Impaired glymphatic clearance links inflammation to accelerated brain aging in schizophrenia
Neuroimaging and post-mortem transcriptomics connect disrupted astrocytic aquaporin-4 polarization and blood-brain barrier breakdown to increased epigenetic and brain age.
bioRxiv · 30 Sept · Tan X, Simon M, Rosebrock D et al.
In this preprint, researchers analyzed human cohorts with schizophrenia using in vivo neuroimaging, peripheral immune profiling, and post-mortem single-nucleus transcriptomics. The team identified impaired glymphatic clearance restricted to an inflammatory subgroup showing peripheral immune activation and pro-inflammatory glial profiles. In post-mortem tissue, this dysfunction correlated with reduced astrocytic expression of SNTA1 and DAG1, components required for polarized aquaporin-4 localization. At the cellular level, impaired clearance coincided with loss of homeostatic microglial and astrocytic programs, elevated inflammatory signaling, and transcriptomic markers of blood-brain barrier disruption. Imaging signatures of glymphatic impairment also tracked with cognitive deficits, polygenic risk scores tied to immune and oxidative stress aging pathways, and accelerated biological aging, including higher brain and epigenetic age.
Why it matters
The findings propose that impaired glymphatic waste clearance serves as a mechanistic link connecting chronic inflammation to accelerated brain and epigenetic aging. Understanding this pathway may help clarify how immune activation drives tissue-level decline and cognitive impairment.
Caveats
The investigation relies on observational human datasets across separate imaging and post-mortem cohorts. Additionally, the study is a preprint and has not yet undergone formal peer review.
The paper
Multimodal evidence for impaired glymphatic brain clearance as a mediator of "inflammaging" in schizophrenia - integrating insights from in vivo neuroimaging, omics, and post-mortem single nucleus-RNA-Seq data
Tan X, Simon M, Rosebrock D et al.
bioRxiv
doi.org/10.64898/2026.09.24.753662