Guidance for clinical management of pathogenic variant carriers at elevated genetic risk for ALS/FTD

There is a growing understanding of the presymptomatic stages of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and nascent efforts aiming to prevent these devastating neurodegenerative diseases have emerged. This progress is attributable, in no small part, to the altruism of people living with pathogenic variants at elevated genetic risk for ALS/ FTD via their willingness to participate in natural history studies and disease prevention trials. Increasingly, this community has also highlighted the urgent need to develop paradigms for providing appropriate clinical care for those at elevated risk for ALS and FTD. This manuscript summarises recommendations emanating from a multi-stakeholder Workshop (Malvern, Pennsylvania, 2023) that aimed to develop guidance for at-risk carriers and their treating physicians. Clinical care recommendations span genetic testing (including counselling and sociolegal implications); monitoring for the emergence of early motor, cognitive and behavioural signs of disease; and the use of Food and Drug Administration-approved small molecule drugs and gene-targeting therapies. Lifestyle recommendations focus on exercise, smoking, statin use, supplement use, caffeine intake and head trauma, as well as occupational and environmental exposures. While the evidence base to inform clinical and lifestyle recommendations is limited, this guidance document aims to appraise carriers and clinicians of the issues and best available evidence, and also to define the research agenda that could yield more evidence-informed guidelines.