Cognitive reserve (CR) shows protective effects on cognitive function in older adult and in Alzheimer’s disease (AD). However, the brain mechanisms underlying the CR effect on the non-dementia AD spectrum (subjective cognitive decline (SCD) and mild cognitive impairment (MCI)) are unknown. The aim of this study was to investigate the potential moderate effect of CR on brain functional networks associated with cognitive performance.

We selected 200 participants, including 48 cognitively normal (CN) and 56 SCD, and 96 patients with MCI from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Seed-based locus coeruleus functional connectivity (LC FC) was conducted to detect early brain functional changes in the nondementia AD spectrum. CR was assessed via years of education and intelligence (IQ). The ANDI composite executive function scores (ADNI-EF) and ADNI composite memory scores (ANDI-MEM) at baseline and 24-month follow-up were used to assess cognitive performance.

Compared to the CN group, the SCD group showed abnormal LC FC with the executive control network (dorsolateral prefrontal cortex, DLPFC), salience network, sensorimotor network, reward network, and hippocampus, while these alterations were inverted at the MCI stage. The LC-hippocampus FC was correlated with ADNI-MEM at baseline and follow-up, and these relationships were moderated by education. The LC-DLPFC FC was correlated with ADNI-EF at baseline, and this association was moderated by IQ.

Our results manifested that higher levels of CR would confer protective effects on SCD and MCI. Furthermore, IQ and education could moderate the relationship between LC FC and cognition through different pathways.