Regional Cerebrospinal Fluid Motility as a Key Determinant of Soluble Amyloid-β Levels and Kinetics

Alzheimer's disease and cerebral amyloid angiopathy are characterized by the accumulation of amyloid-β (Aβ) species, yet the human fluid-physiological mechanisms that regulate soluble Aβ transport and clearance remain poorly understood. Aβ40, the dominant vascular Aβ species, remains relatively soluble and accumulates preferentially along vascular basement membranes, making it especially relevant to CSF-mediated clearance pathways. Here, we used non-invasive low b-value diffusion MRI to quantify regional effective CSF motility in a large multimodal cohort from the Knight Alzheimer Disease Research Center, including participants with CSF biomarkers (n = 502), plasma biomarkers (n = 459), amyloid PET imaging (n = 270), and stable isotope labeling kinetics data (n = 40). Effective CSF motility was quantified as mean pseudo-diffusivity (MΨ) and mapped using CSF pseudo-diffusion spatial statistics with a data-driven CSF Waterways atlas. Higher regional CSF motility was consistently associated with higher CSF Aβ40 concentrations, with convergent voxel-wise and region-of-interest effects across ventricular and extra-axial CSF compartments that were most prominent in peri-Sylvian CSF pathways. Across regions, CSF motility measures collectively explained approximately 18% of the variance in CSF Aβ40. A weaker, spatially restricted association was also observed with plasma Aβ40. In contrast, associations with CSF Aβ42 were smaller, anatomically limited, and further attenuated among participants with amyloid deposition on PET. In participants with stable isotope labeling kinetics, higher transventricular and cranio-cervical CSF motility was associated with earlier peak enrichment of labeled Aβ40 and Aβ42, while greater lateral ventricular motility was associated with faster fractional turnover of both peptides. Collectively, these findings identify effective CSF motility as an important physiological determinant of soluble Aβ levels in plasma and CSF, linking regional CSF dynamics to in vivo Aβ transport and turnover, with potential relevance to cerebral amyloid angiopathy and Alzheimer's disease.