Owing to the global aging of people with multiple sclerosis (pwMS), there is an emerging need to distinguish neurological disability from age-related conditions in this population.

To examine the overlap between frailty, disability, and comorbidity in pwMS, and their associations with quality of life (QoL) and falls.

Two hundred and three pwMS (mean age=51.8 ± 12.6 years; median Patient Determined Disease Steps (PDDS) score=1.0 [IQR=2.0]; 73.9% women) underwent established assessments of frailty (FRAIL scale, Tilburg frailty indicator, and frailty index), disability (PDDS), comorbidity (Charlson comorbidity index), QoL (MSQoL-54), and falls (12-month fall-history survey).

Frailty, disability, and comorbidity were distinct but overlapping: 1.5–10.3% of participants had frailty alone, 4.4–14.3% had disability alone, and 11.8–14.3% had comorbidity alone; between 9.4% and 19.7% had all three. Multivariable quantile and logistic regression analyses revealed that all frailty measures were more strongly associated with lower QoL (median regression coefficients ≤-4.76, p-values˂0.001) and greater odds of falling (ORs ≥1.47, p-values≤0.001) than disability or comorbidity. Participants with all three conditions had significantly worse physical QoL and a higher median number of falls than those with any one condition alone.

Frailty, disability, and comorbidity represent separate conditions in pwMS, as they can present in isolation, and each has distinct associations with QoL and falls. Comprehensive assessment of all three conditions may enhance risk stratification and inform individualized rehabilitation and aging support strategies.