ACE Inhibitors Boost Mobility and Muscle Strength by Reducing Intestinal Permeability in Older Adults with Alzheimer’s Disease

<b>Objectives:</b> Hypertension is common in Alzheimer's disease (AD) and contributes to functional decline. While ACE inhibitors are widely used for hypertension, their systemic effects on intestinal permeability and physical capacity in AD patients remain unclear. <b>Materials and Methods:</b> We investigated the potential contribution of increased intestinal permeability to handgrip strength (HGS) and physical capacity in patients with Alzheimer's disease (AD) taking ACE inhibitors. We investigated hypertensive AD patients taking ACE inhibitors (<i>n</i> = 55) or other anti-hypertensive medications (<i>n</i> = 57) at baseline and one year later, along with age-matched controls (<i>n</i> = 64) and normotensive AD patients (<i>n</i> = 61). We measured plasma zonulin, a marker of intestinal permeability, and HGS, and performed the short physical performance battery (SPPB). <b>Results:</b> AD patients had lower HGS, gait speed, SPPB, and higher plasma zonulin than controls at baseline (all <i>p</i> < 0.05). The use of ACE inhibitors was associated with increased HGS and gait speed, and reduced plasma zonulin in AD patients. Conversely, AD patients on other anti-hypertensive medications had higher zonulin and lower HGS but no change in gait speed and SPPB after one year. The patients taking ACE inhibitors also exhibited significant dynamic correlations of zonulin with HGS, gait speed, and SPPB (<i>p</i> < 0.05). ACE inhibitors also reduced plasma C-reactive proteins and 8-isoprostanes as markers of oxidative stress and inflammation. <b>Conclusions:</b> ACE inhibitors may improve physical performance and cognitive function in hypertensive AD patients, primarily through vascular smooth muscle modulation, leading to better perfusion. These effects may indirectly support intestinal barrier and muscle function, highlighting a novel gut-vascular-muscle interface relevant to therapeutic strategies.