# Ventricular enlargement is associated with early Alzheimer’s disease pathophysiology

## TL;DR

This study finds that changes in cerebrospinal fluid dynamics, like ventricular enlargement, are linked to early amyloid-beta accumulation in Alzheimer’s disease, which may drive later tau pathology.

## Contribution

The study identifies ventricular enlargement and CSF clearance changes as upstream indicators of early Alzheimer’s disease pathophysiology, distinct from later neurodegeneration.

## Key findings

- Larger ventricular and choroid plexus volumes are associated with higher neocortical amyloid-beta accumulation.
- Ventricular enlargement mediates amyloid clearance but not tau clearance, suggesting distinct mechanisms.
- CSF system changes are linked to early AD pathology, not just a result of neurodegeneration.

## Abstract

Alzheimer’s disease (AD) is characterized by progressive brain changes, including protein aggregation and structural changes. Cerebrospinal fluid (CSF) system abnormalities, such as ventricular dilation, increased choroid plexus volume or positron emission tomography (PET) ligand uptake in the CSF, have also been consistently described. We aimed to examine whether changes in CSF production and clearance might be associated with brain protein aggregation across biological stages of Alzheimer’s disease. We hypothesized an association between brain protein aggregation and changes on the CSF system. We examined 378 individuals from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort with T1-weighted magnetic resonance imaging (MRI), amyloid-PET and tau-PET assessments. We assessed the lateral ventricle and choroid plexus volumes, both corrected for intracranial volume, in the MRI native space. Non-specific ventricular tracer standardized uptake value ratio (SUVR), derived from amyloid- and tau-PET images, was used as an indirect marker of choroid plexus-related clearance activity and served as a metric of CSF dynamics. Linear models tested associations amongst lateral ventricular volume (reflecting CSF space enlargement), choroid plexus volume (reflecting secretory tissue morphology) and ventricular SUVR (reflecting tracer activity within the CSF compartment and serving as an indirect marker of choroid plexus-related clearance function and CSF dynamics) with Aβ and tau aggregations. Analyses were restricted to within-modality associations, relating ventricular radioactivity to cortical pathology for each PET tracer. We found that when considered independently, larger ventricular and choroid plexus volumes were associated with higher neocortical Aβ-PET SUVR, particularly in the precuneus and cingulate cortices. Additionally, lower ventricular radioactivity (derived from amyloid-PET) showed strong negative associations in the dorsal apex of the neocortex. However, when all three ventricular parameters were included in the same model, these effects were mediated by ventricular volume. By contrast, the effect of the ventricular parameters on tau load was mediated by Aβ in the neocortex. Therefore, ventricular enlargement appears to be associated with Aβ load. Distinct from neurodegeneration, changes in ventricular parameters, particularly ventricular volume, are associated with upstream Alzheimer’s disease pathophysiology. While ventricular volume significantly mediated ventricular amyloid clearance, no such effect was observed for tau, suggesting distinct clearance mechanisms for these pathologies in Alzheimer’s disease.

Hosseini et al. report that cerebrospinal fluid (CSF) clearance measures, including ventricular and choroid plexus changes, are linked to early amyloid-beta accumulation in Alzheimer’s disease, which in turn drives tau pathology. Their findings suggest CSF clearance dysfunction is an upstream contributor to disease progression, not merely a downstream neurodegenerative marker.

Graphical AbstractFor image description, please refer to the figure legend and surrounding text.