Abstract
Spermidine supplementation benefits brain health and function in animal models, with emerging evidence suggesting cognitive benefits in humans. However, effects on human brain health remain unclear. In this randomized, double-blind, placebo-controlled trial (SmartAge), we investigated 12-month spermidine supplementation (0.9 mg spermidine/day) in individuals with subjective cognitive decline aged 60-90 years. This exploratory secondary MRI analysis included 75 participants and assessed changes in vascular brain health measures, including cerebral blood flow (CBF), white matter microstructure, and white matter hyperintensities. Brain volume and cortical thickness were also assessed. Regression analyses were adjusted for age, sex, and baseline measures. Between-group differences were observed in regional CBF and white matter microstructure. CBF increased in the precuneus from baseline to post-intervention in the spermidine group versus placebo (between-group difference, 4.9 ml/100 g/min; 95%CI, 1.0-8.9; η²p=.11 [90%CI, .012-.250]; P=.015), with a similar trend in the posterior cingulate gyrus (3.7 ml/100 g/min; 95%CI, -.5-7.8; η²p=.06 [90%CI, 0-.182]; P=.08). Fractional anisotropy in the cingulate gyrus white matter bundle remained stable with spermidine but decreased with placebo (.016; 95%CI, .002-.031; η²p=.06 [90%CI, .004-.208]; P=.029). CBF and fractional anisotropy changes were not substantially associated. No substantial between-group differences were found in global or regional brain volume, cortical thickness, or white matter hyperintensities, and regional MRI changes were not associated with changes in memory performance, subjective cognitive complaints, or plasma soluble intercellular adhesion molecule-1 levels. This exploratory analysis identified selected regional MRI differences in cerebral perfusion and white matter microstructure among older adults at risk for cognitive decline. These findings are preliminary and require independent confirmation.