Frailty and associated environmental factors only have small effects on age of onset in Huntington’s disease

Background: Over one third of age of onset variation in Huntington’s disease is unexplained by CAG repeat length. In Alzheimer’s disease, frailty partly modulates the relationship between neuropathology and dementia. Objective: We investigated whether a multi-domain frailty index, reflecting non-genetic factors in Huntington’s disease, similarly modulates the relationship between CAG repeat length and age of onset. Methods: We created a frailty index assessing comorbidities, substance abuse, polypharmacy, and education. We applied multiple linear regression models to 2,741 subjects with manifest Huntington’s disease from the Enroll-HD cohort study, including 729 subjects with late-onset (post-60 years) disease, using frailty index or constituent item scores and CAG repeat length as independent variables. We used actual and “residual” ages of onset (difference between actual and CAG-based predicted onset) as dependent variables, the latter offsetting the increased time available to accumulate comorbidities in older subjects. Results: Higher frailty index scores were associated with significantly lower residual ages of onset in the late-onset subgroup (p = 0.03), though the effect was small (R² = 0.27 with frailty as a predictor vs. 0.26 without). Number of comorbidities was also associated with significantly lower residual ages of onset in the late-onset subgroup (p = 0.04). Drug abuse and smoking were associated with significantly earlier ages of onset in the whole cohort (p < 0.01, p = 0.02) and late-onset subgroup (p < 0.01, p = 0.03). Conclusions: The impact of non-genetic factors on age of onset, assessed using a frailty index or separately, in Huntington’s disease is limited.