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Degenerative cervical myelopathy (DCM) is the most common cause of nontraumatic spinal cord injury in adults worldwide. Surgical decompression is generally effective in improving neurological outcomes and halting progression of myelopathic deterioration. However, a subset of patients experience suboptimal neurological outcomes. Given the emerging evidence that apolipoprotein E4 (ApoE4) allelic status influences neurodegenerative conditions, we examined whether the presence of the ApoE4 allele may account for the clinical heterogeneity of treatment outcomes in patients with DCM. Our results demonstrate that human ApoE4+ DCM patients have a significantly lower extent of improvement after decompression surgery. Functional analysis of our DCM mouse model in targeted-replacement mice expressing human ApoE4 revealed delayed gait recovery, forelimb grip strength, and hind limb mechanical …