The Story of Dementia: The Influence of Sex Hormones in Alzheimer's Disease
Author: Mashiyet Ahmed
Editor: Nadia Hall
The story of dementia is long and uncertain, often involving heartbreaking moments of patients losing touch with their loved ones, and no cures on the horizon. It is a story that increasingly affects women; almost two-thirds of dementia diagnoses in the United States of America are in females over the age of 65 (Budson, 2022). Research in gendered brain science is beginning to reveal why women are at a greater risk for dementia and what therapeutic avenues can be explored as possible treatment options.
Alzheimer’s Disease (AD) and mild cognitive impairment (MCI) are both neuropathologies that impact the functional and emotional lives of people who are diagnosed with them, as well as their families and friends. AD, the most common form of dementia, is characterized by a progressive loss of memory and an overall decline in cognitive function (Hippius & Neundörfer, 2003). In 1906, a German psychiatrist named Alois Alzheimer was examining postmortem female brains when he began to recognize a pattern of physical abnormalities such as damaged tissues, clumps of plaques, and uncharacteristic bundles of fibers. The critical piece to this puzzle for Dr. Alzheimer was that all these women had died from an undiagnosed mental illness (Hippius & Neundörfer, 2003).
Since 1906, substantial progress has been made in understanding the basic neuropathological principles at play in dementia — and only recently have scientists begun to unearth the influence of sex on AD, and precisely why women make up most dementia diagnoses. What Dr. Alzheimer observed in 1906 among his female subjects is known today as tau-protein tangles, neuronal atrophy, and accumulation of beta-amyloid plaques in the extracellular spaces between neurons (Hippius & Neundörfer, 2003). These pathologies originate in the entorhinal cortex of the brain, which includes critical neural circuits for memory, and the hippocampus (memory consolidation center). Gradually, the pathology spreads to the surrounding brain areas critical for executive function, language, social behavior, and emotional abilities (Li et al., 2014).
Estrogen is a key part of the story of dementia in women. This female sex hormone is synthesized both in the ovaries and in the brain by the enzyme aromatase. Notably, high concentrations of estrogen receptors and aromatase exist in the hippocampus, which is important for memory function (Li et al., 2014). Typically, women develop AD in their 50s and 60s when they are postmenopausal and no longer regularly producing endogenous estrogen (Budson, 2022). But why is estrogen central to deciphering the sex disparity in dementia? Brain-derived estrogen is thought to have strong neuroprotective (protection against brain damage) abilities such as promoting neuroplasticity by regulating the processes of synaptogenesis (formation of synapses) and neurogenesis (formation of brain cells), which are processes that increase neural communication (Li et al., 2014). It is unclear exactly how estrogen does this, but the sudden dip in estrogen levels experienced by postmenopausal women is likely a prominent factor in the sex disproportion that has been confirmed by many observational and epidemiological studies. In men, the lifelong process of converting testosterone to estrogen does not stop, whereas, in women, it does stop due to menopause (Janicki & Schupf, 2010). This critical difference is thought to contribute to the sex differences seen in AD.
Another integral part of the story of dementia is that gonadal estrogen (produced by the ovaries) does not have the same neuroprotective effect as brain-derived estrogen. The brain estrogen theory holds support for the idea that brain-produced estrogen is a more potent mediator of female experiences with dementia than gonadally-produced estrogen (Li et al., 2014). For example, one study revealed that mice with reduced aromatase enzymes and estrogen receptors showed greater brain damage in the development of AD than ovariectomized (ovarian-removed) mice (McCullough et al., 2003). In another study, brain-estrogen-depleted mice in an AD model responded better to estrogen replacement therapy (increases estrogen circulation) than ovariectomized mice, thus, strongly suggesting that the properties of brain estrogen are more relevant to combating dementia than those of estrogen produced by the ovaries (Li et al., 2013). Maintaining brain estrogen levels during the aging process might be vitally important for normal cognitive function, as well as for preventing the onset of dementia, in women.
The story of dementia and what it means for women's lives is always changing in light of new research and therapeutic advancements. Acknowledging the importance of estrogen introduces the possibility of using hormonal therapies to tackle the higher prevalence of dementia in women, or, at the very least, motivates scientists to further explore the link between female health, estrogen, and Alzheimer’s Disease.
References
Budson, A. (2022, January 20). Why are women more likely to develop Alzheimer’s disease? Harvard Health Publishing. https://www.health.harvard.edu/blog/why-are-women-more-likely-to-develop-alzheimers-disease-202201202672.
Hippius, H., & Neundörfer, G. (2003). The discovery of Alzheimer's disease. Dialogues in Clinical Neuroscience, 5(1), 101-108. https://doi.org/10.31887/DCNS.2003.5.1/hhippius
Janicki, S., & Schupf, N. (2010). Hormonal Influences on Cognition and Risk for Alzheimer’s Disease. Current Neurology and Neuroscience Reports, 10(5), 359-366. https://doi.org/10.1007%2Fs11910-010-0122-6
Li, R., Cui, J., & Shen, Y. (2014). Brain sex matters: Estrogen in cognition and Alzheimer’s disease. Molecular and Cellular Endocrinology, 389(1-2), 13-21. https://doi.org/10.1016/j.mce.2013.12.018
Li, R., He, P., Cui, J., Staufenbiel, M., Harada, N., & Shen, Y. (2013). Brain Endogenous Estrogen Levels Determine Response to Estrogen Replacement Therapy via Regulation of BACE1 and NEP in Female Alzheimer’s Transgenic Mice. Molecular Neurobiology, 47(3), 857-867. https://doi.org/10.1007/s12035-012-8377-3
McCullough, L. D., Blizzard, K., Simpson, E. R., Oz, O. K., & Hurn, P. D. (2003). Aromatase Cytochrome P450 and Extragonadal Estrogen Play Role in Ischemic Neuroprotection. Journal of Neuroscience, 23(25), 8701-8705. https://doi.org/10.1523/JNEUROSCI.23-25-08701.2003