Preventing frailty in multiple sclerosis is a realistic goal: Yes

Frailty is distinct from neurological disability: a separate therapeutic target

Over the last two decades, geriatric research has emphasized that frailty and disability are related yet distinct concepts in older adults. ² Recent work in MS supports this distinction: (1) frailty is associated with common MS-related symptoms and adverse health outcomes independently of the Expanded Disability Status Scale (EDSS)—the most common measure of neurological disability in MS; ³ (2) there exists a range of frailty within each EDSS category, especially in the 2.0–4.5 range, indicating that pwMS can be frail independently of neurological disability; ⁵ (3) when frailty is assessed using a multidimensional approach, physical components of frailty are strongly correlated with the EDSS, while psychosocial components are not. ³ We have recently postulated this may be responsible for the critical conceptual difference between frailty and disability in MS. ³

Importantly, a recent study directly examined the overlap between measures of frailty, disability, and comorbidity in pwMS. ⁶ While 32.6%–44.3% of participants exhibited at least two of the three conditions, 1.5%–10.3% of participants had frailty alone, 4.4%–14.3% had disability alone, and 11.8%–14.3% had comorbidity alone. These findings provide evidence that frailty, disability, and comorbidity represent separate conditions in MS, as they can present in isolation, and each has distinct associations with patient-centered outcomes. ⁶

The critical difference between frailty and neurological disability in MS has important implications for prevention and rehabilitation. While disability accrual is often considered a direct consequence of MS progression and difficult to modify, frailty represents a more dynamic and actionable therapeutic target, ² as demonstrated by recent research. ⁴

Frailty develops earlier in pwMS: a critical window for prevention

Frailty represents a “double threat” in MS. Namely, pwMS become frail at an earlier age than individuals without MS, and an increasing number are aging with MS. The earlier onset of frailty in MS can be characterized as a state of secondary frailty—a condition in which frailty is mainly driven by disease processes such as neuroinflammation and neurodegeneration. ⁷ On the other hand, people aging with MS may also experience primary frailty—also known as age-related frailty. These two conditions are not mutually exclusive. In other words, secondary and primary frailty likely co-exist in aging pwMS due to the interaction between disease- and age-related impairments.

This distinction has implications for prevention and rehabilitation. For individuals showing signs of secondary frailty, the priority is to reduce or reverse frailty through targeted rehabilitation—an approach supported by evidence demonstrating frailty reversibility when addressed early. ⁴ For individuals without frailty, particularly those experiencing age-related impairments, the primary goal is to delay the onset of frailty through proactive lifestyle and rehabilitation strategies. Both aims contribute directly to the overarching goal of preventing frailty or minimizing its long-term burden.

Lifestyle and rehabilitation interventions can reduce frailty in pwMS

The role of lifestyle factors such as exercise, physical activity, and nutrition in supporting healthspan and preventing frailty in older adults is widely recognized ⁸ and their importance has also been emphasized in pwMS. ⁹ To date, only a few studies have examined the effects of lifestyle interventions on frailty outcomes in MS. While no data on the effects of physical activity and nutrition interventions exist, exercise-based rehabilitation has shown promise in reducing frailty levels in this population. For instance, in a recent study, 6 weeks of treadmill training with and without the addition of a cognitive rehabilitation component resulted in significant improvements in frailty index scores (pooled mean difference = 0.024, 95% CI = 0.010–0.038, p = 0.002) in 83 pwMS. ⁴ In addition, 50.6% of participants were classified as responders and 20.5% exhibited a change in frailty category (i.e. a transition from severe to moderate frailty or from moderate to non-frail).

By logical extension, exercise-based interventions represent a good candidate for preventing frailty in MS. Systematic reviews showing exercise-induced improvements in multiple proxies of physiological reserve, such as muscle strength, aerobic capacity, and gait function, strongly support this possibility as well as the notion that preventing frailty in MS is a realistic goal. ¹⁰

Last, but not least, preventing frailty in MS aligns directly with the Pathways to Cures Research Roadmap. ⁹ Specifically, within the Restore pathway, a central objective is to develop prehabilitation and rehabilitation strategies to achieve preventive, restorative, and compensatory gains. Lifestyle interventions such as physical activity, nutrition, sleep hygiene, and cognitive training map directly onto this objective and target multiple physiological domains implicated in frailty. In addition, Pathways to Cures prioritizes interventions deployed early in the disease course to prevent functional loss. Frailty prevention embodies this proactive approach and will become increasingly important as the MS population continues to age.

In conclusion, preventing frailty in MS is a realistic, evidence-supported, and increasingly necessary goal. Lifestyle and targeted rehabilitation interventions may offer a feasible strategy to maintain or restore physiological reserve, promote successful aging, and extend healthspan in the MS community.