Report from the Society for

Womens Health Research

JOURNAL OF WOMENS HEALTH

Volume 21, Number 10, 2012
Mary Ann Liebert, Inc.
DOI: 10.1089/jwh.2012.3789

Sex and Gender Differences in Alzheimers Disease:

Recommendations for Future Research
Christine L. Carter, Ph.D., M.P.H.,1 Eileen M. Resnick, Ph.D.,
Monica Mallampalli, Ph.D.,1 and Anna Kalbarczyk, M.P.H.

Abstract

Alzheimers disease (AD) disproportionately affects women in both prevalence and severity; however, the
biologic mechanisms underlying these sex differences are not fully understood. Sex differences in the brain, such
as in brain anatomy, age-related declines in brain volume, and brain glucose metabolism, have been documented
and may be important in understanding AD etiology. The full impact of sex as a basic biologic variable on this
neurodegenerative disease remains elusive. To address the evidence for sex differences in AD, the Society for
Womens Health Research (SWHR) convened an interdisciplinary roundtable of experts from academia, clinical
medicine, industry, and the government to discuss the state-of-the-science in sex and gender differences in AD.
Roundtable participants were asked to address gaps in our knowledge and identify specific sex-based research
questions for future areas of study.

Introduction

lzheimers disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive deficits, and behavioral changes. The disease weaves an
insidious path of destruction in the regions of the brain responsible for memory, learning, and higher executive functioning. Although AD was first identified over 100 years ago,
little is known about the physiologic changes that trigger the
disease, and current available treatments are unable to slow or
reverse the damage.
There are an estimated 5.4 million Americans with AD and
related dementias, and AD accounts for 60%80% percent of
all dementias. It is the sixth leading cause of death in the
United States and the fifth leading cause of death of Americans 65. In the United States, the estimate for the number of
women affected with the disease who are 65 years is 3.4
million compared to 1.8 million men 651; that is, almost two
thirds of Americans with AD are women. By the year 2050, the
number of Americans 65 affected by AD is expected to
quadruple to 21 million, and correspondingly, 1116 million
people will be affected with AD if no medical breakthroughs
are developed to stem the tide.
Women not only are disproportionately affected by the
disease itself but also are often primary caretakers of family
members affected by AD. Seventy percent of caregivers of
people with AD and dementia are women,1 and reports indicate that 65% of caregivers suffer from depression.2 Cur1

rently, U.S. families and taxpayers spend almost $200 billion

per year caring for those with AD.3 On a global scale, the cost
of dementia is estimated at a staggering $604 billion.4
AD is characterized by an accumulation of two abnormally
folded proteins in the brain, b amyloid (Ab) and tau. Ab is a
fragment from a larger protein called amyloid precursor
protein (APP), which is important for neuronal growth, survival, and postinjury repair. In AD, APP is divided into
smaller Ab fragments through an unknown process. Ab accumulation causes formation of plaques that are deposited in
the extracellular spaces (outside neurons), disrupting nerveto-nerve communications and causing swelling of the fibers
and other morphologic changes. Tau is a protein that normally functions to bind and stabilize components of the
neurons of the brain. In AD, tau accumulation or aggregation
forms neurofibrillary tangles that disrupt important intracellular signaling. It is these two processes, accumulation of
plaques and formation of tangles, that cause the loss of synaptic integrity and selective neuronal cell death, which contribute to disease progression.5 Brains of patients with
advanced AD show dramatic shrinkage from cell loss and
debris from dead and dying neurons.
Studies of families with early onset AD (before the age of
65) and in Down syndrome patients (trisomy for chromosome
21), who invariably develop AD neuropathology by age 35,
led to identification of the first gene associated with AD on
chromosome 21. APP was identified with mutations that
caused accumulation of Ab in the brains of patients and

Scientific Affairs, Society for Womens Health Research, Washington, District of Columbia.

1018

SEX DIFFERENCES IN ALZHEIMERS DISEASE

affected family members. Rare dominant mutations in other
genes (presenilin-1 and presenilin-2) have also been identified
and are associated with early onset disease (3065 years).5 A
common polymorphism that confers risk, the APOE-4 genotype or allele, increases the chance of developing the disease
over the other forms (APOE-2 or APOE-3). Although the
APOE-4 allele contributes to 40%50% of the genetic basis for
late onset AD, it is responsible for only 10%20% of cases.6
This means that 80% of AD cases are considered sporadic;
that is, they derive from an unknown cause. Although tremendous strides have been made in the molecular and genetic
pathogenesis of AD in the past 20 or 30 years, there is still
much that is unknown, and little research has been conducted
to understand and clarify the role of sex and gender in the
onset, severity, and progression of AD.
Age and gender are the predominant risk factors for AD.7,8
In studies in both the United States and abroad, age appears to
consistently predict AD across studies, but gender results are
inconsistent.9,10 Speculation continues that the gender effect on
disease prevalence is because women live longer.8,11 Because
women survive to later ages than men, it is impossible to know
if men who died would ever have developed AD at the same
rate as that of women. Other risk factors include family history
of AD, low number of years of education, APOE genotype, and
head injury with loss of consciousness.5,1113
Sex differences in AD severity have been found, especially
with regard to dementia and cognition. Cognitive test performance differences have been documented in healthy men
and women as well as in patients with dementia and AD.14
One study demonstrated relatively equal scores on naming
and fluency tests in patients with dementia, but women with
AD had significantly greater impairment.15 Another study
compared global cognitive function (last evaluation before
death) to specific measures of plaque and tangle pathology
derived from brain autopsy.16 AD pathology was more likely
to manifest as dementia in women than in men, and for each
additional unit of AD pathology, women had a nearly 3-fold
increase in the odds of having been diagnosed with AD.17
Further studies are needed to correlate diagnosis and AD
pathology to understand why women bear the burden of AD
prevalence.
AD pathogenesis may also be influenced by metabolic
changes induced by sex hormones. Estrogen is known to be
protective in the brain, and loss of the hormone during
menopause may be responsible for deficits in brain metabolism, which lead to AD. Male and female brains react very
differently to testosterone and estradiol despite the fact that
both sexes have receptors for each hormone. Both sexes can
synthesize estradiol in neurons, but synaptic response in different brain regions appears to be highly sexually dimorphic.
Understanding AD pathogenesis demands broad knowledge
of the complex interplay among genetic, hormonal, and environmental influences. The role of sex and gender differences
in the onset and course of AD remains ill-defined and demands further attention.
The Society for Womens Health Research (SWHR) recently
directed its focus on sex and gender disparities in AD. SWHR
is a nonprofit organization located in Washington, DC, dedicated to building research capacity to focus on biologic differences between males and females and the critical impact of
sex-based and gender-based differences in disease. SWHR
convened a group of nationally recognized thought leaders

1019
Table 1. Proposed Clinical Research Questions
for Study of Sex Differences in Alzheimers Disease
Are there sex differences in the incidence of AD?
Are there sex differences in changes in incidence of AD over
time?
Are there sex-linked risk factors for AD?
How does sex modify the effects of genetic risk factors in
AD?
Do sex and gender differences affect risk, rate of progression
or response to treatment?
Can changes in gynecologic practices contribute to the
prevention of dementia?
Is there a clinical phenotype for women who would most
benefit from hormone therapy?
What type and regimen of progesterone can symptomatic
midlife women take and have at least cognitively neutral
effects?
How can we improve the translation of basic science findings
to clinical research and applications?
AD, Alzheimers disease.

for a roundtable discussion on sex differences in AD, with a

specific focus on women. Before the meeting, roundtable
participants were grouped into four categories based on their
expertise (clinical, basic science, industry, psychosocial) and
were tasked to examine their own research, with a critical eye
toward areas where sex and gender differences could be
identified and explored.
The SWHR Expert Roundtable on Alzheimers Disease in
Women met in Washington, DC, on October 28, 2011. SWHR
moderated the discussions and challenged the group to consider and articulate their ideas for the highest priorities for
sex-based Alzheimers disease research. At the meeting,
leaders of each of the four groups presented data, discussed
gaps in knowledge, and presented concrete questions for future research. The overarching framework or theme was:
How can sex and gender differences research impact our
understanding of Alzheimers disease? This report sheds
some light on this theme and highlights gaps in the form of
research questions (Tables 1, 2, and 3) and recommendations
(Table 4) for future areas of focus.
Clinical Research Group
The clinical group discussed ongoing clinical trials, biomarkers, menopausal hormone use, comorbidities, and the
fact that women have more autoimmune diseases, which
along with systemic inflammation, confers risk for AD.18
Dozens of phase 3 clinical trials are in progress, including
those that use intravenous immunoglobulin, semagacestat,
solanezumab, bapineuzamab, raloxifene, vitamins D3 and E,
thalidomide, and Huperzine. At the time of this writing, only
five drugs (memantine, galantamine, rivastigmine, tacrine
and donepezil) have received Food and Drug Administration
(FDA) approval for AD. Tacrine is rarely prescribed today due
to side effects related to liver damage. Biomarkers for detection of early disease are enormously important and include
detecting levels of Ab and tau in the cerebrospinal fluid,
magnetic resonance imaging (MRI), functional MRI and position emission tomography (PET) scan imaging, and tests for
cognitive performance. Recent studies on possible risk factors

1020

CARTER ET AL.
Table 2. Proposed Basic Metabolic, Physiologic, and Genetic Research Questions for Study
of Sex Differences in Alzheimers Disease

A. Metabolism
Do women and men age bioenergetically at the same rate, and do the pathways of bioenergetic aging differ between
the sexes?
Do the pathways of bioenergetic aging differentially impact AD risk in women and men?
What are the crucial bioenergetic vulnerabilities in the aging brain, and how do they lead to AD?
How can we measure the rate of development of AD and neurodegenerative decline? Where are the therapeutic windows?
B. Physiology
Are natural aging and reproductive senescence in the mouse a good model?
What is the mechanism of the effects of estrogen and testosterone on synapses? Are the effects entirely through synaptic
receptors?
What is the role of adrenal steroids in stimulating estrogen and testosterone receptors in AD?
Are there sex differences in synaptic aging that would lead to sex differences in vulnerability to AD? If so, how are
estrogen and testosterone involved?
What is the basis for the sexual dimorphism in how each sex uses gonadal estrogen and testosterone? Do both sexes use
estrogen and testosterone synthesized within the brain the same way?
How do sex differences in cognitive performance relate to regional differences in the synaptic basis of cognitive aging?
Are there sex differences in regional vulnerabilities?
Are there sex differences in the degree to which age-related synaptic alterations leave a neuron vulnerable to degeneration?
When would clinical interventions protect neurons? Are the best interventions centered on steroid mechanisms?
What are the signaling cascades that are produced by steroid receptors at the synapse?
Will AD drugs under development work effectively in women and men, and how will reproductive steroids modify drug
action?
Does the sudden decline in estrogen experienced at menopause by women have a more profound effect on the vulnerable
neurons than the gradual decline in testosterone experienced by men? If so, what are the best formulations for HT, and
how important is timing?
C. Genetics
What is the sex-specific effect of genetic risk factors (autosomal and X/Y) in AD?
Will pharmacogenetics (early prediction/early prevention) be the same for women and men?
Are there sex-linked risk factors for AD, and how does sex modify the effects of genetic risk factors?
AD, Alzheimers disease; HT, hormone therapy.

show that cardiorespiratory fitness is associated (negatively)

with dementia mortality for both men and women,19 but
women benefit less than men.20 American women on average
get less exercise than men per week, and this may influence
their risk for AD.21 Women have higher rates of depression
and anxiety, and these are emerging as risk factors for AD.22
The role of hormone replacement therapy (HRT) is still a
confused issue, and roundtable experts discussed research
that supports improved cognitive function with HRT when
given at early but not late stages of the menopausal period,
consistent with studies that claim a window of opportunity.2326 The clinical research group agreed that the main gaps
in knowledge pertain to both hormonal influence and biomarkers and how they relate to risk, identifying preclinical
Table 3. Proposed Psychosocial Research
Questions for Study of Sex and Gender
Differences in Alzheimers Disease
Are there are sex differences in service use or participation
in clinical studies?
Are there causes of gender differences in outcome measures
(such as depression) that may be unrelated to caregiving?
Would changes in role expectations influence the response to
caregiving?
Do societal expectations affect caregiver strain?
Can we study gender differences within the context of the
patient-caregiver relationship history?
Are gender differences similar among young people and
older people?
Are there gender disparities in time of diagnosis?

disease, and disease progression. These gaps in knowledge

are addressed as clinical questions in Table 1.
Basic Science Research Group
The basic science working group focused on three topics
that pertain to sex differences: metabolism, physiology of
hormonal regulation, and AD genetics, all relevant to AD
pathology.
Brain hypometabolism is one of the earliest hallmarks of AD.
The brains of AD patients show a deficit of mitochondrial
function and a form of reduced metabolism, changes that apparently precede the development of AD. In normal individuals with a maternal history of AD, there are significant
reductions in brain glucose metabolism.27 This may be important, as mitochondrial DNA is inherited through the maternal
line, and risk to offspring of AD patients may be transmitted
through mitochondrial rather than nuclear DNA. The roundtable experts suggested that further research on brain hypometabolism could lead to personalized interventions to
prevent, delay, or treat bioenergetic deficits in at-risk populations (Table 2A).
AD pathogenesis in women may be influenced by metabolic changes induced by gonadal hormones, such as estrogen, which is known to have a protective effect on the brain,
and loss of estrogen during menopause could, in part, lead to
the deficits seen in brain metabolism in mild cognitive injury
(MCI) and AD. Transgenic animal studies have provided
evidence that both male and female gonadal hormones regulate AD pathogenesis.2830 Several studies in mice support

SEX DIFFERENCES IN ALZHEIMERS DISEASE

1021

Table 4. Proposed Clinical, Basic, and Psychosocial Recommendations for Study of Sex
and Gender Differences in Alzheimers Disease
Clinical
Examine existing data to answer
questions about fundamental
issues at baseline
Accumulate a database or use the
existing AD data-sharing
consortia to examine clinical
data related to sex differences
in AD incidence
Design every clinical trial to
include women and men as a
primary outcome and stratify
and report data by sex
Perform hypothesis-driven
research that poses
fundamental questions to
determine if there are sex
differences in response to AD
treatment
Control for potential biases
(without affecting recruitment)
in clinical trials due to
womens longer life
expectancy
Encourage dialogue with
biotechnology and
pharmaceutical sectors
regarding the impact of sex
differences for pathologyinducible mechanistic pathways
and therapeutic targets

Basic

Psychosocial

Metabolism
Systematically compare sex differences
in brain and endocrine aging with
respect to AD-related risk factors,
multiple outcomes, bioenergetics,
synaptic function, and cognition
Determine the mechanisms of
bioenergetic aging and rate of decline
and the influence of sex-specific
modulators of aging
Physiologic
Incorporate separate, appropriately
powered male and female groups into
all experiments
Establish estradiol status in animal
models at the end point of
experiments
Analyze potential estrogenic properties
of drugs being tested in order to rule
out confounding variables
Improve the availability of resources to
test the impact of sex and increase
understanding of these resources
(including transgenic animal models)
Genetics
Provide greater access to banked clinical
trial samples
Include sex-based analyses in GWAS
studies
Analyze existing databases for genetic
risk factors and incidence of AD by
sex

Examine the emotional and

psychologic impact of AD on men
and women
Examine differential impact of the
caregiving role on men and women
and design interventions to provide
more effective services
All intervention studies need to
examine sex/gender differences
Reexamine existing data for sex/
gender differences
Examine the emotional and
psychologic impact of AD on men
and women
Examine differential impact of the
caregiving role on men and women
and design interventions to provide
more effective services

GWAS, genome-wide association studies.

higher risk for AD in females mediated by Ab or APP or both,

but the key entity is unclear. Increased AD risk in females may
arise from a manifestation of:
 Increased pathology
 Increased synaptic degeneration and cognitive impairment
 Altered inflammatory response
There is evidence for varied effects of sex hormones on tau,
which helps to regulate synaptic plasticity. Mutations in tau
can cause inherited forms of dementia and form pathologic
tangles in the AD brain. Animal models have shown that either female mice develop more tangles or male mice possess
greater protection against tangle formation.31 Despite these
discrepancies in animals, the roundtable scientists pointed out
that significant sex differences in tau pathology in humans
with AD have not been documented. Clearly, tau pathology
deserves more attention with respect to sex differences and
hormones to elucidate the mechanisms surrounding its toxicity (Table 2B).
Roundtable experts discussed the influence of genetics in
AD and clarified that many minor genetic factors combine to
affect brain development and aging over time. Recent genome-wide association studies have identified a broad

range of genetic mutations associated with AD. In 2007, metaanalyses of the AlzGene database maintained by the Alzheimers Research Forum reported 2920 polymorphisms in 666
genes discovered in 1382 studies.32 Although a small minority
of patients develop AD based solely on inherited genetic
mutations, examination of genes and epigenetic factors is an
enormously important area of research for unraveling the
complex etiologic factors underlying this disease. Important
gaps for genetic studies in understanding sex differences in
AD are discussed in Table 2C.
Psychosocial Research Group
Our roundtable psychosocial experts involved with
caregivers indicated that approximately 15 million people
in America are unpaid caregivers for family and friends
with AD. The majority of these people ( > 70%) are women,
and the burden is substantial; typically, between 15% and
40% of caregivers provide > 40 hours a week.1 Gender
differences in spousal care are highly prevalent for patients
with dementia, more so than with other illnesses. Husbands
with AD and related dementias (ADRD) receive an average
of 31% more hours of spousal care than ADRD wives do
from their husbands.33 Wives also continue to provide care

1022

CARTER ET AL.

longer and at greater levels of disability than husbands and

with less help from adult children.34,35 Adult children,
usually daughters, intervene more to help husbands caring
for ADRD wives, particularly as needs increase and the
disease progresses.36
Women also have lower levels of social support and poorer
psychologic and physical health. Gender identity influences
an individuals interpretation of caregiving and receiving.37
Men with traditional beliefs about masculinity are less likely
to report feeling burdened and more likely to articulate the
positive aspects of being a spousal caregiver; they are less
likely to seek help.37,38
Family caregivers for ADRD patients suffer greater stress
than other types of caregivers, which manifests both emotionally and physiologically. Compared to other caregivers,
they have high levels of stress hormones, reduced immune
function, slower wound healing, and onset of both hypertension and coronary heart disease. At least one third of
family caregivers have symptoms of depression. Because
AD typically lasts for 515 years and the nature of symptoms is so variable, a caregiver must learn to adapt continually to the patients needs. The inevitable increase in
cognitive and functional impairments leaves the patient
completely dependent on the caregiver. The research
questions raised by the psychosocial experts are presented
in Table 3.

Participant List: SWHR Expert Roundtable

on Alzheimers Disease in Women

Conclusions

Note: Lester Binder, Ph.D., Northwestern University,

and Samuel Gandy, M.D., Ph.D., Mount Sinai, participated in planning sessions but were unable to attend the
roundtable.

SWHR challenged the Expert Roundtable on Alzheimers

Disease in Women to provide recommendations in the clinical, basic, and psychosocial areas in the studies of sex differences in AD (Table 4). They were further asked to reach a
consensus on this set of recommendations, which encompass
seven overarching themes.
 Examine incidence of AD by sex
 Analyze sex-based differences systematically and comparatively
 Raise awareness to incorporate sex and gender into
experimental design
 Define standards for biomarkers and diagnosis; determine how biomarkers relate to disease burden and risk
for AD
 Examine HRT in the context of AD
 Integrate sex differences in AD drug discovery
 Consider sex and gender differences for the family
caregiver
There is much to be explored in the realm of sex and gender
differences in AD, but a wealth of data ready for meta-analysis is being accumulated. Sex differences research in AD is
aimed toward improving early diagnosis, better quality of
life, and safer, more effective treatments. Sex differences in
AD are important, and every study should stratify and report
data by sex and carefully consider the ramifications for sex
differences across all aspects of the disease. Further, treatments for AD must take into account basic biologic (sex) differences and the gender-specific needs of our patients. Finally,
we need to conduct more research on ways to better meet the
needs of people with this dreadful disease so that both the
caregivers and the patients see an improvement in their
quality and length of life.

Clinical Research Group

Victor Henderson, M.D., M.S., Stanford University
Pauline Maki, Ph.D., University of Illinois, Chicago
Walter Rocca, M.D., M.P.H., Mayo Clinic
Bill Thies, Ph.D., Alzheimers Association
Basic Science Research Group
Roberta Diaz Brinton, Ph.D., University of Southern
California
Skip Binder, Ph.D., Northwestern University
Karen Duff, Ph.D., Columbia University
John Morrison, Ph.D., Mount Sinai
Steven Snyder, Ph.D., NIMH, N.I.H.
Rudy Tanzi, Ph.D., Harvard University
Psychosocial (Caregivers) Research Group
Mary Mittelman, DrPH, New York University
Darby Morhardt, M.S.W., LCSW, Northwestern University
Industry Scientists
Rachel Schindler, M.D., Pfizer, Inc.
David Biondi, D.O., Janssen Scientific

Disclosure Statement
The authors have no conflicts of interest to report.
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Address correspondence to:

Christine L. Carter, Ph.D., M.P.H.
Society for Womens Health Research, Suite 601
1025 Connecticut Avenue, NW
Washington, DC 20036
E-mail: chris@swhr.org

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