Glymphatic dysfunction associates with regional white matter hyperintensities and plasma amyloid-β burden across the Alzheimer's disease continuum.

BACKGROUND

Glymphatic system dysfunction has been increasingly implicated in Alzheimer's disease (AD), yet its relationships with cerebral small vessel disease (CSVD), plasma biomarkers, and cognitive impairment across the AD remain incompletely understood.

METHODS

We prospectively recruited 216 participants from Hainan General Hospital, including healthy controls (HC), individuals with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD dementia. All participants underwent brain magnetic resonance imaging, plasma biomarker testing, and neuropsychological assessments. White matter hyperintensity (WMH) volume from T2-weighted fluid-attenuated inversion recovery images served as a marker of CSVD. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) index assessed glymphatic function. Plasma amyloid β-protein (Aβ) concentrations measured peripheral Aβ levels as a surrogate indicator of amyloid pathology.

RESULTS

The ALPS index was significantly lower in AD patients compared with HC, SCD, and MCI groups (all P < 0.01) and tended to be lower in the MCI group relative to SCD. After controlling for demographics and APOE4 status, ALPS positively correlated with the plasma Aβ42/Aβ40 ratio (r = 0.16, P = 0.038). ALPS index showed significant negative correlations with log-transformed juxtaventricular and juxtacortical WMH volumes (r = -0.32, P < 0.001; r = -0.19, P = 0.010), with marginal correlation for periventricular WMH (r = -0.13, P = 0.052).

CONCLUSION

Plasma Aβ levels and regional WMH burden are associated with glymphatic dysfunction as indicated by reduced ALPS. Impaired glymphatic clearance also correlates with cognitive impairment, providing theoretical support for novel pathophysiological hypotheses and potential therapeutic targets in AD pathogenesis.