Female Sex: The Second Greatest Risk of Alzheimer’s Disease

On November 25, 1901, Auguste Deter was admitted to the Institution for the Mentally Ill in Frankfurt, Germany, where she was first introduced to Dr. Aloysius Alzheimer. Deter, who was 55 at the time, would reply “I have lost myself, so to say,” when asked questions she felt like she could no longer answer [8]. As the first patient diagnosed, Deter did not know how accurately her words described the now widespread condition named after her doctor, Alzheimer’s disease [8]. Today, Alzheimer’s disease (AD) affects over 6 million people above the age of 65 in the United States alone and is the seventh leading cause of death in the country. Of these 6 million people, 4 million are women [1]. Research studies have shown that, following age, being of the female sex is the second greatest risk factor to developing AD [1]. Although the exact correlation between sex and AD is yet to be determined, this article will explore the possible mechanisms and explanations as to why women are more prone to developing Alzheimer’s disease.

Alzheimer’s Disease Pathology

AD is commonly known by its cognitive impairment symptoms, which include progressive memory loss, language and comprehension deficits, change in typical behavior, and mood swings, amongst other issues [1]. Pathologically, AD is characterized by an accumulation of amyloid-β (Aβ) and hyperphosphorylated tau in the brain, particularly the hippocampus [4]. The hippocampus is known as the memory center of the brain, since it is responsible for the formation of memories and learning. Aβ is a protein that acts as a stressor to the mitochondria in cells and is often associated with mitochondria-induced cell death. Tau, on the other hand, is a protein that serves to stabilize the internal structure of neurons. Tau becomes toxic when equilibrium is lost, becoming abnormally regulated and forming tangles in the brain [2]. Research suggests that the accumulation of Aβ and tau tangles are correlated with inflammation in the brain and degeneration of neurons, which is to say neurons lose their function and die, leading to cognitive decline [4]. AD is a progressive disease, meaning that with time, neurons become more severely damaged, impacting more areas of the brain and eventually leading to patient death. Although the survival time after diagnosis varies from patient to patient, it is estimated that the pathological characteristics of AD begin 20 years prior to the appearance of the first symptoms [1].

Presently, there are no known cures for AD, which is a growing concern, considering it is estimated that the number of people affected by the disorder will triple by 2050 [1]. AD is not a disease simply induced by genetic abnormalities. Some patients carry a gene called APOE-4, which was initially thought to cause AD. However, about 60% of patients do not carry the APOE-4 gene at all, indicating that the disease is likely a result of several distinct factors in addition to genetics [7]. Developing AD has been more recently categorized as a consequence of aging, genetic predisposition, environmental factors, and lifestyle choices. While researchers strive to find biological markers of the disease, that is, measurable signals that indicate the presence of AD early in the pathology, one hormone in particular has attracted attention in the field: estrogen.

Estrogen and Menopause

Estrogens are a family of hormones recognized as the female sex hormones responsible for the development and regulation of the female body. In addition to the classic roles of estrogens, current research indicates that estrogens are also beneficial and protective to the  cardiovascular, skeletal, and neurological systems [9]. In fact, studies show that a decline in estrogens, which occurs naturally during menopause transition, is associated with an increased risk of cardiovascular diseases, cancer, obesity, diabetes, stroke, sleep troubles, osteoporosis, cognitive decline, and AD [6]. Hormones like estrogen and testosterone (the primary male sex hormone) were previously thought to only contribute to sexual functions, but have gained more awareness since neuroscientists discovered that sex hormones affect the brain. It is understood that genetic makeup does not only distinguish females and males in reproductive organs, but can also influence environment, lifestyle, and health factors [7]. In fact, 17β-estradiol (E2), the primary form of estrogen present in the female body during reproductive years, has particular anti-inflammatory effects in the brain [6]. E2 is referred to as the major hormonal driver of women’s brain health.

During menopause transition, women experience a rapid depletion of cerebral estrogen levels, particularly of E2 [7]. This depletion during menopause transition may cause women to become more vulnerable to neuroinflammatory diseases, such as AD. It is important to note that women spend approximately one third of their lives in the post-menopausal stage; in other words, one third of their lives with severely increased health risks due to estrogen depletion [6]. Furthermore, scientists have detected a correlation between menopause and the accumulation of Aβ in the brain. Experiments have demonstrated the direct effects of E2 on Aβ production, showing that a higher presence of E2 resulted in decreased production of Aβ in cultured neuronal cells and the presence of these molecules in neuronal vesicles, which are sac-like structures that store molecules before they are released by the neuron [6]. This strengthens the argument that estrogen has protective effects in the nervous system, specifically protecting against the development of molecular components of AD.

Preventative Measures

Due to the overwhelming amount of research relating the depletion of estrogen to numerous diseases and disorders, the scientific community has also been exploring the outcomes of hormonal replacement therapy (HRT). HRT refers to a treatment where synthetic or natural hormones are used to compensate for the decline of natural hormones in the female or male body [3]. Menopause hormonal therapy (MHT) is a type of HRT that aims to ease the symptoms of menopause [3]. MHT has been used in case studies to assess the correlation between MHT and pathological manifestations of AD. Depypere et al. recently reported preliminary results showing that women treated with MHT during the early stages of menopause showed fewer markers of Alzheimer’s pathology compared to women who did not receive the treatment. During the case study, one group of women underwent MHT for six months and were tested for several biomarkers of AD at the beginning and end of the treatment. A control group of women received no treatment and were tested at the same time points. It was expected that over time, and consequently with age, more AD biomarkers would be observed since AD occurs progressively. The expected increase in AD biomarkers was observed in the untreated group of women, whereas the MHT treated women presented fewer of these same biomarkers [3]. These preliminary results indicate that MHT could potentially serve as a preventative treatment against AD. 

While MHT is an optional treatment for women early into menopause, there are other lifestyle-related factors that serve an important role in the prevention of AD. As mentioned, AD is a consequence of a series of factors, including health and lifestyle choices. The daily decisions one makes can have a huge impact on potential cognitive decline, like that seen in AD. It is important to note that, while therapeutic measures are often beneficial, it is always preferable to incorporate natural precautions against diseases into our lifestyle. Making the conscious choice to take a healthier approach on exercise, diet, sleep, and cultivation of the mind with intellectual and social engagements are all factors known to reduce the risk of AD [7]. Several studies support the claims that a balanced lifestyle, including a healthy diet, regular exercise, sleep quality, and less stress are extremely important in the reduction of neuroinflammation, therefore also playing a role in the management of cognitive decline in old age [5,7]. Although these studies are not particularly novel for the AD research community, it is fundamental to remember how much daily choices can affect our future.

Discussion

The realization that Alzheimer’s is a disease that affects females more than males is a fundamental catalyst for further research in the field. Since being of the female sex is the second greatest risk factor of AD, the study of cellular and molecular differences between females and males is important when considering treatment options, such as MHT. While menopause is not solely responsible for the development of AD in women, the depletion of estrogen is known to cause a higher vulnerability towards a number of diseases. MHT has thus far shown exciting results particularly as a preventative measure against AD for women. More studies are needed to determine specific mechanisms of the effects of estrogens, or the lack thereof in the brain, specifically in relation to AD. Currently, there are no precise methods or medications to cure patients diagnosed with AD. Nevertheless, it is crucial to recall that by promoting healthier diets, regular exercise routines, better sleep, reduced stress, and a balanced lifestyle, it is possible to reverse the increasing trend of AD cases. Constantly observing bodily changes with age is important for everyone; however, it is especially indispensable for women in order to avoid the numerous diseases to which women are more prone. With anticipation we await for more studies to be done within the scientific community that will focus on women and be able to answer more questions regarding these still misunderstood changes and their implications in the female body. 

References:

1. Alzheimer’s Association. 2022 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2022;18.

2. Canepa E and Fossati S (2021) Impact of Tau on Neurovascular Pathology in Alzheimer’s Disease. Front. Neurol. 11:573324. doi: 10.3389/fneur.2020.573324

3. Depypere, H., Vergallo, A., Lemercier, P., Lista, S., Benedet, A., Ashton, N., Cavedo, E., Zetterberg, H., Blennow, K., Vanmechelen, E., & Hampel, H. (2022). Menopause hormone therapy significantly alters pathophysiological biomarkers of alzheimer's disease. Alzheimer's & Dementia. https://doi.org/10.1002/alz.12759

4. Int J Mol Sci. 2019 Nov; 20(22): 5536. Published online 2019 Nov 6. doi:10.3390/ijms20225536 

5. Liu W, Zhang J, Wang Y, Li J, Chang J, Jia Q. Effect of Physical Exercise on Cognitive Function of Alzheimer's Disease Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trial. Front Psychiatry. 2022 Jun 16;13:927128. doi: 10.3389/fpsyt.2022.927128. PMID: 35782450; PMCID: PMC9243422.

6. McCarthy, M., & Raval, A. P. (2020). The peri-menopause in a woman's life: a systemic inflammatory phase that enables later neurodegenerative disease. Journal of neuroinflammation, 17(1), 317. https://doi.org/10.1186/s12974-020-01998-9 

7. Mosconi, D. R. L. I. S. A. (2021). Xx Brain: The groundbreaking science empowering women to prevent dementia. ALLEN & UNWIN.

8. The story of Auguste Deter: ASC blog. ASC. (2021, March 30). Retrieved September 20, 2022, from https://www.asccare.com/story-auguste-deter/ 

9. Xu H, Wang R, Zhang YW, Zhang X. Estrogen, beta-amyloid metabolism/trafficking, and Alzheimer's disease. Ann N Y Acad Sci. 2006 Nov;1089:324-42. doi: 10.1196/annals.1386.036. PMID: 17261779.