A large, racially diverse study suggests that the daily rise and fall of cortisol may offer an early window into cognitive aging, while its connection to Alzheimer’s disease remains uncertain.
Study: Salivary Cortisol and Cognitive Decline and Alzheimer Disease in Older Adults. Image Credit: Master1305 / Shutterstock
Daytime salivary cortisol patterns were associated with baseline cognition and subsequent cognitive decline, according to a new study published in JAMA Network Open.
Background
Alzheimer’s disease is an age-related neurodegenerative disease associated with physical disability, cognitive impairment, and mortality in older adults. Abnormal accumulation of beta-amyloid and tau proteins in the brain, alongside neurodegeneration, forms part of the established biomarker framework for Alzheimer’s disease. However, given the rapidly increasing disease burden in aging populations, it is essential to identify new biomarkers that reflect systemic processes underlying disease pathophysiology, such as inflammation, metabolism, and stress physiology.
Among these systemic processes, stress can be conceptualized as a multifactorial and modifiable process triggered by lifetime exposure to individual, social, and environmental factors, which can become biologically embedded and influence health through behavioral and biological changes.
Cortisol, the primary stress hormone, plays an essential role in modulating stress response and maintaining homeostasis. Cortisol secretion, regulated by the hypothalamic-pituitary-adrenal (HPA) axis, rises sharply after waking, followed by a gradual decline across the day, reaching its lowest levels by evening or night.
Since this hormone can easily cross the blood-brain barrier and bind to receptors in brain regions crucial for cognitive functioning, alterations in cortisol levels may contribute to cognitive decline and the pathogenesis of neurodegenerative diseases.
Given the significant association between cortisol and cognition, Rush University Medical Center researchers in Chicago characterized salivary cortisol levels across a day in a racially diverse cohort of nearly 4000 older adults to explore whether cortisol fluctuation patterns are associated with cognitive performance, decline, and incident Alzheimer’s disease, and whether these associations differed by race.
Study Design
This study was part of the Chicago Health and Aging Project, a population-based longitudinal study of aging and Alzheimer’s disease among community-dwelling older adults from urban Chicago.
A total of 3895 older adults, including 2503 Black and 1392 White individuals, participated in the study. During the study follow-up period of up to 11 years and averaging approximately 2.6 years, participants’ cognitive function was assessed using standardized tests every three years.
Saliva samples were collected from participants across a single day, on waking, in the late afternoon, and in the evening, to measure cortisol levels. Eighty-three percent of participants provided all three requested samples. Five salivary cortisol indices of daytime HPA axis activity were derived using salivary cortisol levels to capture intraday variability, total daily cortisol output, and daytime rhythm.
Key Findings
The baseline analysis of salivary cortisol indices revealed that Black participants had lower cortisol fluctuations across the day, lower total daily cortisol levels, and attenuated daytime changes than White participants.
The baseline cognitive assessment indicated lower global cognition scores and a faster average rate of cognitive decline among Black participants than among White participants. In the smaller clinical subsample, a descriptive baseline comparison found that participants who developed incident Alzheimer’s disease exhibited lower cortisol fluctuations across the day and a blunted daytime cortisol rhythm.
Fully adjusted analyses accounting for demographic, health, genetic, medication, and behavioral factors showed that moderate intraday cortisol fluctuation in the third and fourth quintiles was significantly associated with higher baseline cognition and slower cognitive decline. The highest total daily cortisol output was linked to lower baseline cognition and faster cognitive decline. Furthermore, a flatter diurnal slope and more attenuated daytime cortisol change corresponded to lower baseline cognition.
Despite significant associations with cognition, adjusted analyses in the clinical subsample of 825 participants, including 92 incident cases, found that none of the cortisol indices showed any significant association with the risk of developing Alzheimer’s disease. Moreover, no significant differences in cortisol-cognition associations were observed by race.
Study Significance
The study highlights the potential of salivary cortisol as an early research biomarker of modifiable stress physiology associated with cognitive aging. According to the findings, moderate cortisol fluctuation across a day was associated with slower cognitive decline, whereas the highest levels of total daily cortisol exposure were associated with faster decline in community-dwelling older adults. After participants with the lowest baseline cognitive performance were excluded, the association between the highest mean cortisol level and faster decline remained significant.
Despite significant associations between salivary cortisol and cognition, the study did not find any significant association between any of the five cortisol indices and incident Alzheimer’s disease. This may reflect the smaller exploratory sample and the shorter follow-up duration, up to 11 years, compared with the long preclinical disease phase, up to 20 years.
The observational design, possible residual confounding and reverse causation, and the single-day sampling protocol also limit interpretation. The three-sample protocol could not measure the cortisol awakening response or stable day-to-day variability.
Perceived stress was not assessed, Alzheimer’s disease was diagnosed using older clinical criteria, and the analyses were not adjusted for multiple comparisons. The findings may not generalize beyond Black and White older adults living in urban Chicago.
Notably, the study found a blunted daytime cortisol rhythm rather than hypersecretion in Black participants. However, the magnitude of associations between daytime cortisol patterns and cognitive outcomes was similar between Black and White participants.
The distinct cortisol pattern observed in Black participants is consistent with theoretical frameworks suggesting that social and structural adversity may be reflected in cortisol patterning across a day, potentially producing attenuated daily amplitude as a physiological correlate of sustained stress. However, these exposures were not directly measured, and cortisol was not shown to explain the racial difference in cognitive decline.
Overall, the study findings suggest that salivary cortisol may help characterize subtle changes associated with early neurocognitive aging, although its value for predicting incident Alzheimer’s disease remains uncertain.
These findings support future research testing whether behavioral, pharmacologic, and social interventions can address stress-related cognitive aging in diverse populations.
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