Stress in Middle Age Women Linked to Dementia and Alzheimer’s Risk Decades Later

Stress Middle Age Women to Dementia Alzheimer’s Risk
Stress in Middle Age Women – Dementia and Alzheimer’s

Update at BrainImmuneA Swedish study, published in the August 2013 online issue of BMJ Open indicates that stress in middle-age women is associated with increased risk of dementia and Alzheimer’s disease (AD) decades later in life. This is perhaps the first population study on the relationship between midlife stressors and increased risk of dementia in late life.

Stress in adulthood is known to influence mental health later in life, and prolonged exposure to stress and increased levels of glucocorticoids are linked with poorer memory performance and hippocampal atrophy, and an increased production of proinflammatory cytokines in the brain. Stress may lead to a cumulative burden to the brain with dysregulation in neuroendocrine systems. For instance, a study among Holocaust survivors found that higher levels of stress hormones remained decades after the traumatic experience.

Previous research indicates that lifelong work-related stress such as low job control and high work strain (Wang HX et al., Alzheimers Dement, 2012; 8:114) and anxiety and vulnerability to stress contribute to the development of dementia. Also, both physiological (restraint) and psychological stress (social isolation) have been shown to increase brain expression of amyloid-beta and hyperphosphorylated tau (Bissette G., J Alzheimers Dis, 2009; 18:371).

In the BMJ Open study Lena Johansson and colleagues from the Sahlgrenska Academy at Gothenburg University, the Karolinska Institute in Stockholm, Sweden, and the Utah State University in the US, used a prospective longitudinal population study to examine whether common psychosocial stressors in midlife were related to distress, late-life dementia and AD in 800 women, systematically selected for a psychiatric examination in 1968 and followed over 38 years.

The study shows that number of common psychosocial stressors in midlife may have severe and long-standing consequences such as an increased risk of dementia and AD in late life. The authors also report that number of psychosocial stressors in 1968 was related to increased level of distress at every examination conducted between 1968 and 2005.

These results may suggest that further studies investigating the link between midlife stress, dementia and AD are warranted, and that stress management and behavioral therapy might be required in individuals with history of psychosocial stressors.

Source: BMJ Open. 2013; 3(9): e003142.
Read more: BMJ Open


In 2014, here at BrainImmune, we also discussed a recent editorial, where Lena Johansson outlines some current concepts and research trends related to the long terms effects of stress and their impact on risk and development of Alzheimer’s disease (AD) in women.

According to the American Alzheimer’s Association several studies reported at the 2017 Alzheimer’s Association International Conference (AAIC 2017) in London confirmed racial inequities in numbers of people with Alzheimer’s disease and also point to growing evidence that early life stress contributes to dementia risk in late life.

Megan Zuelsdorff, Ph.D., at the University of Wisconsin School of Medicine and Public Health, and colleagues examined the impact of lifetime stressful experiences on cognition as part of the Wisconsin Registry for Alzheimer’s Prevention (WRAP) Study.

The researchers found that a greater number of stressful events was associated with poorer late-life cognitive function for all study participants. Even within a relatively small, highly educated sample, African Americans experienced over 60 percent more stressful events than non-Hispanic Whites during their lifetimes, and these experiences were linked to poorer memory and thinking skills in older age. The researchers determined that, in African Americans, each stressful experience was equivalent to approximately four years of cognitive aging.

As per “researchers found that every stressful event was equal to 1.5 years of brain aging across all participants, except for African-Americans, where every stressful event was equal to 4 years of brain aging”.

A 2018 review summarizes clinical data and relationship between Alzheimer’s disease and stress. Thus, cohorts of patients with Mild Cognitive Impairment (MCI) have higher average circulating cortisol levels, while dementia patients show decreased dexamethasone suppression of cortisol release. These findings suggest that a hyperactive hypothalamic–pituitary–adrenal (HPA) axis is an indication of more advanced disease. Also, recent evidence is summarized indicating that those who experience late-life depression had a two-fold elevated risk of a dementia diagnosis.

A 2019 report based on the Baltimore Epidemiologic Catchment Area study indicates that a greater number of recent stressful life events, but not of more remote stressful events, was associated with greater verbal memory decline by in women but not in men.

The authors of this study concluded that unlike men, middle-aged women with a greater number of recent stressful life events demonstrate memory decline over a decade later. Sex differences in cognitive vulnerability to stressful life events may underlie women’s increased risk of memory impairment in late life.

A 2020 opinion article discusses that the hippocampus is the brain structure most associated with AD so that hippocampal atrophy is considered the gold standard brain biomarker. In the hippocampus, cortisol receptors, both glucocorticoid (GR) and mineralocorticoid (MR), are present. High-affinity MR appear to have a protective role and promote resilience, whereas low-affinity GR may play a role in promoting neuronal death; the balance between both types of receptors is advisable for a proper hippocampal function.

Stress is capable of breaking the balance between both receptors, leading to a loss of thickness in the hippocampus. As per the authors of this opinion article it is precisely the atrophy in the dentate gyrus associated with stress in animals and humans that may be the key; this region plays a critical role in the sustained neurogenesis throughout adult life.

Furthermore, the authors discuss a link between cortisol levels and the progression of dementia. They suggest that the chronic stress suffered especially in midlife may precede and act as a trigger of subjective cognitive decline (SCD) that could appear before MCI, which can take place before the early clinical symptoms of AD.

The authors of a 2021 review propose a mechanism by which genetic factors that influence hypothalamic–pituitary–adrenal (HPA) axis reactivity may also impact inflammation, a key driver of neurodegeneration. They hypothesize that these factors can mediate glucocorticoid priming of the immune cells of the brain, microglia, to become pro-inflammatory and promote a neurotoxic environment resulting in neurodegeneration.

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