Cognitive Reserve Against Alzheimer’s Pathology Is Linked to Brain Activity During Memory Formation

The cognitive reserve (CR) hypothesis posits that individuals can differ in how their brain function is disrupted by pathology associated with aging and neurodegeneration. Here, we tested this hypothesis in the Alzheimer’s disease continuum using longitudinal data from 490 participants of the DELCODE multicentric observational study. Brain function was measured using task fMRI of visual memory encoding. Using a multivariate moderation analysis we identified a CR-related activity pattern underlying successful memory encoding that moderated the detrimental effect of AD pathological load on cognitive performance. CR was mainly represented by a more pronounced expression of the task-active network encompassing the default mode network (DMN), anterior cingulate cortex (ACC) and inferior temporal regions including the fusiform gyrus. We devised personalized fMRI-based CR scores that moderated the impact of AD pathology on cognitive performance and were positively associated with years of education. Furthermore, higher CR scores were associated with slower cognitive decline over time. Our findings suggest maintenance of core cognitive circuits including the DMN and ACC as the primary mechanism of CR. Individual brain activity levels of these areas during memory encoding have prognostic value for future cognitive decline. ### Competing Interest Statement Dr. Stern consults for Eisai, Lilly, and Arcadia. Columbia University licenses the Dependence Scale, and in accordance with university policy, Dr. Stern is entitled to royalties through this license. Dr. Schott is involved in clinical studies by Roche, Biogen, and Hummingbird Diagnostics, but does not receive personal funds from any of them. * ACC : anterior cingulate cortex AD : Alzheimer’s disease ADD : Alzheimer’s disease dementia ADR : AD patient first-degree relatives CN : cognitively normal CR : cognitive reserve CSF : cerebrospinal fluid DMN : default mode network GM : grey matter MCI : mild cognitive impairment PACC5 : Preclinical Alzheimer’s Cognitive Composite 5 PC : principal component PCA : principal component analysis PCC : posterior cingulate cortex PFC : prefrontal cortex PL : pathological load SCD : subjective cognitive decline SD : standard deviation TIV : total intracranial volume t-SNE : t-distributed stochastic neighbor embedding