Context Memo

To: Professor Kimberly Freeman, COLWRIT 161 class, College Writing Program

From: Jessica Buxton

Date: 1 October 2023

Subject: Effects of Estrogen Changes during Pregnancy on Neurodegeneration in Women

My Literature review discusses the present research that has been done on the effects of changing

hormone levels in women and their effects on neurodegeneration progression. Specifically, I will

be focusing on the effects of a particular hormone, estrogen, and its changing levels experienced

during the time of pregnancies. The specific neurodegenerative disease that will be reviewed in

this context is Alzheimer’s Disease (AD). With women in the United States suffering from a

disproportionately higher rate of AD, the effects of female hormones on this associated

neurodegeneration is needed. This review highlights the disagreement between researchers on

the actual effects of estrogen exposure on neurodegeneration as well as reviewing the differing

study approaches that scientists are taking to uncover this truth.

This literature review is composed of multiple sections which are presented in a thematic order

based on study type and result findings. The primary section gives background information on

the main role of estrogen in a woman’s body and the ways in which the levels of estrogen change

during pregnancy. An understanding of the basic roles of estrogen in the body is used to lead into

the subsequent sections on how current studies on these changes are involved in the

neurodegeneration process. The second section reviews the main study types that have been
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utilized by researchers while the third and fourth section looks at these studies as either an

advantageous or disadvantageous contributor to AD progression.

If I were able to submit this literature review to a journal, it would be the Frontiers in Aging

Neuroscience. This journal specifically publishes papers that focus on the advancements in

knowledge regarding central nervous system aging as well as age-related neuronal diseases. This

closely aligns with the subject I am choosing to focus on for my review. In addition, most of the

papers which have been used for this literature review have also been published in this journal.

The citation style for this journal is Vancouver.

While reading this literature review, an understanding of these terms may aid in the

comprehension of the overall paper:

1. Parity- the number of births by a woman (including non-viable offspring) (definition

taken from NHS dictionary)

2. Endogenous- having an internal origin within the body (definition taken from Oxford

Dictionary)

3. Exogenous- having an external origin (not originating from the body) (definition taken

from Oxford Dictionary)

4. Parous- having produced offspring (definition taken from Oxford Dictionary)

5. Myometrium- middle layer of the uterine wall (definition taken from Wikipedia)

6. BMP4- Acronym for Bone Morphogenetic Protein 4, which is a gene encoding protein

specific to bone tissue (definition taken from GeneCards)

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Effects of Changing Estrogen Levels during Pregnancy on Progression of Alzheimer’s

Disease

Abstract

Alzheimer’s Disease (AD) affects millions of people in the United States, but it is more

prevalent in women than men. One of the main differences between males and females is the

presence of the menstrual cycle, pregnancy, and menopause, which are all time periods of high

variations in hormones. Specifically, estrogen, which is found mainly in the form of

17β-estradiol (estradiol), is an important variant during these times. The significant physiological

difference is enough to prompt research regarding whether or not the fluctuation in estrogen

levels during pregnancy have an effect on the rate of AD progression. This review looks at the

various methods of testing estrogen levels, including specific tissues, hormone replacement

therapy (HRT), genetic risk factors, alternative life events, and parity events. Due to the mixed

results that the studies have produced, a discussion of data supporting both disadvantageous and

advantageous effects of increased estrogen exposure will be supplied. While most of the research

reviewed ultimately supports the notion that estrogen has protective effects within a “critical

window”, further research needs to be conducted. One topic for future research includes how the

number and duration of pregnancies affects neurodegeneration.

Introduction

Dementia, and specifically AD, is becoming increasingly prevalent in the American

population (1). With over 5 million individuals suffering from this disease in the United States,

more than half of these individuals are women (2). Thus, the reasons why women are more
 4

susceptible to this disease needs to be a focus for research. Due to the large number of hormonal

changes the female body undergoes within a lifetime, studies regarding the effects of these

hormonal changes on neurodegeneration have been difficult to execute. This might explain the

lack of research that has been completed on this topic.

Although there have not been a significant number of studies done on the effects of

female hormones and neurodegeneration, the current research has identified estrogen as an

important contributor to many of the major hormonal fluctuations in a female’s life (3). While

the increased levels of estrogen during puberty are considered helpful to a woman as their

reproductive system starts to mature (4) , the effects of increased estrogen exposure during later

life are still being studied. The current research studies reveal conflicting results regarding

whether or not an increased amount of estrogen exposure in women has a protective or

detrimental effect on the progression of neurodegeneration.

In this review, I will be discussing the current, but limited, studies that have been

conducted in their attempts to understand the effects of estrogen exposure on women’s rate and

risk of neurodegeneration. I will begin by outlining the role of estrogen in a woman's health,

including its role during the time of pregnancy. We will then look at the study types that have

been utilized by researchers in an attempt to isolate the effects of this hormone and, later, how

their results might be applicable to the overall question of estrogen exposure on AD progression.

Lastly, in order to consolidate and organize the current research, the studies analyzed will be

separated into two sections based on their findings: one concluding increased estrogen exposure

has protective effects against neurodegeneration, and the other concluding increased estrogen

exposure has detrimental effects regarding neurodegeneration. The purpose of this review is to

highlight the overall inconclusive results regarding the effects of estrogen exposure on
 5

neurodegeneration in women across current studies, and ultimately reveal the need for further

research. Overall, this review provides an structured overview of current studies regarding the

effects of a specific female-impacted hormone, estrogen, on neurodegeneration with the aid of

background information regarding the hormone itself and the study types that are utilized.

Background of Estrogen in Female Body

Estrogen is a hormone well known to the female body. The hormone itself is classified as

a steroid hormone and is produced following a cascade of signaling hormones called follicle

stimulating hormone (FSH) and luteinizing hormone (LH) in the ovaries (4). Before puberty, the

secretion of estrogen in the female is minimal but as puberty progresses, levels of estrogen rise

which aid in the development of sexual organs. Later in life when women experience menopause

(an end in the menstruation cycle), the number of gonadotropins drops and so does the level of

estrogen. In addition to the ‘typical’ effects of estrogen, there are specific effects seen within the

central nervous system, including influencing forms of hippocampal-mediated types of both

learning and memory by potentiating excitatory neurotransmitters (5).

The main form of estrogen that is considered in this context is called 17β-estradiol

(estradiol). This isoform acts on the receptor E2 which is located throughout the body and

notably in the hippocampus. This isoform and receptor type is crucial in understanding the role

of estrogen in neurodegeneration precisely because of the effects it has on different brain regions.

Males and females have different forms of this E2 receptor and the signaling pathway subsequent

to binding also shows different effects between genders. Given that estrogen is present in both

males and females, the changes in signaling pathways and levels of 17β-estradiol can be useful in

understanding why more females experience this disease compared to men. While the difference
 6

in amount of estradiol receptors are known between males and females, it is still unknown how

the rise and fall of estrogen in the body during pregnancy alters the progression of the disease.

Background of Estrogen during pregnancy

Estrogen levels increase dramatically during pregnancy. One longitudinal study reported

an almost 7-fold increase in the amount of estradiol in women’s bodies by the time of their third

trimesters (6). At the biological level, estrogen plays a number of roles in preparation for the

development of a fetus. This includes thinning the cervical fluid which allows sperm to reach an

egg located in the ovaries, as well as providing lubrication, making penetration easier. These are

a result of the previously mentioned LH and FSH, which help to regulate the menstruation cycle,

as well as the rise and fall of estrogen levels. Before an egg is fertilized by a sperm, estrogen

levels rise rapidly during what is considered an LH surge (7). If the egg is not fertilized, the

estrogen levels return back to normal. When the egg is fertilized, the placenta maintains estrogen

levels (7). Thus, the increased level of estrogen experienced by a woman during pregnancy is

why they are ideal for studying the effects of estrogen on female neurodegeneration.

Types of Studies Used

Estrogen is difficult to completely isolate in the body, which is why there are a variety of

methods that have been used to study the effects of estrogen on neurodegeneration. These

methods include specific tissue studies, hormonal replacement therapy studies, genetic risk

studies, as well as other alternative life-events for women studies (ex. Menopause, time of

puberty onset, etc.) and parity studies. It is vital to first understand the types of studies used to

understand the implications of the results.

Tissue Studies
 7

Tissues studies are used to focus on the effects of neurodegeneration within a specific

region of the body. The tissue studies included in this review focused on determining the levels

of neurodegeneration that occur within specific areas, including the uterus and axons with their

sympathetic terminals in the myometrium (8). The goal in separating out different bodily tissues

in a woman and analyzing the changes in estrogen levels and neurodegeneration progression is to

localize the main regions of the female reproductive system that seem to be suffering from high

extents of axon degeneration and decreased neuroplasticity. The direct cause of this decreased

neuroplasticity was a result of the effect that estrogen has on sympathetic neuron neurotrophin

receptor expression. The underlying mechanisms of neuroplasticity effects varied among the

different tissues studied but included BMP4 synthesis suppression by estrogen in the vagina (8).

The tissue studies indicate which estrogen producing and utilizing regions may be contributing to

neurodegeneration in the entorhinal cortex and hippocampus.

Hormonal Replacement Therapy Studies

Hormone replacement therapy (HRT) is generally used to treat symptoms of menopause

(9). This type of study is useful in the context of this review because the researcher can directly

manipulate and measure the amount of estrogen in conjunction to measuring AD progression.

The most well known HRT study was the Women’s Health Initiative Memory Study (10) which

followed over 4,000 women in a randomized control study receiving either the hormone

treatment or a placebo in addition to the same study settings following over 2,000 women who

recently had a hysterectomy. Cognitive decline and estrogen was monitored during the trials to

evaluate disease progression and estrogen levels. The results of the study reported mixed effects

of estrogen exposure on neurodegeneration among both groups of women (10). Further studies

have been trying to identify the time period in which women may be the most vulnerable to
 8

changing estrogen levels, as well as how the type of menopause (ie. naturally, early, or externally

induced), which inherently affects the levels of estrogen, influences the progression of AD (11).

The topic of hormone replacement in conjunction with time period and menopause types are still

being studied.

Genetic Risk Studies

While studying the effects of estrogen is essential, understanding the origin of estrogen in

the body is also vital. Estrogen, like all other hormones in the body, is translated from a specific

portion of mRNA that results from the transcription of an individual’s DNA. Identifying the

genes encoding estrogen biosynthesis and the receptors within DNA, provide insight into risk

factors for neurodegeneration and may help identify which genes are specific to

neurodegeneration diseases such as AD (12). Due to the variations in DNA between individuals,

identifying and targeting specific genes has implications for disease treatments. Additional

genetic studies identified important genes, CYP17 and CYP19, as influential risk factors for

neurodegeneration in women (13). Genetic predisposition provides an explanation for genes

encoding estrogen and related hormones to those encoding tau phosphorylation which is a

commonly regarded biomarker for AD (14). These genes may provide a basis for trial screenings

with regards to further studies on estrogen and AD progression.

Alternate Life Events for Women Studies

While the main focus of this literature review is the effects of changing estrogen levels

experienced during the time of pregnancies on AD, most studies have focused on reviewing

these changes in the context of alternative life events, such as onset of puberty and menopause.

The time in a woman's life in which puberty begins, including the subsequent hormonal

fluctuations each month, have been used to quantify the amount of endogenous estrogen
 9

exposure and the potential link it has with neurodegeneration (8). In addition, clinical studies on

natural or surgically induced menopause have been used in measuring the differing levels of

estrogen as well as cognitive decline (11). The time periods of major hormonal changes during a

female’s life, outside of pregnancy, can provide valuable background information on the topic of

how estrogen affects neurodegeneration.

Parity Studies

The number of pregnancies, and the amount of time a woman spends pregnant during her

lifetime, closely reflects major changes in estrogen. The fluctuations can be measured and

correlated with the rate in AD progression, but whether the correlation is positive or negative is

being evaluated. Researchers are attempting to uncover the connection, if there is any, between

how the number and type of pregnancies affects neurodegeneration. The type of pregnancy

(parous vs nulliparous) heavily influences the levels of 17β- estradiol which may influence

neurodegeneration (15). Studies have attempted to find correlations with disease progression and

parity by utilizing a clinical dementia rating in conjunction with previous health history of the

individual (number of menstrual cycles, amount of estrogen exposure, age at first pregnancy, age

at onset of Alzheimer’s Disease symptoms) (16). These ratings and mental cognition tests to

assess correlation with parity provide insight into neurodegeneration in women.

Studies Supporting Disadvantageous Results

The main study type that concluded disadvantages with regard to neurodegeneration from

increased estrogen were HRT studies. Interestingly, the main question being asked in this context

was how the timing of this increased estrogen exposure, known as the “Critical Window”, affects

neurodegeneration (17). This “Critical Window” is a brief amount of time in a woman’s life in
 10

which increased estrogen exposure can result in protective effects. HRT studies reviewed the

effects of increased estrogen exposure outside of this window, and concluded that increased

endogenous estrogen exposure is positively associated with AD progression (9,10,18).

Another study showed that while some individuals who underwent HRT experienced

decreased neurodegeneration, almost 50% of the participants showed increased risk (18). Within

this study, the age in which the therapy was administered was recorded. The researchers

concluded that increased estrogen from these therapies has varied effects depending on the time

exposed (18). There may be advantageous results in early to mid-life females with potentially

deleterious effects in later-life (many years after menopause). While the “critical window” has

been used to identify the time in which the effect of estrogen changes, HRT studies have been

used on individuals who are already experiencing AD symptoms to see whether they are reduced

or enhanced (10). The results of the study concluded that hormone therapy does not offer

protective effects against AD progression after the age of menopause and the hormone therapy

shows adverse influence on this process in women over the age of 65. The final hormone

replacement therapy study analyzed for this literature review showed similar results in the

temporal importance of this increased estrogen exposure (11). Although it is unclear whether or

not the timing of increased estrogen exposure is a determinant of the effect on

neurodegeneration, most studies revealed that outside of this “critical window”, increased levels

of estrogen had detrimental effects on the individual in terms of neurodegeneration.

In addition to HRT studies, grand multiparity studies have also revealed similar

disadvantageous results. A specific longitudinal study sought to discover the effects of multiple

pregnancies on cognitive decline in women (19). Using a Cox proportional hazards model, using

a variety of risk factors and dementia, parity was found to be the most significant risk factor.
 11

These studies concluding disadvantageous effects from estrogen confer that the time of

HRT is affecting the progression of AD (10, 11, 17, 18, 19). While it is understood that estrogen

levels rise during time of pregnancy, whether or not the significance of this study’s conclusion

was due to increased estrogen exposure or not would require further analysis.

Studies Supporting Advantageous Results

It has already been identified that there are many different ways in which hormonal

changes in women may influence their rate of AD progression. While there is most widely a

consensus that estrogen has a role in neurodegeneration, whether the effects are protective or

detrimental are highly debated. Studies that concluded protective effects by estrogen are stated

here.

A particular study noted the densities of different estrogen receptors in specific regions of

the brain (eg. hippocampus, hypothalamus and amygdala) are involved in memory formation and

retention (15). Multimodal imaging revealed that the ERα and ERβ receptors found in these

associated areas were shown to be involved in the biochemical pathway resulting in protective

effects on neurons when acted on by estradiol (20). The ERα receptors showed to contribute

more in neuroprotection and ERβ receptors being closely associated with learning and memory

as well as survival factor for both sympathetic and sensory neurons (21). Estrogen receptors

playing a role in both memory and neuroprotection may provide insight into estrogen's role in

neurodegeneration.

When taking these findings and applying them to parity, researchers found that women

who were pregnant later in life showed better cognitive performance on brain-aging-related tests

(22), as well as lower risk for AD (23). A cumulative number of pregnancy durations was
 12

recorded for each woman involved in the study as well as the duration of each trimester for each

pregnancy (23). These measurements were utilized in a Cox proportional hazards modeling

assessment to determine the associated level of neurodegeneration. The results concluded that a

lower risk of neurodegeneration correlated with a longer duration of the first trimester of

pregnancy (23).

Figure 1: Plot reports the probability of being Alzheimer’s Disease-free for women with the total number of months

the individual was pregnant. “Cox regression of the reliance of AD risk on median-split dichotomous

characterization of cumulative months pregnant demonstrates that women above the cohort median exhibit 37.01%

lower AD risk compared with women below the cohort median.” (23)
 13

In a similar study using a Cox model, a longer reproductive span and longer duration of

life spent being pregnant, was associated with proactive effects against AD progression and risk

(24). This particular study revealed that estrogen may be involved in the disruption of the

precursor of amyloid protein plaques which would confer protective effects. Further evidence for

the involvement of estrogen in disruption of commonly identified AD biomarkers is a study in

which they found estradiol to prevent a specific type of hyperphosphorylation of tau (12). Using

rat models, researchers were able to identify that okadaic acid, which is involved in

hyperphosphorylation of tau in specific genetic sites, was negatively affected by the presence of

increased estradiol levels. These studies all conferred protective effects from estrogen against

neurodegeneration (20, 21, 23, 24, 12).

The main findings of the studies concluding advantageous effects of increased estrogen

exposure against AD progression reveal that, on a biochemical and molecular basis, estrogen

receptors might have neuroprotective abilities (20 ,21) and estradiol is able to disrupt the

formation of a common AD biomarker (12). The studies utilizing a Cox model found

correlations with increased time during pregnancy and reduced risk of AD (23, 24).

Implications of Studies on Neurodegeneration and Pregnancy

The main focus of this literature review is to determine how the recent academic

literature reveals the effects of changing estrogen levels during pregnancy on the progression of

AD. While only a few of these papers have been directly focused on time during pregnancy, it is

possible to make inferences from the alternate study focuses which may lend itself into better

understanding our main topic.

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The genetic studies can be utilized as a starting point to separate cohorts of individuals

for further analysis. In addition, the potential protective effects of decreased estrogen exposure

during menopause may prompt research regarding whether the increased levels of estrogen

during pregnancy might have the opposite effect. One might assume that if decreases in estrogen

during menopause and increased estrogen during puberty cycles and pregnancy may confer

opposite results, the “critical window” may help define the boundaries of these effects (since it

relates to the time of estrogen exposure). Furthermore, it might explain how experiencing a

pregnancy later in life and possibly closer to the time of menopause may result in a higher risk of

neurodegeneration. Alternatively, this hypothesis may also reveal that changes in estrogen levels,

because they are occurring during a time before this significant temporal window, may be

unrelated to the contributions of estrogen in detrimental effects and instead may offer protective

effects.

Concluding Remarks

Estrogen plays one of the most important roles in many stages of a woman’s life. This

literature review sought to analyze the current research that has been done in an attempt to link

estrogen changes and neurodegeneration. Although there is not a clear cohesive conclusion for

the effects of estrogen on neurodegeneration in women across the study types, the papers

reviewed here reveal more papers concluding advantageous effects. The only study type that

revealed disadvantageous results was regarding HRT. With the majority of current studies

showing estrogen having protective effects, it might be predicted that estrogen is not the primary

contributor of more females than men experiencing this disease. In addition, it has been seen that

the effect of estrogen may be related to the time of exposure. This needs to be further looked into
 15

to determine if estrogen has any effect on neurodegeneration at all, and if so, is it dependent on

when the individual is exposed to it. Specifically, the effects of estrogen on neurodegeneration

during the time of pregnancy has not been fully studied and, I believe, that understanding how

the number of pregnancies affects this process is an area that needs to be further researched. It is

understood that females undergo vast hormonal changes throughout their lives, it is now vital

that researchers get to the bottom of whether or not these changes are causing the

disproportionate AD statistic in the United States.

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