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

Objective: To investigate the association between Apolipoprotein E (APOE) genotype and freezing of gait (FOG) in Parkinson's disease (PD). Methods: This cohort study included 339 early PD patients who were divided into APOE 84-positive (n = 88) and 84-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 beta-amyloid 1-42 (A beta(42)) on the association between APOE 84 and FOG, the patients were additionally dichotomized into high-level and low-level groups using three different cutoff values for the CSF A beta(42) levels. Results: At baseline, the APOE 84-positive group had lower CSF A beta(42) levels than the APOE 84-negative group. During a median follow-up of 5.0 years, the APOE 84-positive group had a higher incidence of FOG than the APOE 84-negative group. In the multivariable Cox model excluding CSF A beta(42), APOE 84 was a significant predictor of FOG. However, after adding CSF A beta(42) in the model, APOE 84 did not survive, whereas lower CSF A beta(42) levels were associated with FOG. In the subgroup analyses, the effect of the APOE 84 allele was not found in the lowlevel group. However, in the high-level group, the APOE 84 allele independently increased the risk of FOG, and this association was stronger than the association with CSF A beta(42). Conclusion: The APOE 84 allele may be a novel genetic risk factor for FOG in PD. This association seemed to be mainly mediated by A beta-dependent pathways, but its A beta-independent effects might also contribute to the development of FOG.