Is intracranial volume a suitable proxy for brain reserve?

Brain reserve is a concept introduced to explain why Alzheimer's disease (AD) patients with a greater brain volume prior to onset of pathology generally have better clinical outcomes. In this review, we provide a historical background of the emergence of brain reserve and discuss several aspects that need further clarification, including the dynamic or static nature of the concept and its underlying mechanisms and clinical effect. We then describe how brain reserve has been operationalized over the years, and critically evaluate the use of intracranial volume (ICV) as the most widely used proxy for brain reserve. Furthermore, we perform a meta-analysis showing that ICV is associated with higher cognitive performance after adjusting for the presence and amount of pathology. Although we acknowledge its imperfections, we conclude that the use of ICV as a proxy for brain reserve is currently warranted. However, further development of more optimal measures of brain reserve as well as a more clearly defined theoretical framework is essential.