AbstractBackgroundCognitive reserve (CR) is a concept explaining better than expected cognitive performance given the degree of brain disease. More specifically, as a compensation mechanism, individual differences in patterns of brain activity during fMRI tasks may explain differential susceptibility to pathological burden. CR might already manifest in early preclinical Alzheimer’s disease (AD) stages.MethodParticipants of the longitudinal PREVENT‐AD study have well‐characterized AD biomarkers via [18F]AV1451 and [18F]NAV469 PET for Aβ and tau as well as repeated MRI measurements including a memory retrieval task. Participants also completed cognitive testing with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We selected a subsample of 82 cognitively unimpaired older adults (age: 67.9 ± 4.8 years; 24 male) with (f)MRI data within 2 years of PET. PET‐ and MRI‐based ATN biomarkers were reduced to a single composite measure for AD pathological load (PL; Fig.1). We extracted mean retrieval‐related fMRI activation (hits versus correct rejections) from specific regions, comprising all task‐positive regions (pFWE < 0.05), all task‐negative regions, entorhinal cortex, precuneus, and inferior parietal cortex. Subsequently, we tested fMRI activation as a moderator variable between PL and delayed memory performance in line with the CR framework.ResultActivation in task‐positive regions showed an interaction (moderation) effect with PL on memory performance (p = 0.033). In individuals with low retrieval activation in the task‐positive network, AD pathological load was related to poorer memory performance, whereas this association was diminished in individuals with high retrieval activation. This moderation was not significant for task‐negative regions (p = 0.104). We observed a similar interaction for tau and activity in the entorhinal cortex (p = 0.0003) as well as for Aβ and activity in the precuneus (p = 0.056) and inferior parietal cortex (p = 0.010).ConclusionOur results indicate that the association between early AD pathology and memory performance differs dependent on the level of fMRI activation during memory retrieval, with an attenuated effect of pathology on memory at high levels of activation. It remains open if higher activity in the retrieval network serves as a functional reserve, or whether it reflects adaptive functional changes due to early pathology.