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 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: We describe statistical properties of the regression equation to illustrate why the residual is highly correlated with the cognitive score from which it was derived. Using both simulations and real data, we model common applications of the approach by creating a residual score (global cognition residualized for hippocampal volume) in individuals along the AD spectrum. We demonstrate that in most real-life scenarios, the residual measure of cognitive resilience is highly correlated with cognition, 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. We then assess several strategies proposed as potential solutions to this problem, such as including both the residual and original cognitive measure in a model. 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.

Conclusions: Caution should be taken in the use and interpretation of the residual-based method of cognitive resilience. Rather than identifying resilient individuals, we encourage building more complete models of cognition to better identify the specific adverse and protective factors that influence cognitive decline.