Glymphatic dysfunction links vascular pathology to Alzheimer’s biomarkers and cognitive decline
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Vascular damage, including cerebral amyloid angiopathy (CAA) and non-amyloid cerebral small vessel disease (CSVD), has been linked to glymphatic dysfunction, which may contribute to Alzheimer's disease (AD) pathology and cognitive decline. We investigated the associations among vascular damage, glymphatic function measured by the DTI-ALPS (Diffusion Tensor Imaging-Analysis Along the Perivascular Space) index, AD plasma biomarkers, and cognitive decline. METHODS: This study includes 1,249 participants recruited from Samsung Medical Center. We performed linear regression analysis to identify factors associated with the DTI-ALPS index. Further, linear regression analysis with vascular imaging markers, including CAA and CSVD summary scores, as predictors and DTI-ALPS index as an outcome was performed to investigate the effect of vascular pathology on glymphatic function. We conducted mediation analyses to investigate whether the DTI-ALPS index mediates the effect of vascular imaging markers on plasma biomarkers (phosphorylated tau 217 [p-tau 217], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NFL]). Additionally, mediation analyses with the DTI-ALPS index as a predictor, each plasma biomarker as a mediator, and annual MMSE or CDR-SOB change as an outcome to investigate whether plasma biomarkers mediate the effect of the DTI-ALPS index on longitudinal cognitive decline. RESULTS: First, the DTI-ALPS index was negatively associated with both CAA (β [95% CI] = -0.163 [-0.214, -0.112], p < 0.0001) and CSVD (β [95% CI] = -0.195 [-0.247, -0.143], p < 0.0001) summary scores after controlling for age, sex, BMI status, and APOE genotype. Second, the DTI-ALPS index fully mediated the relationship between these vascular markers and p-tau 217 (CSVD summary score, indirect effect β [95% CI] = 0.016 [0.010, 0.023], p < 0.001; CAA summary score, indirect effect β [95% CI] = 0.013 [0.008, 0.020], p < 0.001) and GFAP (CSVD summary score, indirect effect β [95% CI] = 0.015 [0.008, 0.022], p < 0.001; CAA summary score, indirect effect β [95% CI] = 0.012 [0.007, 0.019], p < 0.001), while partially mediating the relationship for NFL, regardless of Aβ uptake on PET. Finally, the DTI-ALPS index was significantly associated with cognitive decline and this association was partially mediated by plasma biomarkers. CONCLUSIONS: These findings highlight glymphatic dysfunction as a key mechanism linking vascular pathology with tau, inflammation and neurodegeneration, independent of Aβ uptakes.
Source: Alzheimer s Research & Therapy
Authors: Sung Hoon Kang, Seongmi Kim, Young Ju Kim, Heejin Yoo, Eun Hye Lee, Hyemin Jang, Daeun Shin, Jihwan Yun, Jun Pyo Kim, Hee Jin Kim, Duk L. Na, Henrick Zetterberg, Kaj Blennow, Fernando Gonzalez-Ortiz, Nicholas J. Ashton, Theresa A. Day, Marco Duering, Seong-Beom Koh, Sang-Young Kim, Eung Yeop Kim, Sung Tae Kim, Beomseok Sohn, Sang Won Seo
Institutions: Samsung Medical Center, Korea University Guro Hospital, Sungkyunkwan University, Kyung Hee University, Kyung Hee University Medical Center, University of Wisconsin–Madison, Sahlgrenska University Hospital, UK Dementia Research Institute, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London, University of Gothenburg, University of Science and Technology of China, Sorbonne Université, Pitié-Salpêtrière Hospital, Institut du Cerveau, King's College London, Stavanger University Hospital, Eli Lilly (United States), University of Basel, LMU Klinikum, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,290
OpenAlex ID: W7126039759