Could Menopause Explain Why Alzheimer’s Disease Is More Common in Women?

Menopause is a natural process that occurs in approximately half of the population and signifies the end of fertility as the ovaries gradually decrease the production of sex hormones and menstruation ceases. However, menopause has also caught the attention of researchers who are seeking to understand why nearly two-thirds of individuals with Alzheimer’s disease (AD) are women.

AD is the most prevalent form of dementia, characterized by the progressive loss of memory and other cognitive functions. Symptoms can significantly impact daily life and include recurring memory loss, difficulty engaging in conversations, and impaired decision-making.

While the exact cause of AD is not fully understood, scientists have identified a range of factors, both biological and lifestyle-related, that may contribute to an increased risk of developing the disease.

For many years, it has been known that being a woman is a significant risk factor for AD, particularly as women tend to live longer than men. However, recent research suggests that hormones, specifically the hormonal changes associated with menopause, may play a prominent role in the development of the disease.

Lisa Mosconi, PhD, an associate professor of neuroscience, highlights menopause as an activating factor in the context of AD risk. This new understanding adds complexity to the relationship between gender, hormones, and AD, shedding light on the need for further investigation into this intriguing connection.

Menopause as a Potential Risk Factor for Alzheimer’s Disease

The menopause transition, known as perimenopause, typically occurs between the ages of 45 and 55 and can last for several years, ranging from 7 to 14 years. During this period, the ovaries gradually produce fewer sex hormones, including estrogen and progesterone, which are also involved in the regular menstrual cycle. Menopause is officially reached when a year has passed since the last menstrual period, marking the cessation of ovarian function.

As the ovaries undergo changes during and after the menopause transition, the brain undergoes changes as well. Symptoms commonly associated with menopause, such as hot flashes, night sweats, anxiety, depression, insomnia, and cognitive difficulties, originate in the brain rather than the ovaries, according to Lisa Mosconi.

However, it is currently unknown whether menopausal symptoms can serve as predictors of Alzheimer’s disease later in life. What researchers do know is that natural levels of estrogen and progesterone play a protective role in the brain. The brain has specific proteins that interact with these hormones, and it also produces its own estrogen and progesterone, although in lower quantities compared to the ovaries. The decline of sex hormones during menopause transition can lead to changes in the brain.

To comprehensively study whether menopause is a risk factor for Alzheimer’s disease, long-term research following the same group of women from their early 50s (when perimenopause typically begins) to their early 70s (when Alzheimer’s disease may start) would be necessary. However, such extensive studies have yet to be conducted.

Brain Changes with Menopause

Researchers are currently investigating early signs of dementia in the female brain that can appear years before the onset of Alzheimer’s disease symptoms. In the past, one of the key markers they looked for was increased levels of beta-amyloid proteins in brain regions associated with memory control, based on a study published in Nature in 2006. However, a recent investigation reported potential evidence fabrication related to this study, and the role of beta-amyloid proteins in Alzheimer’s disease remains uncertain.

Nevertheless, researchers are exploring other indicators of Alzheimer’s disease, such as reduced energy production and loss of gray matter in relevant brain regions. Gray matter refers to areas of the brain with a high concentration of neurons, which are the brain’s communication cells. In brain imaging studies focusing on individuals aged 40 to 60, researchers, including Lisa Mosconi, have observed these early signs of Alzheimer’s disease more prominently in perimenopausal and postmenopausal women compared to men of the same age.

Estrogen and the Brain

Estrogen, particularly estradiol, plays a significant role in protecting the female brain against dementia. Estrogen-related proteins are found in brain regions responsible for learning and memory, such as the prefrontal cortex, hippocampus, and amygdala. This hormone acts as a "master regulator" in the female brain, supporting brain energy levels, immunity, cellular growth, and communication.

The loss of estrogen during menopause transition may increase the risk of developing Alzheimer’s disease and other dementias. This theory, known as the estrogen hypothesis, is gaining acceptance among researchers as a potential explanation for the higher risk of Alzheimer’s disease in women. Christian Pike, a professor of Gerontology at the University of Southern California, specializes in researching sex differences in Alzheimer’s disease and supports this hypothesis.

Early Menopause and Risk for Alzheimer’s Disease

The timing of menopause transition can vary among individuals, with some experiencing it earlier than the average age of 51. Surgical menopause, resulting from the removal of the uterus or ovaries, can cause an immediate onset of menopause, whereas natural menopause occurs gradually. Studies have shown that women who undergo early menopause from surgery may have an increased risk of dementia. This is likely because the loss of estrogen occurs at a younger age, leaving more years without its protective effects on the brain.

Early menopause, occurring before age 45, has also been associated with a higher likelihood of developing dementia earlier in life, according to preliminary research. Women who experience early menopause have the option of using hormone therapy, including estrogen, to manage menopausal symptoms. However, the use of estrogen-based hormone therapy for Alzheimer’s disease is a topic of controversy. Estrogen therapy may be beneficial for individuals near the onset of menopause to potentially reduce the risk of dementia, but it may worsen symptoms in those who already have Alzheimer’s disease.

The FDA warns that hormone therapy in individuals aged 65 or older may increase the risk of dementia. Further clinical trials are needed to investigate the effects of hormone therapy on the brain and develop safer formulations. The exploration of hormone therapy’s impact and the development of improved formulations are important areas of ongoing research.

Sex Differences with Alzheimer’s Disease

The question arises: How does menopause and andropause affect men? While males do produce estrogen, the levels are much lower than in females. Estrogen plays vital roles in bone health, cell production, fertility, and liver and brain functions for both males and females. However, males do not experience a significant decline in estrogen as women do during menopause.

Instead, males undergo andropause, typically occurring around their 40s, which involves a gradual decrease in testosterone production by the testes—the primary sex hormone in males. This decline in testosterone during andropause has been associated with an increased risk of Alzheimer’s disease in men.

Exploring sex differences allows researchers to identify specific brain changes that are unique to menopause or andropause when comparing individuals of the same age. However, it’s important to note that sex differences encompass more than just estrogen differences. For instance, women have a higher likelihood than men of having a major gene mutation (APOE4 gene) linked to Alzheimer’s disease. Although it remains uncertain whether menopause is related to any genetic risk for AD, this is an area of ongoing investigation for researchers.

How to Reduce Your Risk of Alzheimer’s Disease

Currently, there is no cure for Alzheimer’s disease and no guaranteed prevention strategies. However, experts recognize that the transition to menopause can increase the risk of various health conditions, including high blood pressure, heart disease, diabetes, and susceptibility to head injuries, all of which are risk factors for Alzheimer’s disease.

To help reduce the risk of developing Alzheimer’s disease, experts recommend adopting a well-rounded healthy lifestyle, which includes:

• Eating a healthy diet: Focus on a nutritious diet rich in fruits, vegetables, limited protein, and whole grains.
• Regular exercise: Engage in at least 150 minutes of moderately intense exercise, such as brisk walking, each week to maintain a healthy weight. Routine vigorous exercise is associated with a reduced risk of Alzheimer’s disease and other dementias.
• Getting sufficient sleep: Aim for at least 7 hours of good-quality sleep per day, as it contributes to overall health.
• Managing stress: Take time to relax and engage in activities you enjoy, as excess stress during the menopause transition can be harmful to both your body and brain.
• Avoiding environmental toxins: Minimize exposure to harmful toxins like air pollution, which has been linked to greater cognitive decline.
• Maintaining social connections: Stay socially engaged and connected to others, as social isolation is associated with an increased risk of dementia. Regularly visiting loved ones can help reduce this risk.
• Keeping mentally active: Engage in mentally stimulating activities throughout adulthood, such as mentally challenging work, to help reduce the risk of dementia.
• Regular medical checkups: Visit your OB-GYN to discuss ways to prepare for menopause and manage menopause symptoms, ensuring you stay up to date with medical checkups.

Experts emphasize that maximizing overall health is currently the most effective approach to reducing the risk of Alzheimer’s disease and promoting brain resilience. However, more information, education, and research are needed specifically regarding menopause and its relationship to Alzheimer’s disease.