Many brain-based phenotypes and disorders are accompanied by gross brain anatomic changes or differences when compared to brains from individuals without such phenotypes. These anatomical differences provide foci for many pathophysiological inquiries. However, in many other disorders and phenotypes, brains do not reveal reproducible gross pathologies. In these circumstances, investigations more often focus on molecular and biochemical pathways. Pharmacological mechanisms can even provide foci for exploration, when drugs that ameliorate disease symptoms are discovered serendipitously. Roles for mechanisms involved in “no gross pathology” phenotypes can be inferred in a number of disorders in which gross brain pathologies have been identified. Cognitive abilities at baseline, accompanied by no gross pathology, can play substantial roles in individual differences in vulnerability to dementing illnesses with gross pathological brain changes, such as Alzheimer’s disease, for example [227].
