Alzheimer's disease: Stress may increase risk in females

• Women are twice as likely as men to develop Alzheimer’s disease, the most common form of dementia.
• The greater life expectancy of women is a major factor, but longevity alone cannot account for the huge difference in risk. Hormones, genetics, and lifestyle factors are all possible explanations.
• Now, a study has found that stress leads to a rise in beta-amyloid — the protein that forms the plaques found in the brains of people with Alzheimer’s — in female mice.
• More research is needed to confirm the mechanisms behind the difference and whether the same happens in people.

Alzheimer’s disease is the most common form of dementia, causing up to 70% of dementia cases. According to the Alzheimer’s Association, it affects some 6 million people in the United States, and around two-thirds of those affected are women.

Increasing age is the greatest risk factor for Alzheimer’s disease, and women, on average, live longer than men. According to the Centers for Disease Control and Prevention (CDC), in 2021, women’s life expectancy at birth in the United States was 79.1 years, compared with 73.2 for men.

Dr. Emer MacSweeney, CEO and consultant neuroradiologist at Re:Cognition Health, told Medical News Today that “the risk of developing Alzheimer’s disease is multifactorial, with a higher incidence in women than men, even when adjusted for the longer average life span for women.”

Why are women more at risk than men?

Those extra life years alone cannot fully explain the difference in Alzheimer’s disease risk between women and men. Recent research has suggested that hormonal changes after menopause may contribute to risk.

And women may have a greater genetic risk, too — the APOE e4 gene variant, which increases dementia risk and is carried by around 15% to 25% of people, seems to have more effect in women than men.

Also under investigation are societal and lifestyle factors. The Alzheimer’s Association recently reported that women who undertook paid employment had slower memory decline in late life than those who did not.

Recent research has focused on whether stress is a contributing factor. It has been shown that stress can accelerate symptoms of Alzheimer’s, but how might it increase the risk of developing Alzheimer’s disease?

Stress and cognitive function

A new study has found that stress leads to a rise in beta-amyloid in female mice, and not in males. Beta-amyloid forms plaques in the brain that interfere with nerve impulses and trigger inflammation and are widely thought to be responsible for many of the symptoms of Alzheimer’s disease.

The study, from Washington University School of Medicine, St. Louis, is published in Brain.

“Stress can have a profound effect on the body and we are understanding more about the implications it can have to our mental and physical health — both positive and negative,” explained Sebnem Unluisler, genetic engineer and chief longevity officer at the London Regenerative Institute in the United Kingdom, not involved in the study.

“Stress triggers the release of hormones such as cortisol and adrenaline, which, if produced excessively or over a prolonged period of time, can have a hugely negative effect on the body, causing inflammation, damage to DNA and cells, and accelerating the aging process, which of course can affect the brain and cognition,” she added.

Dr. John Cirrito, co-lead study author, and a professor in the Department of Neurology at Washington University School of Medicine in St. Louis, also told us why stress might play a role in Alzheimer’s risk in women:

“Many other studies have demonstrated that women are more likely to be stressed, that stress is linked to increased risk of Alzheimer’s disease, and that women are at higher risk of Alzheimer’s disease. We are not the first to put together this possible link. However, there could many possible reasons that link stress, women and Alzheimer’s disease, including correlational, comorbidities, and lifestyle.”

“Our study demonstrates a direct link between stress and Alzheimer’s disease in women at a cellular level,” he told MNT.

Measuring the stress response

“Whilst stress has been accepted as a significant risk factor, Edwards et al have provided new data from studies on mice to explain why a different response to stress may account for the higher incidence of Alzheimer’s disease in women, compared to men,” said Dr. MacSweeney.

Using mice, the researchers in the current study investigated the effect of stress on levels of beta-amyloid in the interstitial fluid of the hippocampus. The hippocampus is an area of the brain that is affected in the early stages of Alzheimer’s disease and continues to deteriorate as the disease progresses.

They exposed mice to one of two stressors — restraint stress or olfactory stress — for 3 hours.

Restraint stress involved placing the mouse in a small, clear, plastic container with air holes that restricted their movement.

For olfactory stress, a small tube containing 0.1 milliliters (ml) of urine from a predator (fox, bobcat, or coyote) was placed in their normal cage. The urine was swapped every 30 minutes so the mice did not become accustomed to the scent of one predator.

Beta-amyloid levels were measured before, during, and after stress, for a total of 22 hours.

Sex differences, stress, and beta-amyloid

The researchers measured levels of stress hormones in the blood of the mice, and found that males and females were experiencing similar levels of stress. But there was a significant difference in beta-amyloid levels.

In female mice, beta-amyloid levels in the interstitial fluid rose by around 50% within the first 2 hours of stress, and stayed elevated for the rest of the monitoring period. Only about 20% of male mice exhibited a small, delayed increase in beta-amyloid.

Dr. Cirrito explained the importance of raised beta-amyloid in the interstitial fluid: “In mice there is a tight correlation between the concentration of [interstitial fluid] beta-amyloid within a brain region and if/ how much that region develops beta-amyloid plaques. Elevated [interstitial fluid] beta-amyloid also drives plaque formation (vice versa with suppressed [interstitial fluid] beta-amyloid).”

However, he added that “it is difficult to make that direct comparison in humans since we cannot measure [interstitial fluid] as readily in people.”

Cellular pathway

Key to the difference between males and females was the cellular response to the stress hormone, corticotropin-releasing factor (CRF).

In female mice, nerve cells take up this hormone. The cascade of events that follows increases levels of beta-amyloid in the brain. The nerve cells of male mice do not take up the hormone.

The researchers suggest that this is due to the CRF receptor acting differently in males and females.

“Whilst the study strongly suggests stress is one potential factor that may influence risk, quite significantly, it is still only one of many factors. However, the authors are the first to determine, at the cell signaling level, why stress differentially affects disease-related proteins in males and females.”

– Dr. Emer MacSweeney

Might the same happen in people?

While this finding in mice is important, the researchers recognize that the mechanism may not be the same in people. However, their findings may help show directions for further research and treatment, as Dr. MacSweeney explained.

“It is not possible to extrapolate, with confidence, that this differential response to stress in mice translates precisely to humans,” she told us. “However, the physiological explanation in mice is interesting, and could provide, at least in part, the explanation for the gender differences between men and women for risk of Alzheimer’s.”

“The finding is, in turn, important in guiding future pharmaceutical research towards new treatment options, that may differ between males and females,” she added.

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