A new study suggests that childhood and midlife stressful life events (SLEs), such as divorce or the death of a loved one, are associated with higher levels of Alzheimer's disease (AD) pathophysiology and neuroinflammation.

Palpatzis E, Akinci M, Aguilar-Dominguez P, et al. Lifetime stressful events associated with Alzheimer's pathologies, neuroinflammation and brain structure in a risk enriched cohort. Ann Neurol. 2024;95(6):1058–1068.

About the study

The ALFA study assessments included lumbar puncture, structural MRI, cognitive tests, clinical interviews and questionnaires related to lifestyle and health, and blood tests for genotyping. The study participants had reported a history of SLE on semi-structured interviews.

The investigators used phosphorylated-tau(181) (p-tau[181]) and β-amyloid (Aβ) to reflect core AD processes and interleukin-6 (IL-6) to reflect neuroinflammation. They also examined brain gray matter (GM) volume. Covariates in the main models and analyses included age, sex, years of education, and apolipoprotein E (APOE) ε4 carrier status, as well as lifetime history of cardiovascular and psychiatric disease.

Interpreting the study results

Additionally, men as well as individuals with a history of psychiatric conditions showed lower Aβ(1-42/1-40) with higher SLEs. Moreover, participants with a history of psychiatric conditions showed reduced GM volumes in somatic brain regions, and women showed reduced GM volumes in prefrontal and limbic regions. 

“We don’t completely understand the mechanism of action that might predispose someone with stressful life events to developing later Alzheimer’s disease,” Rebecca Edelmayer, PhD, a senior director for the Alzheimer’s Association, tells MDLinx.

“Across the life course, we know that Alzheimer’s disease and other types of dementia are quite complex, and a variety of biological changes are happening in the brain as part of the disease process,” Dr. Edelmayer continues. “But we also know it’s more complex than that, and that neuroinflammation plays a role. Changes in the immune system and changes in the blood vessels throughout the brain, and a variety of stressful events across the life course may impact multiple aspects of that disease biology."

She noted that the study was a cross-sectional analysis, but a longitudinal design might have been more helpful to “tease out the reason that early and midlife stressors had more of an impact than whole-life stressors.”

“Although the study focused on the impact of neuroinflammation in the brain, we know that inflammation can exist across the body as well,” Dr. Edelmayer says. “And the kind of stress that induces inflammation in one individual may not induce inflammation in another. A lot more research needs to be conducted before we can make sustainable and attainable recommendations for people regarding the role of stress in neuroinflammation and, subsequently, in Alzheimer’s disease and dementia.”

Modifiable risk factors

Another study of 1,262,548 people in Stockholm, Sweden, examined the relationship between chronic stress, depression, or both, recorded during 2012 and 2013, and the outcome of a diagnosis of AD, mild dementia, or mild cognitive impairment (MCI) recorded between 2014 and 2022.

Wallensten J, Ljunggren G, Nager A. et al. Stress, depression, and risk of dementia – a cohort study in the total population between 18 and 65 years old in Region Stockholm. Alz Res Therapy. 2023;15:161.

The OR of developing MCI was similarly higher in those with chronic stress, depression, and the combination of chronic stress plus depression (1.87 [1.20–2.91], 2.85 (2.53–3.22), and 3.87 [2.39–6.27, respectively). However, the OR was significant for dementia only in patients with depression (2.39 [1.92–2.96]).

“We know, based on available data, that depression is a risk factor not only for Alzheimer’s disease but also for other types of dementia,” Dr. Edelmayer tells MDLinx.

Although it’s too soon to make specific recommendations based on this research, certain takeaways are clear, according to Dr. Edelmayer. “Mental illness is something we really encourage people to talk to their clinicians about, not letting stress and mental illness go unchecked, especially since there are both behavioral and drug treatments available.”

According to Dr. Edelmayer, both studies suggest “we have to consider, across our life course, the types of things that might be impacting our risk for developing Alzheimer’s disease or any other type of dementia.”

Although we cannot change our age, family history, or genetics, “we need to do as much as we can to address modifiable risk factors, including our nutrition, physical activity, cardiac health, and traumatic brain injury if that occurs. Stress and depression are among those modifiable risk factors,” she says.

The importance of a healthy lifestyle

A recent study, published June 2024 in the journal Alzheimer's Research & Therapy, corroborates the powerful role that lifestyle modifications, including stress reduction, can play in staving off or even reversing the impact of Alzheimer’s.

Ornish D, Madison C, Kivipelto M, et al. Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer's disease: a randomized, controlled clinical trial. Alz Res Therapy. 2024;16:122.

The researchers studied 51 AD patients, with a mean age of 73.5 years. Of these, 26 were randomized to a lifestyle intervention group while 25 were randomized to a usual-care control group.

The lifestyle intervention included a vegan diet, daily aerobic exercise, dietary supplements (a daily multivitamin, omega-3 fatty acids with curcumin, coenzyme Q10, vitamins C and B12, magnesium, a probiotic, and lion’s mane mushroom Hericium erinaceus), and regular support groups. 

Notably, the intervention included stress reduction techniques, including meditation, gentle yoga-based poses, stretching, progressive relaxation, breathing exercises, and imagery led by a certified stress management specialist. Patients were offered the option of using flashing-light glasses at a theta frequency of 7.83 Hz plus soothing music as an aid to meditation and insomnia and were also encouraged to get adequate sleep.

At the end of 20 weeks, significant between-group differences were found on the Clinical Global Impression of Change (CGIC), the Clinical Dementia Rating-Sum of Boxes (CDR-SB), and CDR GLobal tests (Ps = 0.001, 0.032, and 0.037, respectively).

In people with mild cognitive impairment or early dementia due to Alzheimer’s disease, “comprehensive lifestyle changes may improve cognition and function in several standard measures after 20 weeks,” the authors concluded.