Issues and Recommendations for the Residual Approach to Quantifying Cognitive Resilience and Reserve

Background: Cognitive reserve and resilience are terms used to explain interindividual variability in maintenance of cognitive health in response to adverse factors, such as brain pathology in the context of aging or neurodegenerative disorders. There is substantial interest in identifying tractable substrates of resilience to potentially leverage this phenomenon into intervention strategies. One way of operationalizing cognitive reserve/resilience that has gained popularity is the residual method: regressing cognition on an adverse factor and using the residual as a measure of resilience. This method is attractive because it provides a statistical approach that is an intuitive match to the reserve/resilience conceptual framework. However, due to statistical properties of the regression equation, the residual approach has qualities that complicate its interpretation as an index of resilience and make it statistically inappropriate in certain circumstances. Methods and Results: Using both simulations and real data, we demonstrate that in most real-life scenarios, the residual measure of cognitive resilience is highly correlated with cognition, the dependent variable from which it is derived, and the degree of this correlation depends on the initial relationship between the adverse factor and cognition. Subsequently, any association between this resilience metric and an external variable may actually be driven by cognition, rather than by an operationalized measure of resilience. This limitation becomes especially troublesome when the resilience metric is incorporated into models testing a cognition-dependent variable, such as cognitive decline or change in cognitive status. Conclusions: : We briefly summarize strategies proposed as potential solutions. However, we conclude these solutions may be insufficient, and we instead recommend against "pre-regression" strategies altogether, in favor of using statistical moderation (e.g., interactions) to quantify resilience. Caution should be taken in the use and interpretation of the residual-based method of cognitive resilience, but we encourage continued work toward operationalizing this very important phenomenon.