Alzheimer’s risk associated with stressful life events during childhood and midlife, study finds

Alzheimer’s disease, a major cause of dementia, currently affects approximately 50 million people worldwide, a number expected to triple by 2050.

A recent study published in the Annals of Neurology explores the relationship between stressful life events and the risk of developing Alzheimer’s disease, focusing on how the timing and nature of these stressors might influence disease onset.

The study finds that not all stressful events are equally impactful, with midlife or childhood stressors showing a stronger association with Alzheimer’s disease risk factors compared to stress accumulated over a lifetime.

Prior research has identified various psychological factors such as depression, anxiety, and chronic stress as potential risk factors for Alzheimer’s disease. These factors can activate biological responses that may predispose individuals to the disease.

The new study aimed to expand on this understanding by specifically focusing on the role of stressful life events and their impact on Alzheimer’s disease biomarkers, brain inflammation, and brain structure. This was particularly relevant as previous studies have primarily concentrated on neuropsychiatric symptoms rather than the broader category of life stressors.

Stressful life events are incidents that significantly disrupt an individual’s usual routine, requiring considerable psychological and emotional adjustment. These events can range from personal losses, such as the death of a loved one, to major life changes like divorce, job loss, or serious health issues.

For their study, the researchers utilized a well-established cohort from the ALFA (ALzheimer’s and FAmilies) study. This longitudinal project involves a large group of 2,743 cognitively unimpaired participants who are at increased risk of developing Alzheimer’s disease, primarily due to having at least one parent diagnosed with the condition.

Participants underwent a series of assessments which included clinical interviews to gather detailed health and lifestyle information, cognitive tests to assess mental function, blood tests for genetic analysis (genotyping), and lumbar punctures to collect cerebrospinal fluid (CSF). This fluid was analyzed for key biomarkers of Alzheimer’s disease, such as phosphorylated-tau (p-tau) and beta-amyloid (Aβ) ratios, which are proteins associated with Alzheimer’s disease pathology. Additionally, magnetic resonance imaging (MRI) scans were performed to evaluate brain structure, focusing on gray matter volume.

To specifically measure exposure to stressful life events, the researchers conducted semi-structured interviews using a predefined list of 18 life events known to potentially require significant psychological adjustment. Participants were asked if they had experienced these events at any point in their lives, the number of occurrences, and their ages at the time of these events. This method allowed the researchers to compile a comprehensive profile of each participant’s exposure to stress across different life stages.

The overall number of stressful life events experienced across a person’s lifetime did not uniformly associate with increased risk of Alzheimer’s biomarkers, neuroinflammation, or brain structure changes typically indicative of Alzheimer’s disease progression.

However, the analysis did reveal more nuanced associations when considering the timing of these stressors and certain demographic factors. Specifically, stressors occurring during childhood and midlife were more strongly correlated with indicators of Alzheimer’s disease risk.

For instance, childhood stress was linked to increased levels of neuroinflammation, measured through elevated interleukin 6 (IL-6) levels, a pro-inflammatory cytokine associated with various diseases including Alzheimer’s disease. This suggests that early-life stress may trigger long-term inflammatory responses that could potentially contribute to the development of Alzheimer’s disease later in life.

On the other hand, stressful life events experienced during midlife showed a connection to changes in Alzheimer’s biomarkers such as the beta-amyloid (Aβ) ratios. Beta-amyloid plaques are one of the hallmark pathologies of Alzheimer’s disease, and their accumulation can begin years before the onset of clinical symptoms. The study’s findings imply that stressors during this critical period of life might influence the early pathological processes associated with Alzheimer’s disease, particularly the accumulation of these damaging proteins.

“We know midlife is a period when Alzheimer’s disease pathologies start to build up. It is possible that these years represent a vulnerable period where experiencing psychological stress may have a long-lasting impact on brain health,” said Eleni Palpatzis, a researcher at the Barcelona Institute for Global Health and first author of the study.

The researchers also found that the effects of accumulated stressful life events over a lifetime differ between men and women in relation to Alzheimer’s disease risk factors. Specifically, in men, a higher number of stressful life events was linked to increased levels of beta-amyloid (Aβ) protein. On the other hand, in women, a greater number of stressful events was correlated with reduced volumes of grey matter in the brain, suggesting that the impact of stress may vary significantly based on sex.

Individuals with a history of psychiatric disorders appeared to be particularly vulnerable to the effects of stressful life events. In this group, increased stress was associated with higher levels of beta-amyloid (Aβ) and tau proteins. Additionally, these individuals exhibited lower volumes of grey matter.

“Our study reinforces the idea that stress could play a significant role in the development of Alzheimer’s disease and provides initial evidence regarding the mechanisms behind this effect, but additional research is needed to replicate and validate our initial findings,” said Eider Arenaza-Urquijo, the senior author of the study.

While the study provides valuable insights, it has limitations. The reliance on participant recall for stressful events can introduce bias, and the measure of stress did not account for the personal significance or severity of the events. Furthermore, the study population was largely homogeneous (primarily White Caucasian), which may limit the generalizability of the findings to other ethnic groups.

The research opens several paths for future investigation, suggesting the need for more nuanced studies that consider the type and perceived severity of stressors. It also underscores the potential for early interventions that could target specific life periods to reduce Alzheimer’s disease risk.

“Our findings demonstrate moderate support that in some contexts, [stressful life events] may have a long-lasting impact on brain health through the [Alzheimer’s disease], neuroinflammation, and atrophy pathways decades after exposure to [stressful life events]… Future research is needed to refine the identification of risk profiles that would most benefit from such type of interventions,” the researchers concluded.

The study, “Lifetime Stressful Events Associated with Alzheimer’s Pathologies, Neuroinflammation and Brain Structure in a Risk Enriched Cohort,” was authored by Eleni Palpatzis, Muge Akinci, Pablo Aguilar-Dominguez, Marina Garcia-Prat, Kaj Blennow, Henrik Zetterberg, Margherita Carboni, Gwendlyn Kollmorgen, Norbert Wild, Karine Fauria, Carles Falcon, Juan Domingo Gispert, Marc Suárez-Calvet, Oriol Grau-Rivera, Gonzalo Sánchez-Benavides, Eider M. Arenaza-Urquijo, and the ALFA study.