Reserve in Alzheimer's disease: update on the concept, functional mechanisms and sex differences

Purpose of review Epidemiological evidence suggests that higher reserve significantly delays the dementia onset in Alzheimer's disease. Yet, confusion in terminology of reserve and related concepts exists and the lack of quantitative measures and unclear neural substrates of reserve have hampered progress. We review here the latest advances in the concept, measures and functional brain mechanisms of reserve, as well as their moderating factors including sex and gender. Recent findings The definition of reserve has been revised towards a more simplified concept, and the development of quantitative measurements of a cognitive advantage in disease has been advanced. Functional MRI and FDG-PET studies have provided for the first time converging evidence for the involvement of the cognitive control and salience network and temporal pole in reserve. Women tend to show lower resilience than men at advanced stages of AD. Neuroimaging studies have provided substantial evidence for putative brain mechanisms supporting reserve in Alzheimer's disease. However, the findings are still somewhat disparate and call for the development of unifying and testable theory of functional and structural brain properties that subserve reserve. Sex differences emerged as a moderating factor of reserve in Alzheimer's disease and need to be made a major research focus in Alzheimer's disease.