Epigenetic Clocks: An emerging role for Biomarkers of Aging in Psychiatry.

The glucocerebrosidase gene () encodes for the lysosomal enzyme β-glucocerebrosidase. Mutations in this gene are the most common genetic risk factor for Parkinson's disease (PD). PD patients with a mutation (GBA1mut) have a younger age at disease onset, a faster decline of motor, non-motor and cognitive functions, and have a shortened life expectancy compared to PD patients without a mutation (GBA1wt). Mutations in the gene are classified as ‘severe’, ‘mild’, or ‘polymorphisms/common variants’ based on their association with Gaucher's Disease The risk of PD is higher in individuals with severe mutations compared to those with mild mutations or polymorphisms. Severe mutations are also linked to an increased risk of developing dementia. However, clear differences in the progression of motor symptoms between severe and mild mutations, or polymorphisms, have not yet been demonstrated. Findings concerning disease progression in GBA1mut patients are mostly based on retrospective data, on prospectively gathered data from PD patients with advanced disease, and on fewer data from incidence cohorts in which clinical assessments were performed with intervals of six, 12 or 18 months over a longer time course. GBA1mut patients are clinically indistinguishable from GBA1wt patients at the moment of PD diagnosis. It is unclear when in the course of the disease symptoms progress faster in GBA1mut patients. This information would be relevant for counseling patients, but also for trial design of disease modifying treatments as these treatments are often studied in patients with early PD over the time course of about two years. We performed post-hoc analyses of the Levodopa in EArly Parkinson's disease (LEAP) study concerning the association between mutation carrier status and disease progression in early PD patients. Eight study visits were performed within the first 80 weeks of the trial, with prospective follow-up visits three and five years after baseline.