Epidemiologic research has examined late-life, individual demographic, socioeconomic, and physiologic factors associated with cognitive performance and decline in multiple neurological domains. Research addressing the physiologic correlates of cognition focuses on its links with cardiovascular, hepatic, renal, and endocrine systems(1
). Dysregulation of blood pressure, including both orthostatic hypotension and hypertension, has been persistently associated with diminished cognitive function, above and beyond sociodemographic and additional medical factors(4
). Additionally, other cardiovascular disease risk factors (e.g., elevated BMI, history of diabetes)(9
), prior history of stroke (2
), elevated systemic inflammation(3
), and decreased kidney and liver function (1
) have all been associated with lower cognitive performance in older adults. Furthermore, it is known that some of these biological parameters are dynamically interrelated (in particular, the cardiovascular, metabolic, and inflammatory parameters) (11
). These findings suggest that a measure of overall physiological dysfunction, integrating cardiovascular risk factors and various biological parameters of declining physical health, may be an even stronger correlate of cognitive function than risk factors considered in isolation.
The allostatic load model proposed by McEwen and Stellar integrates these different biological parameters into one unifying framework that may be particularly useful in predicting cognitive decline (12
). This model details how continual adaption to demands and stimuli over the life course may damage the body’s response system and associated physiological functioning, potentially resulting in dysfunction or disease of many body systems including (but not limited to) cardiovascular, renal, and hepatic systems(12
). Fundamentally, allostasis is the physiologic process by which the human body responds and adapts to acute and chronic stressors through activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the release of physiologic mediators of adaptation, such as cortisol(12
). The allostatic load model provides a framework for examining biological “wear and tear” and has been operationalized in a wide range of recent epidemiologic studies(16
The relationship between a global measure of cumulative physiologic dysfunction and specific domains of cognitive function has rarely been empirically evaluated. A study of 765 high functioning elderly subjects (age 70–79 years) noted cross-sectional associations between a physiological dysfunction summary score (comprising 10 biomarkers of physiologic activity) with memory, spatial ability, and abstract reasoning deficits(20
). This physiological dysfunction summary score was guided by the allostatic load model(14
). A recent study of 195 adolescents (mean age 17.3 years) noted how higher childhood allostatic load predicted deficits in adolescent working memory(21
). Another epidemiologic study reported that heart rate recovery, blood pressure, and cortisol response patterns, constituting cumulative physiologic dysregulation, were associated with poorer memory in 133 elderly adults (mean age 70.6 years)(22
). These studies suggest that physiologic dysfunction may be associated with cognitive status in adults of all ages. However, these studies did not rely on nationally-representative samples and did not examine the impact of physiologic dysfunction on early to mid-life adult cognitive performance.
The mechanisms to explain the association between cumulative physiologic dysfunction and cognitive performance are complex and likely vary with different domains of cognitive function. However, one potential explanation can be inferred through endocrine system dysregulation(13
). A recent analysis demonstrated that the endocrine disruption that drives allostatic load is statistically explained by multiple domains of physiologic dysfunction, including the cardiovascular, metabolic, and immune systems(13
). Endocrine system dysfunction can be described through the collective functioning of these various bodily systems, as the HPA-axis exerts direct effects on all organs and tissues of the body(24
). Thus, simultaneous elevation of leukocytes levels, blood pressure, heart rate, as well as abnormal serum lipid profiles and abnormal markers of hepatic and renal function is likely to signal dysfunction of the HPA-axis(15
The HPA-axis endocrine cascade affects glutamatergic transmission in synapses involving glutamate receptor subunits in the pre-frontal cortex (PFC) (25
). The PFC is thought to be crucial in the deployment of short-term memory(26
). In addition, it has also been suggested that hippocampal plasticity, a function critical in learning, is affected by endocrine hormones of the HPA-axis(27
). Physiologic dysfunction (including cardiovascular, immunologic, kidney, and liver function) is thought to reflect HPA-axis dysregulation that could result in diminished cognitive performance. Because it has been shown that physiologic dysfunction accumulates from early adulthood onward(16
), it is plausible that cognitive performance among early or middle-age adults could be associated with physiologic dysfunction.
Nevertheless, the etiology of cognition in early to mid-life adults is an understudied phase in the trajectory of cognitive functioning across the life course(28
). In addition, while existing studies have generally investigated associations between specific domains of physiologic functioning and global or general cognition, there is a gap in the literature in our understanding of linkages between overall physiologic dysfunction and specific domains of cognition. It is imperative to address this gap because the various unique domains of cognition exhibit different associations with age, sociodemographic factors, and environmental factors(30
). Improvements in our understanding of interconnected physiologic and cognitive processes among early to mid-life adults may provide additional insights into age-related physiological decline among older adults and may expand targets for intervention to maintain cognitive function (28
We address this gap by exploring the association between measures of specific domains of cognitive function and two different scores summarizing measures of cardiovascular, immunologic, kidney, and liver function, among adults of age 20–59 years, in the third National Health and Nutrition Examination Survey (NHANES), a nationally representative, multistage survey. We adjusted for a range of sociodemographic factors, test-performance-related factors, and specific health indicators, which were selected based on an assessment of prior literature. Given prior evidence of a link between HPA-axis activity and learning and memory ability(32
), we hypothesize that a summary score measuring physiological dysfunction, as conceptualized through the allostatic load model, will be negatively associated with working memory performance.