SorCS1 promotes synaptic and cognitive resilience despite amyloid pathology in Alzheimer’s disease model mice

Alzheimer’s disease (AD) lacks effective therapies despite extensive efforts targeting amyloid-β (Aβ) and its precursor processing. Synapse loss is the strongest correlate of cognitive decline, driven partly by Aβ oligomers (AβOs), which bind multiple synaptic membrane proteins including the synaptic organizer neurexin and disrupt synaptic integrity and function. The protein-sorting receptor SorCS1 blocks interactions between AβOs and β-isoforms of neurexins (β-Nrxns), but its therapeutic relevance in vivo remains unclear. Using 5xFAD mice, which overproduce AβOs, combined with forebrain-specific neuronal SorCS1 overexpression, we show that SorCS1 preserves working memory, synaptic integrity, and basal excitatory transmission without altering amyloid deposition, in part by restoring synaptic β-Nrxn expression. SorCS1 also reduces tau hyperphosphorylation in 5xFAD synaptosomes and binds the tau kinase GSK3β. These results identify SorCS1 as an AD resilience-promoting factor that maintains synaptic connectivity and attenuates tau pathology, revealing a therapeutic strategy that operates independently of amyloid reduction.