ALPS measurements are strongly influenced by ROI definition, ventricular morphology, and surrounding periventricular tissue architecture, suggesting that rather than functioning as a direct measure of glymphatic transport in isolation, ALPS appears to represent a composite anatomical diffusion biomarker shaped by both methodological implementation and underlying neuroanatomy.
Key Findings
Results
Reference ALPS implementations demonstrated substantial hemispheric variability, with a median left-right difference of 12.5%.
Study used diffusion MRI data from 850 healthy young adults and 150 healthy ageing participants from the Human Connectome Project.
Marked asymmetry was observed in the underlying numerator and denominator tensor components.
Residual hemispheric asymmetry persisted even after ROI optimization, suggesting an intrinsic anatomical contribution to ALPS variability.
Results
A two-stage optimisation framework incorporating fibre-pool alignment, hemispheric symmetry, component stability, and directional purity identified anatomically improved ROI configurations.
The optimisation significantly increased fibre specificity and reduced measurement variability in independent validation cohorts.
Optimisation increased coupling between ALPS and ventricular anatomy.
Despite improvements, residual hemispheric asymmetry persisted after optimisation.
Results
In the healthy ageing cohort, ventricular volume was the strongest predictor of ALPS, explaining substantially more variance than chronological age.
The healthy ageing cohort consisted of 150 participants from the Human Connectome Project.
Ventricular volume explained substantially more variance in ALPS than chronological age.
This finding was identified in participants characterized as healthy ageing, not a clinical population.
Results
Voxel-wise deformation-based morphometry demonstrated that lower ALPS values were associated with ventricular and periventricular expansion.
The analysis linked lower ALPS values specifically to ventricular and periventricular expansion.
ROI optimisation increased coupling between ALPS and ventricular anatomy.
These findings indicate that periventricular tissue architecture contributes to ALPS measurements.
Discussion
ALPS appears to represent a composite anatomical diffusion biomarker shaped by both methodological implementation and underlying neuroanatomy, rather than a direct measure of glymphatic transport in isolation.
The study systematically evaluated the influence of ROI placement and ventricular anatomy on ALPS measurements.
Both ROI definition and ventricular morphology were identified as significant determinants of ALPS values.
The authors propose a framework for improving methodological standardisation and interpretation of ALPS measurements in future neuroimaging studies.
What This Means
This research evaluated a brain imaging technique called DTI-ALPS, which is increasingly being used as a non-invasive way to measure glymphatic function — the brain's waste-clearance system. Using MRI data from over 1,000 participants (850 young adults and 150 older adults from the Human Connectome Project), the study found that how and where researchers place measurement regions on brain images dramatically affects the results. Specifically, measurements taken from the left versus right side of the brain differed by about 12.5% on average, and this asymmetry was partly reduced but not eliminated by an improved measurement approach developed in the study.
A key finding was that the size of the brain's fluid-filled ventricles — not a person's age — was the strongest factor predicting ALPS scores in older adults. Areas of larger ventricular and surrounding tissue expansion were associated with lower ALPS values, suggesting that the metric is heavily shaped by individual brain anatomy. When the researchers improved how measurement regions were defined, the link between ALPS and ventricular anatomy became even stronger.
This research suggests that DTI-ALPS may not be a straightforward, direct window into glymphatic function as previously hoped, but rather a composite measure that reflects both brain anatomy and methodological choices. This matters because many studies are using ALPS as a biomarker for conditions like Alzheimer's disease or sleep disorders, and these results highlight that differences in ALPS scores between individuals or groups may partly reflect differences in brain structure or measurement approach rather than differences in glymphatic activity. The study provides a framework for more standardized and carefully interpreted use of this technique in future research.
Wright D. (2026). Anatomical determinants of DTI-ALPS: Effects of ROI definition, ventricular morphology, and periventricular deformation.. Imaging neuroscience (Cambridge, Mass.). https://doi.org/10.1162/IMAG.a.1399