American Journal of Epidemiology

Copyright 2001 by The Johns Hopkins University School of Hygiene and Public Health
All rights reserved

Vol. 153, No. 2

Printed in U.S.A.

Alzheimers Disease Risk among Women and Men Hebert et al.

Is the Risk of Developing Alzheimers Disease Greater for Women than for
Men?

Liesi E. Hebert,1 Paul A. Scherr,2 Judith J. McCann,1 Laurel A. Beckett,1 and Denis A. Evans1

Alzheimers disease; incidence; mortality; prevalence; prospective studies; risk factors; sex factors; women

Although most people with Alzheimers disease (AD) are

women, it is unclear whether this sex difference is due solely
to greater longevity of women or women have a greater risk
of developing AD. An increased prevalence of AD among
women has been reported in many studies (111). Incidence
studies have generally found no significant sex difference
(1219), but many of these studies were small and included
few men of the ages at which incidence is highest. In this
investigation, we evaluated the risk of incident AD among
women and men in a community population and examined
the interrelations of incidence, prevalence, and mortality due
to AD, which were independently measured in the same
community.

of the Elderly (EPESE) Project. The studies were approved

by the Institutional Review Board of Brigham and Womens
Hospital (Boston), and written informed consent was
obtained from all study subjects. All noninstitutionalized
community residents aged 65 years or more on January 1,
1982, were eligible for the EPESE home interview. A total
of 3,809 people (85 percent of the population) participated
(20). Three years later, the survivors were interviewed again
(participation rate, 93 percent). Tests of immediate and
delayed memory were administered during both interviews.
Two samples of participants were selected to undergo
detailed clinical evaluationone for prevalent AD (21) and
one for incident AD (22). Stratification by age, sex, and memory performance permitted sampling a larger proportion of
high risk groups in order to enhance the efficiency of the
analyses, while weighted estimates reflect the relations in the
entire population. A total of 714 persons were selected for clinical evaluation of AD prevalence (21). Of these, 54 died before
evaluation and 467 (71 percent of survivors) participated.
Mortality was monitored for these 467 people through
December 1992. A total of 2,313 persons were determined to
be free of prevalent AD on the basis of either a good memory
score upon initial interview or detailed clinical evaluation (22).
Of these persons, 303 died before reevaluation, 409 refused to
participate, and 1,601 (80 percent of survivors) participated. A
sample of 642 underwent evaluation for incident AD.

MATERIALS AND METHODS

Study population

Data were collected in East Boston, Massachusetts, a center of the Established Populations for Epidemiologic Study
Received for publication August 11, 1999, and accepted for publication February 15, 2000.
Abbreviations: AD, Alzheimers disease; CI, confidence interval;
EPESE, Established Populations for Epidemiologic Study of the
Elderly.
1
Rush Institute for Healthy Aging, Rush University and RushPresbyterian-St. Lukes Medical Center, Chicago, IL.
2
Health Care and Aging Studies Branch, National Center for
Chronic Disease Prevention and Health Promotion, Centers for
Disease Control, Atlanta, GA.
Reprint requests to Dr. Liesi E. Hebert, Rush Institute for Healthy
Aging, 1645 West Jackson Blvd., Suite 675, Chicago, IL 60612 (email: lhebert1@rush.edu).

Diagnosis of AD

People in both samples received the same structured clinical evaluation, including neuropsychological tests, a neurologic examination, a brief psychiatric evaluation, laboratory
132

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A large proportion of people with Alzheimers disease (AD) are women; however, it is not clear whether this
is due to higher risk of disease or solely to the larger number of women alive at ages when AD is common.
Beginning in 1982, two stratified random samples of people aged 65 years in East Boston, Massachusetts
underwent detailed, structured clinical evaluation for prevalent (467 people) and incident (642 people from a
cohort previously ascertained to be disease-free) probable AD. The prevalence sample was followed for mortality
for up to 11 years (through December 1992). The age-specific incidence of AD did not differ significantly by sex
(for men vs. women, odds ratio = 0.92; 95% confidence interval (CI): 0.51, 1.67). Controlled for age, prevalence
also did not differ significantly by sex (for men vs. women, odds ratio = 1.29; 95% CI: 0.67, 2.48). The increase
in risk of mortality due to AD did not vary by sex. The odds ratio for women with AD compared with women
without AD was 2.07 (95% CI: 1.21, 3.56). For men, the odds ratio was 2.22 (95% CI: 1.02, 4.81). These findings
suggest that the excess number of women with AD is due to the longer life expectancy of women rather than
sex-specific risk factors for the disease. Am J Epidemiol 2001;153:1326.

Alzheimers Disease Risk among Women and Men 133

tests, a brief medical history, and an informant interview

(21). Diagnosis of clinical probable AD was made within the
study, using the criteria of the Joint Work Group of the
National Institute of Neurological and Communicative
Disorders and Stroke and the Alzheimers Disease and
Related Disorders Association (23).
Control variables

Age, formal schooling (in years), income (in 10 categories, modeled continuously), occupational status (24),
smoking (indicators for current or past smoking and cumulative pack-years), and alcohol intake (current daily consumption) were measured at the initial interview.
Statistical methods

RESULTS
Incidence of AD among women and men

Among the 642 persons who were initially free of AD, 57

of the 362 women and 38 of the 280 men developed AD,
over an average of 4.3 years. There was no significant difAm J Epidemiol Vol. 153, No. 2, 2001

Prevalence of AD among women and men

There was no significant sex difference in the agespecific prevalence of AD. Of the 467 persons clinically
evaluated for AD, 84 of the 262 women and 50 of the 205
men had AD. In analysis controlling for single year of age
and sample design, the odds ratio for AD among men compared with women was 1.29 (95 percent CI: 0.67, 2.48).
Controlling for education, income, occupational status,
smoking, and alcohol intake did not affect the results. Linear
terms for age and education were adequate. The effect of sex
on disease risk did not vary significantly with age.
Risk of death due to AD among women and men

We observed no significant sex difference in the relative

increase in risk of death for persons with AD. Of the baseline sample of 467 persons, 143 of the 262 women and 133
of the 205 men died. In Cox regression analysis, the overall
odds ratio for death among people with AD compared with
those without AD was 2.14 (95 percent CI: 1.34, 3.42). With
addition of a sex AD interaction term, the risk for women
was 2.07 (95 percent CI: 1.21, 3.56). The additional risk for
men with AD compared with women with AD was small
(odds ratio  1.07; 95 percent CI: 0.43, 2.68), adding to a
total risk of 2.22 (95 percent CI: 1.02, 4.81) for men with
AD compared with men without AD.
Lifetime risk of AD among women and men

Lifetime risk of AD is determined by the rate of AD

development and the death rates among people with and
without AD. Life tables showing this process separately for
women (figure 1) and men (figure 2) demonstrate the differences in disease experience that are attributable solely to
different mortality rates. In both sexes, the number of people alive and disease-free decreases as people develop AD
and die. Men die at a faster rate than women, leaving fewer
men alive, both with and without AD. At each age, however,
the proportions of living people who have AD are similar
among women and men, and the proportions of people
developing AD are the same. The total number of people
who have developed AD up to a given age is the sum of
those with AD who have died and those with AD who are
still alive. By age 90 years, 33 percent of women and 23 percent of men will have developed AD. Extension of calculations from birth to the point at which everyone has died pro-

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Womens and mens risks of prevalent and incident disease were compared using logistic regression analysis, controlling for age and follow-up interval for incident disease
and adjusting for the complex sampling (25, 26). The form
of the curve relating age to disease risk was evaluated by
adding higher-order terms for age and interaction terms for
age and sex to the models and by examining residual plots.
Similar model-fitting procedures were used to test the form
of the association with education.
Sex-specific risk of death with AD was assessed with a
sample-weighted proportional hazards model (27), using
age as the time line. AD was modeled as a time-varying
covariate (28) to account for development of AD during
follow-up. Other predictors were sex and sex AD interaction. The form of the age and sex relations to mortality and
interactions with AD were tested in the same way as in the
logistic regression models. Bootstrap resampling (29) by
stratum was used to calculate the variance.
To assess the effects of differing mortality on lifetime risk of
AD, we created life tables summarizing the outcomes for hypothetical cohorts of 100,000 women and 100,000 men, starting
disease-free at age 65 years and progressing to age 90. At each
successive year of age, those still alive and free of disease could
either die before the next year, develop AD, or remain free of
AD. Those alive with AD at the start of a year could either die
or survive. The only difference between the tables was that one
used womens death rates and the other used mens. The US
rates for Whites were used to provide stable single-year rates.
Identical age-specific (single years) but not sex-specific AD
incidence rates from East Boston were used for both sexes.
Total deaths were divided between persons with AD and persons without AD for each sex, so that the odds of dying among
persons with AD relative to the odds of those without AD was
the East Boston odds of 2.14 for both sexes.

ference between women and men in the age-specific risk of

developing AD. The odds ratio for men compared with
women was 0.92 (95 percent confidence interval (CI): 0.51,
1.67) in analysis controlling for single year of age, followup interval, and sample design. The addition of education,
income, occupational status, smoking, and alcohol intake
did not affect this result (odds ratio  0.97; 95 percent CI:
0.41, 2.27). Linear terms for age (corresponding to an exponential increase in risk with age) and education were adequate, and the effect of sex on disease risk did not vary significantly with age.

134

Hebert et al.

FIGURE 2. Projected numbers of living and deceased men with

and without Alzheimers disease (AD) in a hypothetical cohort of
100,000 men who are disease-free at age 65 years, by age. (Based
on data from East Boston, Massachusetts, 19821992.)

vides the lifetime risk of AD: 32 percent for women and 18

percent for men.
DISCUSSION

In this study, we found no significant sex difference in the

prevalence or incidence of AD or the increased risk of death
among people with AD. Variations in the results of previous
studies of AD prevalence and incidence in defined populations were likely due more to methodological factors than to
actual differences in the effect of sex on disease risk. A number of studies have found a higher prevalence of AD among
women, but many had small sample sizes and lacked tests

Am J Epidemiol Vol. 153, No. 2, 2001

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FIGURE 1. Projected numbers of living and deceased women with

and without Alzheimers disease (AD) in a hypothetical cohort of
100,000 women who are disease-free at age 65 years, by age.
(Based on data from East Boston, Massachusetts, 19821992.)

for statistical significance. Of 19 previous population studies, 11 reported a higher prevalence for women (111), one
reported a higher prevalence for men (30), and seven found
no difference (3137). Of the eight studies that tested for
significance, four (14) found a significantly higher prevalence in women and four found no difference (3134). Most
population-based incidence studies have found less difference between women and men.
It has been difficult to achieve adequate sample sizes for
studies of AD incidence, especially because fewer men than
women survive during follow-up at the oldest ages, at which
disease is most common. Of 12 incidence studies (1219,
3841), nine included fewer than 20 male incident cases
(1217, 19, 38, 39). Only one study reported higher incidence among women with a probability less than 0.05 (38);
another found that the risk was significantly greater for men
under age 80 and greater for women over age 80 (40). Two
recent reports in which data from several studies were combined by meta-analysis (42) or pooled analysis (43) found
significantly higher incidence among women. The pooled
EURODEM analysis resulted in an odds ratio of 0.65 for
men compared with women (43), which is just below the 95
percent confidence interval of our results, while our estimate
of 0.92 is above the 95 percent confidence limit of the
pooled analyses. Such pooled or meta-analyses have the
advantage of large numbers but the disadvantages of variation in methods across studies (44) and inability to account
for the effect of complex sampling in computations of effect
estimates or confidence intervals.
Precise control for age is also a critical methodological
component in assessment of sex differences in AD risk.
Nearly all previous studies have assessed differences by
comparing rates in age groups rather than modeling risk.
Controlling by age groups may not be adequate, because the
risk of disease is not uniform within each age group and
there are more women at the older, higher-risk end of each
group. The wider the age range in each age group, the
greater the distortion. Ten of 13 studies reporting a single
rate for everyone over age 65 found that women had 23
times the AD rate of men (3, 5, 7, 8, 10, 17, 18, 32, 39, 41).
The four studies that found statistically significant sex differences in prevalence controlled for age in 10-year or larger
age groups (14). The two studies (38, 40) and the one metaanalysis (42) that found sex differences in incidence controlled by 5-year age groups.
Comparable ascertainment of disease for each risk group
is also important for assessing the impact of risk factors. In
some incidence studies, AD status was determined by direct
examination of survivors and by questioning of informants
or review of medical records for people who died during
follow-up (10, 12, 1517, 19, 38, 41). Because alternative
sources of data collection tend not to find all cases (17, 41),
the higher mortality among men may result in apparent sex
differences. The pooled analysis that found a higher incidence for women (43) had limited ability to control for interstudy variation, which may have the effect of comparing
women and men from substantively different populations.
Prevalence studies face an additional challenge in
addressing this issue, because prevalence is determined by

Alzheimers Disease Risk among Women and Men 135

ACKNOWLEDGMENTS

This study was supported by grants AG11862, AG05362,

and AG10161; cooperative agreement AG06789; and contracts NO1-AG-1-2106 and NO1-AG-0-2107 from the
National Institute on Aging.
The authors thank the staff of the East Boston Neighborhood Health Center for their cooperation and support.

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