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Glymphatic dysfunction links vascular pathology to Alzheimer's biomarkers and cognitive decline

Sung Hoon Kang1,2, Seongmi Kim1, Young Ju Kim1,3

  • 1Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.

Alzheimer'S Research & Therapy
|January 30, 2026
PubMed

Insights

Glymphatic dysfunction, measured by Diffusion Tensor Imaging-Analysis Along the Perivascular Space (DTI-ALPS), is a key mechanism linking cerebral amyloid angiopathy (CAA) and small vessel disease (CSVD) to Alzheimer's pathology and cognitive decline.

Area of Science:

  • Neuroscience
  • Radiology
  • Biomarkers

Background:

  • Cerebral amyloid angiopathy (CAA) and cerebral small vessel disease (CSVD) are linked to glymphatic dysfunction.
  • Glymphatic dysfunction may contribute to Alzheimer's disease (AD) pathology and cognitive decline.

Purpose of the Study:

  • To investigate the associations among vascular damage (CAA, CSVD), glymphatic function (DTI-ALPS index), AD plasma biomarkers (p-tau 217, GFAP, NFL), and cognitive decline.
  • To determine if glymphatic function mediates the relationship between vascular damage and AD biomarkers.
  • To explore if plasma biomarkers mediate the effect of glymphatic function on cognitive decline.

Main Methods:

  • 1,249 participants underwent DTI-ALPS imaging and assessment of vascular markers (CAA, CSVD).
  • Linear regression and mediation analyses were used to examine associations and mediation effects.
  • Plasma biomarkers (p-tau 217, GFAP, NFL) and longitudinal cognitive changes (MMSE, CDR-SOB) were analyzed.

Main Results:

  • The DTI-ALPS index was negatively associated with both CAA and CSVD scores.
  • Glymphatic dysfunction (DTI-ALPS) fully mediated the link between vascular damage and p-tau 217/GFAP, and partially mediated the link with NFL.
  • The DTI-ALPS index was associated with cognitive decline, with partial mediation by plasma biomarkers.

Conclusions:

  • Glymphatic dysfunction is a crucial mechanism connecting vascular pathology to tau, inflammation, and neurodegeneration.
  • This link is independent of amyloid-beta (Aβ) uptake.
  • Findings underscore the role of glymphatic function in Alzheimer's disease pathogenesis.
Abstract

Keywords:
Alzheimer’s diseaseDiffusion tensor imagingGlymphatic dysfunctionPlasma biomarkersVascular diseases

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