Long‑Term Physiologic Stress Predicts Accelerated Cognitive Decline

Higher cumulative physiologic stress, as measured by salivary cortisol, was associated with a more rapid decline in cognitive function, according to a prospective study.

Older adults with greater cumulative cortisol exposure exhibited lower 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 results appeared in JAMA Network Open.

A moderate level of intra‑day cortisol variability correlated with slower cognitive decline, Ng said. Although Black and white participants displayed different baseline cortisol profiles, the relationship between cortisol and cognitive decline was similar across racial groups.

“Our study suggests that the pattern of cortisol fluctuations throughout the day may offer valuable insights into cognitive aging,” Ng noted.

“We evaluated five complementary indices that capture three key 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. “These dimensions showed distinct relationships with cognitive aging, indicating that various aspects of stress physiology may provide complementary insights.”

Cortisol follows a circadian rhythm with a sharp rise after awakening and a gradual decline throughout the day. It penetrates the blood‑brain barrier and binds receptors in brain regions essential for cognition.

Alterations in hypothalamic‑pituitary‑adrenal (HPA) axis activity have been linked to cognitive aging, Ng and colleagues observed. It remains unclear how prospective associations between cortisol and cognitive outcomes differ by race, they added.

The researchers tracked 3,895 individuals in the Chicago Health and Aging Project for up to 11 years. The sample comprised 2,503 Black and 1,392 white participants, with a mean age of 77.

Participants provided three salivary cortisol samples on a single day (upon waking, mid‑afternoon, and bedtime) and underwent repeated cognitive assessments.

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

All baseline cortisol measures were associated with cross‑sectional cognitive performance. “Although Black participants exhibited distinct baseline diurnal cortisol patterns, including a more attenuated diurnal slope, the relationships between cortisol indices and cognitive outcomes were broadly similar across Black and white participants,” Ng reported.

“This indicates that while diurnal cortisol patterns may vary between populations, their associations with cognitive aging appear broadly consistent,” he added. “Further research is needed to elucidate the factors underlying these baseline differences.”

No significant link was found between cortisol levels and incident Alzheimer’s disease during the follow‑up period. “This likely reflects several factors, including the relatively small subset with adjudicated Alzheimer’s disease, the limited number of incident cases, and the relatively short follow‑up compared to the prolonged preclinical course of Alzheimer’s disease,” Ng noted.

“An alternative interpretation is that changes in diurnal cortisol patterning may be more informative as early physiological indicators of neurocognitive aging than as predictors of short‑term Alzheimer’s disease incidence,” he added.

The findings were based on a single day of cortisol sampling. Multi‑day sampling could improve reliability of within‑person variability and reveal longer‑term HPA‑axis dynamics, but a single‑day protocol collected at multiple time points is standard in large epidemiologic studies. The study also did not assess perceived stress.

“As stress‑related health challenges have become increasingly important public health concerns, our findings underscore 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.

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