Frequent Stress In Midlife Could Trigger Early Alzheimer’s Disease

We all face stressful events throughout our lives — the loss of a loved one, a major illness, financial hardships. While it’s well-known that chronic stress can take a toll on our mental health, a new study suggests that for certain people, a lifetime of stress may also leave its mark on the brain in ways that could increase the risk of Alzheimer’s disease.

The study, conducted by researchers from the Barcelona Institute for Global Health (ISGlobal) and published in the Annals of Neurology, looked at nearly 1,300 cognitively healthy adults in late middle-age who are part of the ALFA project, an ongoing study in Spain focused on identifying early risk factors for Alzheimer’s. Most of the participants had a family history of the disease, putting them at heightened risk.

Woman feeling sick, upset, sad
Constant stress can take a deep toll on the brain, leading to changes that could fuel Alzheimer’s-related proteins and plaques. (Photo by Andrea Piacquadio on Pixels)

As part of the study, participants underwent brain scans and spinal fluid tests to measure levels of key Alzheimer’s-related proteins and inflammatory markers. They also completed detailed interviews about stressful life events they had experienced throughout their lives.

Alzheimer’s, the most common form of dementia, is characterized by the buildup of two proteins in the brain: beta-amyloid, which forms sticky plaques, and tau, which creates tangled fibers inside neurons. As these proteins accumulate, they lead to the death of brain cells, inflammation, and the progressive memory loss and confusion typical of Alzheimer’s.

Researchers hypothesized that people who had undergone more stressful life events would show higher levels of these Alzheimer’s-related changes. When looking at the entire study group, they were surprised this wasn’t the case. The total number of stressful events a person experienced was not related to their levels of beta-amyloid, tau, or inflammatory markers.

However, a different picture emerged when researchers looked at certain subgroups. For participants who had a history of psychiatric conditions like depression or anxiety, more stressful life events did correlate with higher levels of tau and inflammation in their spinal fluid. Among men with a psychiatric history, lifetime stress was also linked to a less favorable ratio of beta-amyloid proteins, another warning sign for Alzheimer’s.

Researchers found a similar pattern when they examined the participants’ brain scans. While lifetime stress wasn’t associated with brain shrinkage overall, it was linked to reduced volume in stress-related brain regions like the hippocampus and amygdala in certain subgroups.

“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”, says study first author Eleni Palpatzis, a researcher at ISGlobal, in a media release.

Women with a history of psychiatric illness who had undergone more stressful events showed shrinkage in several key brain areas involved in memory, emotion and stress regulation, including the hippocampus, amygdala and prefrontal cortex. Men with a psychiatric history, on the other hand, showed volume reductions in sensory and motor-related brain regions.

Researchers propose that for most cognitively healthy people, stressful life events alone may not be enough to trigger the brain changes of Alzheimer’s. But in individuals with a pre-existing vulnerability, such as a history of psychiatric illness, the effects of stress may be amplified. Chronic stress is known to cause long-term changes in the brain’s structure and chemistry, and these changes could potentially accelerate the Alzheimer’s disease process in susceptible people.

The study also found that the timing of stress may matter. Within the entire sample, people who experienced more stressful events in childhood or midlife had higher levels of inflammation and amyloid, respectively, compared to those with fewer stressful events during these periods. This fits with other evidence suggesting the brain may be especially vulnerable to the effects of stress during critical developmental periods.

Researchers caution that their findings are correlational — they can’t prove that stress causes Alzheimer’s changes, only that there are notable associations in certain at-risk groups. The study looked at a single point in time, so it will be important to follow these participants over the coming years to track how their stress exposure and brain health change.

Man suffering headache, stress, depression or mental health disorder
(Photo by Mental Health America (MHA) on

“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,” notes study author Dr. Eider Arenaza-Urquijo, researcher at ISGlobal.

Still, the results add to growing recognition that our life experiences, particularly adverse ones, can shape our brain health in complex ways that may affect our risk of Alzheimer’s and other brain diseases late in life. By shedding light on who may be most vulnerable to the effects of chronic stress, and when, the study opens up new avenues for personalizing dementia prevention strategies.

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