Clinical assessment is the gold standard of diagnosis, differential diagnosis, and assessment of the success of therapeutic interventions. Changes in clinical state are the principal indicator of disease presence and progression. Clinical status is a complex state determined by an interaction of host and disease factors. Host factors manifest as cerebral reserve, determined by genetic and environmental-historical influences. Variability in host factors creates variability in clinical states not attributable to disease burden and compromises the extent to which clinical evaluation and disease activity are directly related. The utility of biomarkers is judged by the degree to which they reflect clinical outcomes. Some biomarkers are more directly related to disease activity, are less influenced by host factors, have smaller standard deviation of measures, and require fewer patients to establish between-group differences than clinical assessment. Biomarkers must closely reflect clinical outcomes to be useful as evaluations of disease progression or as outcomes in clinical trials.