Effects of Spermidine Supplementation on Vascular Brain Health in Older Individuals with Subjective Cognitive Decline – An Exploratory MRI Analysis

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• spermidine (5 posts to September 2013)

 Effects of Spermidine Supplementation on Vascular Brain Health in Older Individuals with Subjective Cognitive Decline – An Exploratory MRI Analysis

Claudia Schwarz1,2,3#,*, Katharina Wurdack2,3#, Stefan Hetzer4, Andrea Dell’Orco2,3,5, Silke M. Wortha1,6, Daria Antonenko1, Gloria S. Benson2,3,7, Nora Horn2,3, Ulrike Grittner8,9, Sebastian J. Hofer10,11, Tobias Eisenberg10,12,13, Stephan J. Sigrist3,14, Dietmar Schmitz3, Miranka Wirth2,3,15, Frank Madeo10,12,13, Agnes Flöel1,16 1Department of Neurology, University Medicine Greifswald, Greifswald, Germany; 2Department of Neurology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; 3NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; 4Berlin Center for Advanced Neuroimaging (BCAN), Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; 5Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Department of Neuroradiology, Berlin, Germany; 6Centre for Mathematical Cognition, Loughborough University, Loughborough, United Kingdom; 7Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; 8Institute of Biometry and Clinical Epidemiology, Charité – Universitätsmedizin Berlin, Berlin, Germany; 9Berlin Institute of Health (BIH), Berlin, Germany; 10Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria; 11Max Delbrueck Center for Molecular Medicine (MDC), Berlin, Germany; 12BioTechMed Graz, Graz, Austria; 13Field of Excellence BioHealth – University of Graz, Austria; 14Institute for Biology/Genetics, Freie Universität Berlin, Berlin, Germany; 15German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany; 16German Center for Neurodegenerative Diseases (DZNE), Standort Rostock/Greifswald, Greifswald, Germany. [Received May 7, 2026; Revised August 13, 2026; Accepted August 14, 2026]

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.