Faster Cognitive Decline Linked to Cumulative Physiologic Stress

Higher cumulative physiologic stress reflected in salivary cortisol was associated with faster cognitive decline, a prospective study showed.

Older adults with high cumulative cortisol exposure had worse composite global cognition scores over time, reported Ted K. S. Ng, PhD, of Rush University Medical Center in Chicago, at the Alzheimer’s Association International Conference. The findings were published in JAMA Network Open.

A moderate level of intra-day cortisol variability was associated with slower cognitive decline, Ng said. Black and white participants had different cortisol profiles at baseline, but associations between cortisol and cognitive decline were similar across racial groups.

“Our study suggests that how cortisol fluctuates across the day may provide important insights into cognitive aging,” Ng noted.

“We examined five complementary indices capturing three key physiological dimensions of diurnal cortisol regulation — intra-day variability, cumulative daily exposure, and diurnal change — rather than relying on a single cortisol measure,” he told MedPage Today. “We found that these different dimensions showed distinct relationships with cognitive aging, suggesting that different aspects of stress physiology may provide complementary insights.”

Cortisol follows a circadian rhythm with a sharp post-awakening rise and a gradual decline across the day. It crosses the blood-brain barrier and binds receptors in regions critical for cognition.

Changes in hypothalamic-pituitary-adrenal (HPA) axis activity have been implicated in cognitive aging, Ng and colleagues noted. It’s not clear how prospective associations between cortisol and cognitive outcomes may differ by race, they added.

The researchers followed 3,895 people in the Chicago Health and Aging Project for up to 11 years. The cohort included 2,503 Black and 1,392 white participants; the mean age was 77.

Participants provided three salivary cortisol samples across a single day (waking, afternoon, and bedtime) and had repeated cognitive assessments.

“A major strength of the study is its scale and diversity,” Ng pointed out. “We studied nearly 4,000 community-dwelling older adults, including more than 60% women and more than 60% Black participants, making this one of the largest and most racially diverse population-based studies of salivary cortisol and cognitive aging.”

All baseline cortisol indices were associated with cross-sectional cognitive performance. “Although Black participants had distinct baseline diurnal cortisol profiles, including a more blunted diurnal rhythm, the associations between cortisol indices and cognitive outcomes were broadly similar across Black and white participants,” Ng said.

“This suggests that while patterns of diurnal cortisol may differ between populations, their relationships with cognitive aging may be broadly consistent,” he added. “Further research is needed to better understand the factors underlying these baseline differences.”

No significant associations between cortisol and incident Alzheimer’s disease were seen over the follow-up period. “This likely reflects several factors, including the substantially smaller subset with adjudicated Alzheimer’s disease, the relatively small number of incident cases, and the shorter follow-up relative to the long preclinical course of Alzheimer’s disease,” Ng noted.

“An alternative, and not mutually exclusive, interpretation is that alterations in diurnal cortisol patterning may be more informative as early physiological indicators of neurocognitive aging than of shorter-term clinical Alzheimer’s disease incidence,” he added.

The findings were based on a single day of cortisol sampling. Multi-day sampling may improve reliability of within-person variability and show longer-term HPA-axis dynamics, but a single-day protocol over multiple time points is commonly used in large epidemiologic studies, the researchers noted. The study also did not measure perceived stress.

“As stress-related health challenges have become increasingly important public health concerns, our findings reinforce the need to better understand how different aspects of stress physiology influence brain health over time,” Ng said.

“Because salivary cortisol is non-invasive, relatively inexpensive, and feasible to collect repeatedly outside clinical settings, it represents a promising research tool for large-scale population studies investigating stress biology, brain health, and aging,” he added.