Identifying individuals at risk of developing neurodegenerative conditions prior to clinical manifestation of disease, has become a popular subject for recent neurological research. It is well established that by the time patients present with these disorders, a significant degree of irreversible neuronal loss has already occurred. Understanding the evolution of preclinical disease may, therefore, highlight methods by which the pathological processes can be slowed or curtailed; either through modifying environmental factors or by the use of novel disease modifying agents. Encouragingly this approach already has a number of successful precedents and is widely employed in the prevention of heart disease and indeed in many other branches of medicine. An important first step in this process will be the ability to screen individuals at risk for predictive biomarkers of disease, but identifying the population at risk for sporadic neurodegenerative conditions has proved problematic. However, the study of fully penetrant autosomal dominant disorders, in which a reliable genetic test is currently available, offers an opportunity to identify specific predefined cohorts. These very specific cohorts can then be assessed in detail, if necessary over prolonged time periods, for a large range of potential clinical, biological and radiological biomarkers. Although the numbers of individuals at risk of these relatively rare genetic disorders are commonly limited, the hope is that studies of this important group of individuals may offer important insights into more common sporadic conditions. In this month’s journal club, we examine three articles; each one addressing these issues in seperate neurodegenerative disorders, all of which are autosomal dominant and fully penetrant conditions and in which the age at onset can be predicted with varying degrees of accuracy: Huntington’s disease (HD), autosomal dominant cerebellar ataxias (SCA) and presenilin 1 autosomal dominant Alzheimer’s disease. In the first paper Tabrizi et al., examine premanifest carriers of HD and early HD patients in a 36-month longitudinal study. The second paper by Jacobi et al., examines carriers of the SCA1, SCA2, SCA3 and SCA6 mutations prior to disease onset. The final paper describes a cross sectional analysis of a Colombian cohort of Presenilin 1 mutation carriers. All three studies have employed different methodologies in search of a common goal; to identify informative clinical, biological or radiological biomarkers for these diseases.