The ‘reserve’ hypothesis posits that the brain undergoes structural and functional reorganisation to actively cope with brain damage or disease. Consistent with passive and active components of ‘reserve’, the brain moderates its biological substrates (brain reserve) and differentially changes the level of neural activity in tasks-specific networks and/or by recruiting additional non-task related brain regions (cognitive reserve) to optimise behavioural performance. How the ‘reserve’ hypothesis applies in neurodegenerative disorders such as Huntington's disease (HD) remains unknown. We postulate that unless the ‘reserve’ hypothesis is tested empirically, it is impossible to draw firm conclusions about how task-related neural activity is providing a neuroplastic change in HD and possibly other neurodegenerative disorders. We conclude that there is a pressing need to operationalise cognitive reserve, as well as incorporate different biological substrates into a model of ‘reserve’. We suggest that it is important to identify and embed potential neuroprotective modulating factors of ‘reserve’ in randomised controlled multi-domain non-pharmaceutical interventions to potentially enhance ‘reserve’ and thus preserve cognitive and psychosocial functioning in HD patients.