International Psychogeriatrics (2014), 26:10, 1579–1584 

C International Psychogeriatric Association 2014

G U E S T E D I TO R I A L
Sex differences in Alzheimer’s disease risk: are we looking at
the wrong hormones?

Two-thirds of individuals with Alzheimer’s disease pathology a half century later, however, is not
(AD) are women, owing largely to the fact altogether convincing for several reasons. First, the
that women outlive men (https://www.alz.org/ notion that pregnancy induces long-term decreases in
downloads/facts_figures_2012.pdf). Women’s in- basal estrogen has been suggested to explain the
creased longevity, however, is not sufficient to delayed temporal association between pregnancy
explain the fact that women are 1.5 times more and AD. This explanation does not account
likely than men to develop the disease (Gao et al., for similar associations among parenthood, sex
1998). After age 80, the incidence of AD is much hormone levels, and risk of AD in men. Specifically,
higher in women than in men, such that the just as low estrogen levels increase the risk of
proportion of women with AD is almost twice the AD in women, low testosterone is associated with
proportion of men with the disease (e.g., Zandi an increased risk of AD in men. Moreover, men
et al., 2002; Plassman et al., 2007). Moreover, once who become fathers evince a steeper decline in
diagnosed with AD, women decline more rapidly, testosterone levels over time compared to men who
both cognitively and functionally, compared to men remain childless (Gettler et al., 2011). Thus, if
(Ito et al., 2011; Tschanz et al., 2011). both motherhood and fatherhood are associated
To explain women’s increased risk for AD, with decreased sex hormone levels, then fertility
and faster progression after onset, sex hormones— would be expected to increase the risk for AD in
estrogens in particular—are often invoked. Nu- both sexes. But it does not. Second, the results
merous studies have established that age-related of hormone replacement studies suggest strongly
depletion of sex hormones increases the risk of AD, that hormone replacement increases AD risk, the
prompting researchers to hypothesize protective opposite of what was predicted (e.g., Shumaker
roles of these hormones against AD (see Vest & et al., 2003). Most importantly, the line of work
Pike, 2013, for a review). Further support for based on the sex hormone hypothesis has not
the sex-hormone hypothesis came from a series of led to treatments for AD, suggesting a need to
studies on the relation between fertility and AD. consider alternative hypotheses linking female sex
Based on the hypothesis that pregnancy-induced and AD risk. Findings from several lines of research
changes in estrogen levels would increase AD risk, implicate sex differences in the stress response as a
this line of work has revealed that women with promising candidate.
a greater number of pregnancies have a higher
risk of developing AD and/or a younger age of
onset (Sobow and Kloszewska, 2004; Colucci et al.,
2006). Even more persuasive is that having children The stress response
increases the likelihood of developing AD in women In response to threat, a complex interaction among
but not in men (Colucci et al., 2006), and is glands, hormones, and parts of the mid-brain
positively correlated with AD neuropathology in ensues. In humans, stress triggers the release
women but not in men (Beeri, 2009). Furthermore, of corticotropin-releasing hormone (CRH) from
the association between parity and age of AD onset the para-ventricular nucleus of the hypothalamus.
appears confined to women without the APOE4 CRH stimulates the pituitary gland to release
allele, as it was not observed in women with the adrenocorticotrophic hormone (ACTH), which in
APOE4 allele in one study (Corbo et al., 2007), turn causes the adrenal glands to release cortisol.
suggesting fertility is an independent risk factor The hypothalamic-pituitary-adrenal (HPA) axis is
for AD in women. Taken together, these findings thus a key component of the stress response system,
provide perhaps the most compelling evidence for aberrations of which are associated with various
the sex hormone hypothesis of sex differences in risk stress-related illnesses.
for AD. Prolonged stress-induced release of glucocor-
The notion that brief periods of altered sex ticoids leads to alterations in the hippocampus
hormone levels lead to the development of AD (Sapolsky, 1996; Gould et al., 1998), including
1580 C. A. Munro

remodeling of dendrites (Gourley et al., 2013), dependent on factors such as type of stressor, age of
reductions in long-term potentiation (Tadavarty subjects, and the timing of hormone measures (see
et al., 2009; Kamal et al., 2014) or brain-derived Kudielka and Kirschbaum, 2005, for a review).
neurotrophic factor (BDNF; Bath et al., 2013), In studies examining the effects of stress on
increases in markers of oxidative stress (as reviewed cognition, the degree of cortisol response to stress,
by Rothman and Mattson, 2010), and reduced rather than the mere experience of it, better
volume (Lupien et al., 1998). Stress also suppresses predicts the cognitive effects of stress (Wolf et al.,
neurogenesis in the dentate gyrus (Gould et al., 2001; Takahashi et al., 2004). Whereas findings
1997, 1998), an effect that increases with advancing in young adults do not consistently favor men or
age (Simon et al., 2005). Additionally, stress alters women, advancing age appears to place women at
dendritic morphology of prefrontal cortical neurons a disadvantage. In a meta-analysis of 45 studies,
(Radley et al., 2004; Liston et al., 2006). The Otte and colleagues (2005) found that the effect of
functional consequences of these changes include age on the cortisol response to a pharmacological or
cognitive impairment, particularly in memory (see psychological stressor was almost three times higher
Lupien et al., 2005, for a review), and also in in women than in men. Importantly, the effect
executive functioning (Plessow et al., 2012). sizes of studies that controlled for sex hormone
variations in women (e.g., standardizing menstrual
cycles, excluding women on oral contraceptives or
Stress and AD hormone replacement therapy) did not differ from
those that did not, suggesting that sex hormones do
In rodents, stress provokes misprocessing of the not alter the effect of aging on the stress response in
amyloid precursor protein, leading to increased women. In line with this finding, studies examining
levels of Aβ 40 and Aβ 42 in the hippocampi the effect of stress on cognition in older men and
(Martisova et al., 2013), increases tau phosphoryla- women find that an acute psychosocial stressor
tion in the hippocampus and prefrontal cortex causes memory impairment in women only (Wolf
(Yang et al., 2014), and accelerates cognitive et al., 1998; Almela et al., 2011).
impairment (Cuadrado-Tejedor et al., 2012).
Interestingly, these effects are observed in only
“stress-sensitive” (rather than “stress-resistant”)
animals (Briones et al., 2012), suggesting that the BDNF
apparent AD-inducing effects of stress are not In addition to cortisol, the association between
inevitable, but require a particular vulnerability to the stress and BDNF is another mechanism by which
effects of stress. women may be more vulnerable than men to AD.
In patients with AD, both plasma and In mice, stress reduces hippocampal BDNF in
cerebrospinal fluid contain increased cortisol, the females but not in males (Yamaura et al., 2013).
level of which is positively correlated with the In rats exposed to stress, females show greater
degree of cognitive impairment (see, e.g., Dong and stress hormone (corticosterone) response, less cell
Csernansky, 2009), but unrelated to symptoms of proliferation in the dentate gyrus, and lower levels
depression (Hoogendijk et al., 2006). Longitudinal of hippocampal BDNF than males (Malheiros et al.,
studies have found that experiencing major stressful 2014). In non-human primates, stress alters plasma
life events is associated with younger age of onset BDNF in females but not males (Cirulli et al.,
in familial AD (Mejia et al., 2003). Furthermore, 2009).
death of a spouse more than doubles the risk of In humans, a cross-continent meta-analysis
AD in those who never remarry, a risk that is found that the Met66 polymorphism of the BDNF
further increased in individuals who carry at least gene, shown to reduce the transport of BDNF,
one APOE4 allele (Håkansson, 2009). conferred an increased risk of AD in women
but not in men (Fukumoto et al., 2010). While
the role of estrogen in BDNF expression was
Sex differences in the stress response postulated to underlie this finding, it is notable
that BDNF is correlated with cortisol (Begluiomini
Cortisol et al., 2008). In a study of young adults, women
Both preclinical and human studies show sex with the Met66 (compared to the Val/Val) BDNF
differences in the cortisol response to stress. In polymorphism had an increased cortisol response to
rodents, stress induces a greater cortisol response a social stressor, whereas the same polymorphism
in males compared to females (Beck and Luine, was associated with a decreased cortisol response in
2002; Luine, 2002; Bowman et al., 2003). Findings men (Shalev et al., 2009). Taken together, these
in humans are less consistent, as they are more findings underscore the potential importance of
 Guest Editorial 1581

Figure 1. Influence of stress on the development of AD. Factors for which women show greater vulnerability than men are shaded in red.
∗ Increased vulnerability in women considers that pregnancy is a stressful event.

stress hormones in explaining women’s increased widowed (U.S. Census Bureau, 2006). If stress
risk of AD. can induce the development of AD pathology or
hasten its clinical manifestation in both sexes, then
women would be at greater risk for AD simply
Sex differences in stress vulnerability by virtue of being much more likely than men to
experience death of a spouse, even if there were no
In a 35-year longitudinal study of women, sex differences in the stress response. In this sense,
Johansson and colleagues (2010) found that the higher incidence of AD in women after age 80
reports of “frequent/chronic” stress during mid-life could, indeed, be explained by the fact that they
increased the risk of AD at follow-up. Similarly, outlive men.
a recent meta-analysis of five prospective studies
(Terraccino et al., 2014) found that individuals in
the top quartile of distress proneness (high scores Pregnancy and stress hormones
on neuroticism) had a three-fold risk of AD. Sex
Considering the studies reviewed above, it is
differences in neuroticism are consistently found
intriguing to consider whether findings from the
across the world, with women scoring higher than
fertility studies might lend themselves to re-
men (Lynn and Martin, 1997). The magnitude of
interpretation in the context of stress, rather than
the sex difference, slightly greater than one-half of a
sex, hormones. During pregnancy, the adrenal
standard deviation, is almost identical in young and
glands become hypertrophic, and basal cortisol
older adults (Costa et al., 2001; Chapman et al.,
levels rise. By the third trimester, cortisol increases
2007). These findings correspond to those from
to two to three times higher than in the non-
animal studies, and suggest that “stress-sensitive”
gestational period (Dörr et al., 1989), similar to
individuals are at increased risk for AD, and also
the levels seen in Cushing’s syndrome (Magiakou
that women are more vulnerable than men to this
et al., 1997). At the same time, women’s cortisol
particular risk.
response to acute stress is attenuated (Kammerer
et al., 2002). That repeated states of pregnancy-
induced alterations in the stress response might lead
Sex differences in major stressful life events to enduring perturbations of the HPA axis in a
Given the links between stress and risk of AD, it manner that increases the risk for AD is a tempting
is notable that one of life’s most stressful events— hypothesis. Indeed, multiparity reveals alterations
death of a spouse—is much more common in in both diurnal cortisol and cortisol response to
women than in men. Not only do women marry stress that are not evident in primiparous mothers
men who average two years their senior (Copen (Tu et al., 2006a; 2006b).
et al., 2012), they also live longer than men (81
vs. 76 years; Population Reference Bureau 2013 Conclusion
World Population Data Sheet). For these reasons,
the sex difference in the proportion of individuals Efforts to elucidate the mechanisms underlying sex
experiencing widowhood increases with age. From differences in risk of AD have been dominated by
ages 75–84, fewer than 20% of men, but over half research on sex hormones. While this work has done
of women (54%) have lost a spouse to death. After much to increase our knowledge of hormonal risk
age 85, 35% of men and 72% of women have been factors for AD, it has not led to effective treatments.
1582 C. A. Munro

As depicted in the Figure, the preponderance of the 2006–2010 National Survey of Family Growth. National
evidence reviewed herein convincingly argues that Health Statistics Reports; no 49. Hyattsville, MD: National
stress hormones should be afforded their rightful Center for Health Statistics.
place in the lineup of suspects underlying women’s Corbo, R. M. et al. (2007). Combined effect of
increased vulnerability to AD. apolipoprotein e genotype and past fertility on age at onset
of Alzheimer’s disease in women. Dementia and Geriatric
Cognitive Disorders, 24, 82–85.
Costa, P., Terracciano, A. and McCrae, R. R. (2001).
Conflict of interest Gender differences in personality traits across cultures:
Robust and surprising findings. Journal of Personality and
None Social Psychology, 81, 322–331.
Cuadrado-Tejedor, M., Ricobaraza, A., Frechilla, D.,
CYNTHIA A. MUNRO Franco, R., Pérez-Mediavilla, A. and Garcia-Osta,
Johns Hopkins School of Medicine Baltimore, MD, A. (2012). Chronic mild stress accelerates the onset and
progression of the Alzheimer’s disease phenotype in
USA
Tg2576 mice. Journal of Alzheimer’s Disease, 28:567–578.
Email: [email protected]
doi: 10.3233/JAD-2011-110572.
Dong, H. and Csernansky, J. G. (2009). Chronic mild
stress accelerates the onset and progression of the
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