Ventricular remodeling and astrocyte activation drive early protein aggregation in Alzheimer’s disease

BACKGROUND: Pro-inflammatory astrocyte activation, choroid plexus dysfunction, and ventricular enlargement may collectively impair cerebrospinal fluid (CSF) clearance, a process which removes metabolic waste, including amyloid-β and tau. Dysregulated clearance mechanisms may contribute to Alzheimer's disease pathogenesis (AD) by facilitating protein aggregation. This study investigated whether ventricular remodeling and astrocyte activation drive amyloid-β and tau accumulation in AD. METHOD: We analyzed multimodal neuroimaging and fluid biomarker data from 500 participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, 383 of whom had longitudinal imaging data (2-4 years follow-up). Structural MRI and PET scans with [18F]AZD4694 (amyloid-β), and [18F]MK6240 (tau) tracers were utilized. Choroid plexus and ventricular volumes were segmented using FreeSurfer and adjusted for intracranial volume. Ventricular radioactivity served as a proxy for choroid plexus function. Plasma glial fibrillary acidic protein (GFAP) levels were used as a biomarker for astrocyte activation. Associations between ventricular remodeling, astrocyte reactivity, and amyloid-β and tau burden were assessed using both region-of-interest and voxel-wise approaches. RESULT: We observed significant reductions in ventricular radioactivity, indicative of choroid plexus dysfunction, along with significantly increased choroid plexus and ventricular volumes in individuals with amyloid-β and tau pathology (Figure 1). The [18F]MK6240 time-activity curves in the lateral ventricles highlighted initial peak differences across diagnostic groups (CN (Y), A-T-, A-T+, A+T+), suggesting impaired CSF production and altered choroid plexus function (Figure 1F). Voxel-wise analyses revealed that amyloid-β accumulation was significantly associated with ventricular volume and GFAP levels (Figure 2). Furthermore, the impact of ventricular enlargement and astrocyte activation on tau accumulation was secondary to amyloid-β (Figure 3), where individuals with larger ventricles and higher amyloid burden exhibited higher tau load (Figure 1c). Kaplan-Meier survival analysis demonstrated that individuals in the highest tertiles of GFAP, ventricular volume, and choroid plexus volume exhibited faster cognitive decline (Figure 1G-J). These effects survived adjustment for amyloid-β and tau loads, without evidence of interaction or mediation. CONCLUSION: Our findings suggest that astrocyte activation and ventricular remodeling independently contribute to early amyloid-β and tau aggregation. Elevated GFAP and enlarged ventricles may serve as biomarkers for individuals at risk of accelerated disease progression, emphasizing the importance of CSF clearance in AD pathophysiology.

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