Stress a Key Driver of Link Between Mild Cognitive Impairment and Anxiety

Batya Swift Yasgur, MA, LSW

March 13, 2023

Older adults with anxiety are at increased risk of developing mild cognitive impairment (MCI) and vice versa, with perceived stress (PS) mediating this bidirectional relationship, new research shows.

Investigators found PS was responsible for 37% of the total effect of anxiety on incident MCI and 27% of the total effect of MCI on anxiety.

"For practicing clinicians, the take-home message is that anxiety and cognitive decline are related to each other in both directions, and that this relationship is mediated by stress. Therefore, it's important to screen for anxiety in patients with MCI for anxiety, and those coming with anxiety for cognitive impairment," study investigator Neha Jain, MD, medical director of the Mood and Anxiety Disorders Program, University of Connecticut Health Center, Farmington, told Medscape Medical News.

The study was published online February 28 in the International Journal of Geriatric Psychiatry.

Two-Way Street

The relationship between anxiety and cognition in older adults is "complex," with several neurochemical mechanisms and structural brain alterations implicated in both conditions, the researchers note.

"While many cross-sectional studies have looked at the associations between anxiety symptoms and MCI, few have explored their longitudinal relationship," they add.

"As a geriatric psychiatrist, I often see patients who start to think that their memory is declining and become anxious as a result," said Jain. And "we have known about the reverse relationship — that is, anxiety leading to memory impairment — for a while."

Jain was "curious if the reverse would also be true — that is, the stress of knowing that your memory was declining would lead to anxiety."

To investigate, the researchers turned to the Monongahela-Youghiogheny Health Aging Team (MYHAT), an ongoing population-based cohort study in several small-town communities in western Pennsylvania.

The initial (original) study consisted of a cohort of 1982 older adults (≥ 65 years) recruited between 2006 and 2008, with a second (new) cohort of 703 people (aged 65-74 years) recruited between 2016 and 2019.

To be included, individuals had to reside within the community at study entry, have the capacity to make decisions, and an age- and education-corrected Mini Mental State Examination (MMSI) of 21 or higher.

Annual assessments were conducted in overlapping data collection waves, so at any given time during the study period, up to three waves per cohort were being assessed.

The researchers assessed depressive symptoms, instrumental activities of daily living (IADLs), and the presence of clinical dementia. Incident MCI was measured through the Clinical Dementia Rating (CDR) scale, with MCI defined as a CDR score of 0.5 vs 0.

During the 11th and 13th annual assessment (for the original cohort) and the first and second assessment (for the new cohort), the researchers added an anxiety symptom assessment (GAD-7) and the Perceived Stress Scale (PSS-4) in 2019 (waves 12-14 for the original participants and 1-3 for the new cohort). Perceived stress was defined as a PSS-4 score of 4 or higher vs less than 2.

In particular, they focused on two potential pathways: one with anxiety as a predictor (earlier in time) and the other with anxiety as the outcome (later in time), with PS as a "mediator in either direction."

The current analysis included only participants where all relevant data was available at three successive waves, with the predictor variable (anxiety or MCI) at the first wave, the mediator variable (PS) at the second wave, and the outcome variable (MCI or anxiety) at the third wave.

Conquering Stress

At the predictor wave, the sample consisted of 368 older adults (mean age, 75 years, 61.2% female), with a little over half (51.6%) drawn from the new cohort. Of the total sample, 13.9% had MCI, and the mean GAD-7 anxiety score was 2.2).

The logistic regression analyses that adjusted for covariates including age, sex, education, IADLs, and baseline depressive symptoms showed "significant associations in all pairs of predictor-outcome, predictor-mediator, and mediator-outcome for tested pathways from anxiety to incident MCI, and from MCI to anxiety, with PS as the mediator," the investigators write.

Table. Mediation Analysis Estimation Results – Analysis Cohort

Pathway Mediator Total Effect (Percentile Bootstrap 95% CI) Mediated Effect (%)
Anxiety→Incident MCI PS Odds ratio, 1.25 (1.09 - 1.61) 37.1
Incident MCI→Anxiety PS Mean ratio, 2.60 (1.70 - 3.80) 27.1


Every 1-point increase in GAD-7 score at the predictor wave was associated with an almost 25% higher risk of developing MCI at the outcome wave.

The ratio of predicted mean GAD-7 score at the outcome wave among people with MCI at the predictor wave was 2.6 times higher than that of the predicted mean GAD-7 score among participants without MCI at the predictor wave.

The authors suggest potential mechanisms through which perceived stress might influence cognitive decline, including stress activation of the HPA axis, release of inflammatory and hormonal markers of accelerated aging, and alterations in telomere length.

"Future studies examining the impact of stress management interventions on these adverse outcomes may prove beneficial," they add.

"It's important to help patients figure out ways to reduce this stress, for example, by helping them find ways to re-establish their sense of control and mastery over their own life," added Jain, who is the assistant program director of the Geriatric Psychiatry Program.

Cortisol at Work

Commenting for Medscape Medical News, Yuko Hara, PhD, director of aging and prevention, Alzheimer's Drug Discovery Foundation (ADDF), said the findings are "consistent with the literature on stress and its negative impacts on cognitive function.

She pointed out that "high levels of the stress hormone cortisol have been associated with memory impairments and smaller volumes of the hippocampus, a brain region important for memory functions."

Perceived stress is "not just determined by the stressor itself but also by one's perception of the stressor," noted Hara, an adjunct faculty member at Icahn School of Medicine at Mount Sinai in New York City. She was not involved with the study.

Although one may not always be able to control the stressor, "one's perceptions can be modified by many factors, including one's emotional support systems (family, friends), having methods or resources to mitigate the stress, and a resilient mindset," Hara said.

The study was funded by the National Association of Statutory Health Insurance Funds (Germany). The authors and Hara declare no relevant financial relationships.

Int J Geriatr Psychiatry. Published online February 28, 2023. Abstract

Batya Swift Yasgur MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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