Relapse-associated worsening in apolipoprotein E ε4 carriers with relapsing multiple sclerosis

Background: In multiple sclerosis (MS), disability accrual can arise from relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA). While genetic variants associated with increased MS severity have been identified, little is known on apolipoprotein E (ApoE) gene. This study aims to investigate the impact of the ApoE ε4 allele (ApoE4) on disability accrual in relapsing MS patients. Methods: Patients with relapsing MS, aged >18 years, consecutively referred to the MS centre at the University of Florence, Italy, were recruited (n=160). Patients were classified as ApoE4 carriers and non-carriers. The first confirmed disability accrual (CDA) was defined as ≥24-week confirmed disability increase from roving baseline. PIRA was defined as a CDA with absence of relapses <90 days before and <30 days after the onset of disability accrual and confirmation event. The association between APOE4 and type of first CDA was assessed using multivariable Cox proportional hazard regressions. Results: After a follow-up of 12.3±6.3 years, a first CDA occurred in 97 patients (60.6%). PIRA accounted for 58 (59.8%) CDA events in the whole sample and for 7 out of 18 (38.9%) CDA events in APOE4 non-carriers (p=0.045). Indeed, RAW was associated with ApoE4 in the whole sample (HR=3.33, 95% CI 1.53 to 7.27, p=0.002) and in patients with relapses during follow-up (HR=3.60, 95% CI 1.62 to 8.02, p=0.002). Interpretation: Our study underscores the importance of genetic factors such as ApoE4 in MS pathogenesis. The identification of genetic markers associated with specific patterns of disability accrual could unveil mechanisms of damage accumulation and provide new therapeutic targets.