Frailty and Associated Environmental Factors Only Have Small Effects on Age of Onset in Huntington's Disease

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.

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.

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.

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).

The impact of non-genetic factors on age of onset, assessed using a frailty index or separately, in Huntington's disease is limited.