Disrupting SORL1-retromer endosomal recycling in mice drives the age-dependent neurodegenerative signature of Alzheimer's disease

In over 140 wildtype and SORL1-deficient mice, SORL1 loss produces an age-dependent AD-like atrophy pattern centered on the trans-entorhinal cortex, which is prevented by SORL1 restoration.

• Why it matters: AD shows an age-dependent neurodegenerative atrophic signature, but how endosomal recycling disruption contributes is unclear. This work tests whether the SORL1–retromer pathway can drive that process.
• What they did: Across multiple yearlong MRI studies in mice modeling SORL1 causative mutations, the authors assessed atrophy and then used SORL1 restoration via retromer protein VPS26b overexpression. They confirmed neuronal loss postmortem and linked proteomic changes to cell death suppressors, including one deficient in trans-entorhinal cortex of AD patients.
• The result: SORL1 deficiency-linked atrophy is associated with reduced cell death suppressors and is validated as neuronal loss. Together with patient proteomics, the findings suggest SORL1–retromer disruptions may represent a therapeutically amenable neurodegeneration pathway in AD.

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