Apolipoprotein E as a Susceptibility Gene Beyond Brain Degenerative Diseases: A Systematic Review

Apolipoprotein E (APOE), particularly the ϵ4 allele, is a well-established susceptibility gene for dementias. However, its role in other neurological diseases and injuries remains unclear. This study aims to evaluate APOE as a risk factor for nervous system conditions beyond dementias.

A systematic review was conducted from inception to May 2025 across six databases: PubMed, Embase, CINAHL, APA PsycInfo, Web of Science and Cochrane. Studies were included if they employed clinical research methodologies, involved adult participants, completed APOE genotyping and examined APOE as a susceptibility gene in nervous system injuries other than dementias.

Thirty-three studies met inclusion criteria, encompassing stroke (n = 16), traumatic brain injury (n = 11), cranial or peripheral neuropathies (n = 4) and degenerative cervical myelopathy (n = 2). The ϵ4 allele was most consistently associated with increased susceptibility to intracerebral hemorrhage and chronic traumatic encephalopathy. In contrast, no relationship was observed between APOE and cerebral concussion risk. Findings across other conditions including ischemic and hemorrhagic stroke, subarachnoid hemorrhage, post-traumatic seizures, decompressive hemicraniectomy, degenerative cervical myelopathy and peripheral neuropathies were inconsistent or limited by small sample sizes.

While the APOE genotype may influence susceptibility in intracerebral hemorrhage and chronic traumatic encephalopathy, further research is needed to clarify its broader role and underlying mechanisms in non-dementia nervous system diseases and injuries.