The moderating effect of cognitive reserve on the association between neuroimaging biomarkers and cognition: a systematic review

This systematic review aims to investigate the moderating effects of cognitive reserve (CR) on the relationships between cognitive function and multimodal Alzheimer's disease (AD)-signatured brain changes, measured by positron emission tomography (PET), structural magnetic resonance imaging (sMRI) and functional MRI (fMRI). Through a comprehensive search of PubMed, Scopus, and Web of Science, we identified 55 eligible studies examining the moderating effect of CR on the relationship between neuroimaging biomarkers and cognitive outcomes. CR measurements include sociobehavioral proxies (e.g., education, leisure activities), residual approaches, and functional imaging approaches. Findings were mixed. Of the fifty-five studies, 41 studies reported a protective effect of CR, suggesting its buffering effect against cognitive decline or AD progression during ageing. However, eleven studies reported no interaction between CR and neuroimaging biomarkers. Six studies suggested a detrimental effect of CR in the middle-to-late stages of the disease e.g., mild cognitive impairment (MCI) and AD (three studies reported both protective and detrimental effects). The discrepancies may reflect that the influence of CR on the association between neuroimaging biomarkers and cognitive function depends on disease stage. In early stages, it exhibits protective effects, but as pathology accumulates, it may accelerate cognitive decline. This review revealed CR has heterogeneous effects on AD progression. We preliminarily identified a "critical point" for CR within the continuum between cognitively unimpaired (CU) and MCI, although its precise pathological determinants require further clarification. Establishing standardized CR metrics and conducting longitudinal biomarker-integrated studies are critical to pinpoint optimal intervention windows for maximizing CR's protective effects.