Apolipoprotein E ε4 genotype and risk of freezing of gait in Parkinson's disease

To investigate the association between Apolipoprotein E (APOE) genotype and freezing of gait (FOG) in Parkinson's disease (PD).This cohort study included 339 early PD patients who were divided into APOE ε4-positive (n = 88) and ε4-negative (n = 251) groups. They were followed-up for up to 6 years to identify the development of FOG. To investigate the influence of CSF β-amyloid 1-42 (Aβ42) on the association between APOE ε4 and FOG, the patients were additionally dichotomized into "high-level" and "low-level" groups using three different cutoff values for the CSF Aβ42 levels.At baseline, the APOE ε4-positive group had lower CSF Aβ42 levels than the APOE ε4-negative group. During a median follow-up of 5.0 years, the APOE ε4-positive group had a higher incidence of FOG than the APOE ε4-negative group. In the multivariable Cox model excluding CSF Aβ42, APOE ε4 was a significant predictor of FOG. However, after adding CSF Aβ42 in the model, APOE ε4 did not survive, whereas lower CSF Aβ42 levels were associated with FOG. In the subgroup analyses, the effect of the APOE ε4 allele was not found in the "low-level" group. However, in the "high-level" group, the APOE ε4 allele independently increased the risk of FOG, and this association was stronger than the association with CSF Aβ42.The APOE ε4 allele may be a novel genetic risk factor for FOG in PD. This association seemed to be mainly mediated by Aβ-dependent pathways, but its Aβ-independent effects might also contribute to the development of FOG.