Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by gradual cognitive decline and ultimately death. A range of shared pathophysiological pathways interconnect the cardiovascular and cerebrovascular systems, forming the heart–brain axis, whose disruption is thought to contribute to both cardiovascular disease and AD, two major chronic conditions of aging. 24-h movement behaviors, including moderate-to vigorous physical activity (PA), light PA, sedentary behavior and sleep, are increasingly recognized as key, interrelated modulators of cardiometabolic and brain health. However, the molecular mechanisms linking these behaviors to the heart–brain axis remain unclear. Using NULISAseq proteomics, we examined associations between 24-hour movement behaviors and CNS-focused plasma protein profiles in middle-aged and older adults with coronary artery disease.

Methods

104 coronary artery disease adults aged 50 to 75 years (NCT06214624) were included in this cross-sectional analysis from the Heart-Brain trial. PA, sedentary behavior, and sleep were assessed using AX3 from Axivity wrist-worn accelerometer, with raw accelerations processed with GGIR R package using harmonized procedures. CNS-related plasma proteins were quantified using the NULISAseq CNS disease panel, profiling over 120 plasma proteins across key pathological pathways of the brain, including vascular/metabolism, synuclein/synaptic, neurodegeneration, inflammation and amyloid/tau. Compositional data analysis explored the association of moderate-to-vigorous PA, light PA, sedentary behavior, and sleep with NULISAseq CNS plasma proteins adjusting for age, sex, education and body mass index.

Results 

A total of twenty-eight associations between 24-h movement behaviors and CNS panel proteins were identified (t values ranging from –3.231 to 3.611; all unadjusted p < 0.05), with sleep accounting for the largest number of associations. However, only the sleep-related associations with CCL3 and TNF remained significant after FDR correction (FDR < 0.05). 24-h movement behaviors were most strongly associated with proteins involved in inflammatory pathways (n = 17), followed by neurodegeneration-related pathways (n = 5), with all pathways represented (n ≥ 1).

Conclusions

Our findings indicate that associations between 24-h movement behaviors and CNS plasma proteins are predominantly driven by inflammatory pathways, with secondary involvement of neurodegeneration-related processes. These results support a potential inflammatory-to-neurodegenerative pathway through which daily movement behaviors may influence brain health in adults with coronary artery disease.