Background: Alzheimer's disease (AD) causes significant disability and mortality for individuals aged ≥65 years old—19% of the U.S. Emerging evidence shows an association of cardiorespiratory health with cognitive outcomes, suggesting vascular endothelial dysfunction exacerbates dementia development. We found functional changes in endothelial K + channels in the 3xTg mouse model of AD that, in part, underlie compromised functional hyperemia. Cardiorespiratory function is regulated via the nucleus tractus solitarius (NTS), an autonomic control center in the brainstem. Dysregulation of the NTS due to hypoperfusion, Aβ, and/or tau deposition may impair the body’s ability to dynamically respond to environmental stimuli. A cycle of cardiovascular and autonomic control dysregulation may exacerbate cognitive decline in AD. Focusing on bolstering cardiovascular function using SKA-31 (a KCa channel activator) may allow oxygen and nutrients to be more effectively distributed throughout the brain, resulting in less degradation of the NTS, slowing the progression of cognitive decline. Hypothesis: We tested the hypothesis that boosting the function of endothelial Ca 2+ -activated K + channels (KCa2.3/3.1) would preserve cardiovascular function and overall brain health.MethodsSKA-31 (10 mg/kg) was fed daily over 9 weeks to early (4–9 mo) and late (22–27 mo) AD 3xTg mice and C57BL/6J (males and females; n=3–15). To examine cardiac performance at baseline (week 0) and at the end of the study (week 9), we used echocardiography. To assess changes in autonomic and cardiorespiratory control, we recorded whole-body plethysmography and electrocardiogram (ECG) recordings simultaneously in awake mice between weeks 5 and 7. Results: Our results show that left ventricular mass, an index of cardiovascular systolic function, significantly (p< 0.05) differed among old male and female AD animals, an effect of rescued SKA-31 relative to vehicle. This is consistent with sex-based differences in activation of KCa channels with SKA-31 at the endothelial cell level, where KCa channel function is enhanced in males during AD, while unchanged in females. Preliminary plethysmography and ECG show no changes in mean breaths per minute (bpm), but significant differences in standard deviation increase with SKA-31 administration. Mean heart rate and its standard deviation showed the same pattern.We also observed that AD animals exhibit decreased heart rate variability (RMSSD and SDNN). More experiments need to be performed to determine if autonomic and cardiopulmonary control is altered in AD animals. Conclusion: We conclude that dietary treatment of SKA-31 to activate vascular endothelial K + channels can preserve, and even improve, cardiac health during the advancement of AD pathology in a sex-based manner. Future studies will comprehensively assess molecular mechanisms alongside central regulation of cardiopulmonary function during the development of dementia. Funding: This research is supported by NIH grant R01AG073230 (“Role of Endothelial K + Channels in Age-Related Dementia”). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Shih et al. (Fri,) studied this question.