of these other
An important limitation of this and all other observational studies
is unsuspected confounding. We cannot exclude the possibility that HRT users
differ from nonusers in other attributes related to health in general and
to AD in particular. Specifically, we considered whether current HRT users
of short duration might have initiated use because they were concerned about
mild (possibly prodromal) memory difficulties and had learned of other recent
evidence for possible neuroprotective benefits of HRT. We discount this possibility,
however, because all current users were taking oral estrogen preparations,
available only by prescription. Numerous conversations over several years
with the county's physicians failed to reveal any practitioner prescribing
HRT for this indication. Nonetheless, the only way definitively to avoid this
sort of difficulty is to conduct large-scale randomized prevention trials.
Two such trials are currently in progress.30,32 Our
observations suggest that the benefits of HRT, if any, may take years to appear,
and a considerable latency period may intervene between treatment and perceptible
effect. Thus, caution would be in order when interpreting null or disappointing
early trial results. Our findings, along with other recent work, suggest that
HRT may be effective for the primary prevention of AD—if not for its
treatment—and that patience in awaiting definitive trial results is
Andersen K, Launer LJ, Dewey ME.
et al. for the EURODEM Incidence Research Group. Gender differences in the incidence of AD and vascular dementia: the
EURODEM Studies. Neurology.1999;53:1992-1997.Google Scholar
Fratiglioni L, Viitanen M, von Strauss E.
et al. Very old women at highest risk of dementia and Alzheimer's disease:
incidence data from the Kungsholmen Project, Stockholm. Neurology.1997;48:132-138.Google Scholar
Miech RA, Breitner JC, Zandi PP, Khachaturian AS, Anthony JC, Mayer L. Incidence of AD may decline in the early 90s for men, later for women:
the Cache County Study. Neurology.2002;58:209-218.Google Scholar
Skoog I, Gustafson D. HRT and dementia. J Epidemiol Biostat.1999;4:227-251.Google Scholar
Heyman A, Wilkinson WE, Stafford JA.
et al. Alzheimer's disease: a study of epidemiological aspects. Ann Neurol.1984;15:335-341.Google Scholar
Amaducci LA, Fratiglioni L, Rocca WA.
et al. Risk factors for clinically diagnosed Alzheimer's disease: a case-control
study of an Italian population. Neurology.1986;36:922-931.Google Scholar
Broe GA, Henderson AS, Creasey H.
et al. A case-control study of Alzheimer's disease in Australia. Neurology.1990;40:1698-1707.Google Scholar
Graves AB, White E, Koepsell TD.
et al. A case-control study of Alzheimer's disease. Ann Neurol.1990;28:766-774.Google Scholar
Henderson VW, Paganini-Hill A, Emanuel CK.
et al. Estrogen replacement therapy in older women. Arch Neurol.1994;51:896-900.Google Scholar
Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer's disease in women. Am J Epidemiol.1994;140:256-261.Google Scholar
Mortel KF, Meyer JS. Lack of postmenopausal estrogen replacement therapy and the risk of
dementia. J Neuropsychiatry Clin Neurosci.1995;7:334-337.Google Scholar
Lerner A, Koss E, Debanne S.
et al. Smoking and oestrogen-replacement therapy as protective factors for
Alzheimer's disease. Lancet.1997;349:403-404.Google Scholar
Baldereschi M, Di Carlo A, Lepore V.
et al. Estrogen-replacement therapy and Alzheimer's disease in the Italian
Longitudinal Study on Aging. Neurology.1998;50:996-1002.Google Scholar
Brenner DE, Kukull WA, Stergachis A.
et al. Postmenopausal estrogen replacement therapy and the risk of Alzheimer's
disease. Am J Epidemiol.1994;140:262-267.Google Scholar
Waring SC, Rocca WA, Petersen RC.
et al. Postmenopausal estrogen replacement therapy and risk of AD: a population-based
study. Neurology.1999;52:965-970.Google Scholar
Tang MX, Jacobs D, Stern Y.
et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's
disease. Lancet.1996;348:429-432.Google Scholar
Kawas C, Resnick S, Morrison A.
et al. A prospective study of estrogen replacement therapy and the risk of
developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology.1997;48:1517-1521.Google Scholar
Seshadri S, Zornberg GL, Derby LE.
et al. Postmenopausal estrogen replacement therapy and the risk of Alzheimer
disease. Arch Neurol.2001;58:435-440.Google Scholar
Breitner JC, Wyse BW, Anthony JC.
et al. APOE
-∊-4 count predicts age when prevalence
of AD increases, then declines: the Cache County Study. Neurology.1999;53:321-331.Google Scholar
Teng EL, Chui HC. The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry.1987;48:314-318.Google Scholar
Jorm AF. A short form of the Informant Questionnaire on Cognitive Decline in
the Elderly (IQCODE). Psychol Med.1994;24:145-153.Google Scholar
Silverman JM, Breitner JC, Mohs RC, Davis KL. Reliability of the family history method in genetic studies of Alzheimer's
disease and related dementias. Am J Psychiatry.1986;143:1279-1282.Google Scholar
McKhann G, Drachman D, Folstein M.
et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA
Work Group under the auspices of Department of Health and Human Services Task
Force on Alzheimer's Disease. Neurology.1984;34:939-944.Google Scholar
Allison P. Event History Analysis: Regression for Longitudinal
Event Data. Beverly Hills, Calif; Sage Publications; 1984.
Anthony JC, Breitner JC, Zandi PP.
et al. Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists:
the Cache County Study. Neurology.2000;54:2066-2071.Google Scholar
Finch CE, Kirkwood TBL. Chance, Development and Aging. New York, NY: Oxford University Press; 2000.
Matthews K, Cauley J, Yaffe K, Zmuda JM. Estrogen replacement therapy and cognitive decline in older community
women. J Am Geriatr Soc.1999;47:518-523.Google Scholar
in t' Veld BA, Ruitenberg A, Hofman A.
et al. Nonsteroidal anti-inflammatory drugs and the risk of Alzheimer's disease. N Engl J Med.2001;345:1515-1521.Google Scholar
Henderson VW, Paganini-Hill A, Miller BL.
et al. Estrogen for Alzheimer's disease in women. Neurology.2000;54:295-301.Google Scholar
Marder K, Sano M. Estrogen to treat Alzheimer's disease: too little, too late? so what's
a woman to do? Neurology.2000;54:2035-2037.Google Scholar
Mulnard RA, Cotman CW, Kawas C.
et al. for the Alzheimer's Disease Cooperative Study. Estrogen replacement therapy for treatment of mild to moderate Alzheimer
disease. JAMA.2000;283:1007-1015.Google Scholar
Shumaker SA, Melton BA, Espeland MA.
et al. The Women's Health Initiative Memory Study (WHIMS): a trial of the
effect of estrogen therapy in preventing and slowing the progression of dementia. Control Clin Trials.1998;19:604-621.Google Scholar