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Two out of three Americans who are diagnosed with Alzheimer\u2019s disease are women. And outside of a specific diagnosis, women tend to experience faster cognitive decline compared to men. The umbrella term for these symptoms affecting the brain, memory, and thinking is dementia<\/em>.<\/p>\n\n\n\n For years, researchers thought this phenomenon was because women live longer than men on average, so they have more chances to show these symptoms. However, one research group from the Women\u2019s Health Neuroscience Program at Texas A&M University is trying to find specific biological reasons for the prevalence of dementia in women<\/a>.<\/p>\n\n\n\n They’re looking at female-specific therapies that, when combined with hormones, could actually prevent and reduce cognitive decline. This article will explore several research studies from this group in an attempt to uncover some of the reasons behind female dementia and what we can do about it.<\/p>\n\n\n\n The burden of Alzheimer\u2019s disease (AD) falls hardest on women. They make up the majority of Alzheimer\u2019s patients (almost two-thirds<\/a>!), and women over age 60 are almost twice as likely<\/a> to develop AD as breast cancer.\u00a0<\/p>\n\n\n\n Yes, women tend to live longer than men and dementia is a consequence of aging, but even among men and women living to the same age, women are more likely<\/a> to be diagnosed with AD compared to men [1] [2]. Interestingly, women were not<\/em> more likely to be diagnosed with general dementia compared to men. According to one study, the chances of developing dementia from a cause other than AD were comparable between women and men [1].\u00a0<\/p>\n\n\n\n Yes, women tend to live longer than men and dementia is a consequence of aging, but even among men and women living to the same age, women are more likely to be diagnosed with AD compared to men.<\/p><\/blockquote><\/figure>\n\n\n\n Remember, dementia<\/a> is the umbrella term for any cognitive decline. AD is the most common disease that causes dementia, and specifically refers to nerve cell damage in the brain. Plaque deposits of a sticky protein called beta-amyloid and twisted fibers called tau build up among the nerve cells and prevent them from communicating with each other. This makes it harder to remember and process information and causes mood and behavior changes.<\/p>\n\n\n\n Another explanation for the prevalence of AD and dementia among women is the incidence of stroke. The result of a blocked blood vessel, a stroke cuts off blood and oxygen to the brain which causes brain cells to die. After age 50, women are more likely<\/a> to experience stroke compared to men. Stroke can increase the risk for further cognitive impairment and eventually dementia. The American Heart Association<\/a> recently shared the risk of dementia may be up to three times higher following a stroke.<\/p>\n\n\n\n Women and men share some of the risks for stroke, like high blood pressure, but there are also risk factors unique to women. For example, pregnancy complications are one of the most important risk factors for stroke. Pregnancy<\/a> puts extra strain on the heart as the woman\u2019s blood volume increases, and preeclampsia<\/a> can cause high blood pressure.<\/p>\n\n\n\n Early menopause<\/a> (or when ovulation and menstruation stop before age 45) also increases the risk for stroke. Unsurprisingly, hormonal contraception<\/a> also doubles the risk for heart attack and stroke, because it interferes with biological hormone production and increases the risk for blood clots<\/a>. The hormone estrogen<\/a> is protective for cardiovascular health<\/a>, and the drop-off in estrogen production with menopause increases a woman\u2019s risk for heart disease.\u00a0<\/p>\n\n\n\n In fact, even aside from stroke, estrogen also plays a pretty significant role in brain health<\/a>.<\/p>\n\n\n\n Estrogen<\/a> is known to have fairly protective effects on many of your body\u2019s systems, including bone health<\/a>, skin, mucous membranes, and brain health<\/a>. In the brain, estrogen suppresses inflammation by reducing the activity of brain immune cells called microglia, which limits nerve cell damage [3]. It also improves mitochondrial function, which can protect neurons from degeneration [3]. Several research groups have also been studying the protective effect of estrogen after stroke, specifically how estrogen can help reduce brain damage.<\/p>\n\n\n\n One of the leading researchers investigating women\u2019s brain health, stroke, and dementia risk is Farida Sohrabji, PhD, at Texas A&M University. For years, she\u2019s been asking questions about how estrogen is protective, when it becomes damaging, and how researchers can use this knowledge to discover sex-specific treatment options to reduce female dementia risk. Her team\u2019s research largely uses rat models of young and aging female brains (younger rats of reproductive age, or older rats that no longer have reproductive cycles are used to mimic pre- and postmenopausal women, respectively). They use these rats to study what estrogen does in the brain<\/a> after a stroke.<\/p>\n\n\n\n First, they found that estrogen protects the brain after stroke. Sohrabji\u2019s team used younger rats with their ovaries removed (which meant they couldn\u2019t produce their own estrogen), and induced stroke in these animals. Then, they measured the rat\u2019s brain damage. These rats had worse brain damage than the control group, but when the research team gave the rats estrogen replacement therapy, the stroke outcomes were better. They thought they\u2019d found the magic bullet: Why not give estrogen therapy to any female patient after a stroke? <\/p>\n\n\n\n But Sohrabji\u2019s team tested this theory in their older rats (postmenopausal ones) and saw the opposite. Estrogen was no longer protective! The research team\u2019s big discovery was that estrogen\u2019s effect on the brain changes from protective to harmful after<\/em> menopause [4]. Brain tissue damage, cognitive impairment, and neurodegeneration was more severe in older rats treated with estrogen.<\/p>\n\n\n\n Because both the younger rats without ovaries and the older postmenopausal rats both lacked the ability to produce their own estrogen, Sohrabji\u2019s team hypothesized there must be some other<\/em> factor in the older rats that was missing that was required to help estrogen do its helpful work. And (spoiler alert!) they found one.<\/p>\n\n\n\n Because both the younger rats without ovaries and the older postmenopausal rats both lacked the ability to produce their own estrogen, Sohrabji\u2019s team hypothesized there must be some other<\/em> factor in the older rats that was missing that was required to help estrogen do its helpful work.<\/p><\/blockquote><\/figure>\n\n\n\n The researchers found a protective growth factor called insulin-like growth factor (IGF-1) that is reduced in aging brains. It\u2019s a hormone that has many functions, but in the brain, it turns on cell survival pathways to help neurons resist damage, helps the body create new neurons, and reduces inflammation [5]. <\/p>\n\n\n\n Interestingly, estrogen also<\/em> performs some of these roles. And, like estrogen, IGF-1 levels also naturally decline with age, so it would make sense that estrogen would \u201close\u201d its benefits in older females lacking IGF-1. When IGF-1 levels are high (as they are in younger animals) estrogen can trigger these protective pathways and reduce stroke damage. But when IGF-1 levels are low (as they are in older animals), estrogen may no longer be able to activate the same repair signals in the brain. In the latter environment, estrogen can shift from activating survival pathways to promoting inflammatory or damaging responses instead.<\/p>\n\n\n\n So, Sohrabji\u2019s team wondered, could it be that estrogen just needs a helper (i.e., IGF-1) to improve stroke outcomes in middle-aged brains? They did the experiment and they were right! <\/p>\n\n\n\n Older rats that received estrogen and<\/em> IGF-1 no longer suffered the toxic effects of the estrogen-only treatment [4]. Sohrabji\u2019s team\u2019s research showed that the decline of estrogen\u2019s effectiveness in the aging brain was correlated to the decline of IGF-1 levels. This introduced an important nuance to estrogen therapy: rather than being simply \u201cgood\u201d or \u201cbad,\u201d estrogen\u2019s effects on the brain appear to depend on timing and the hormonal environment in which it operates.<\/p>\n\n\n\n This introduced an important nuance to estrogen therapy: rather than being simply \u201cgood\u201d or \u201cbad,\u201d estrogen\u2019s effects on the brain appear to depend on timing and the hormonal environment in which it operates.<\/p><\/blockquote><\/figure>\n\n\n\n Further work from Sohrabji\u2019s research group showed that IGF-1 actually protects the older brain in several ways after stroke. In middle-aged female rats, treatment with IGF-1 reduced inflammation and helped stabilize the blood-brain barrier (the protective layer that prevents harmful molecules from entering the brain). When this barrier breaks down after a stroke, inflammatory molecules can flood the brain and worsen injury. By strengthening this barrier and suppressing inflammatory cytokines, IGF-1 helped limit the spread of damage after stroke [6].<\/p>\n\n\n\n Dr. Sohrabji\u2019s work supports the idea that the timing of exposure to exogenous estrogen matters. In other words, estrogen all the time<\/a> isn\u2019t what we want. Instead there\u2019s a concept known as the \u201ccritical window\u201d or timing hypothesis [7]. According to this idea, estrogen\u2019s effects on the brain depend on when hormone exposure occurs relative to menopause. When estrogen is present during the reproductive years, it works alongside other protective signals like IGF-1 to support neuronal survival and recovery after injury. But once the hormonal environment of the brain changes with aging, the same hormone may produce very different effects.<\/p>\n\n\n\nIs there a dementia gender gap?<\/span><\/h2>\n\n\n\n
Stroke is a major risk for dementia<\/span><\/h2>\n\n\n\n
Estrogen\u2019s role in protecting brain health after<\/em> stroke<\/span><\/h2>\n\n\n\n
Using estrogen after stroke in younger rats<\/span><\/h3>\n\n\n\n
Using estrogen after stroke in older rats<\/span><\/h3>\n\n\n\n
Discovering a key brain-protective growth factor<\/span><\/h2>\n\n\n\n
Consider IGF-1 \u201cestrogen\u2019s little helper\u201d<\/span><\/h3>\n\n\n\n
What these findings mean for future medical research<\/span><\/h2>\n\n\n\n