Functional connectivity signatures of olfactory networks linked to cognitive risk: A functional MRI study in subjective cognitive decline at risk for Alzheimer's disease

Background: Individuals with subjective cognitive decline (SCD) are at high risk of preclinical Alzheimer's disease (AD). While olfactory dysfunction is evident in AD and mild cognitive impairment (MCI), its presence and neural mechanism in SCD remain unclear. Objective: This study examined functional connectivity (FC) alterations across olfactory networks and their mediating role between olfactory and cognitive functions in SCD and MCI. Methods: Eighty SCD, 51 MCI, and 80 normal controls underwent cognitive and olfactory tests and resting-state functional magnetic resonance imaging scanning. Two olfactory networks (primary and advanced), each with six selected spherical regions, were defined. We compared FCs within and between networks, examined correlations with olfactory and cognitive functions, performed mediation analysis, and evaluated classification via receiver operating characteristic curves. Results: SCD participants presented increased FCs in key regions with normal olfactory scores, while MCI patients exhibited reduced FCs and olfactory scores. Altered FCs correlated with olfactory performance and mediated the relationship between olfactory and cognitive functions. FC features effectively distinguished SCD from normal controls. Conclusions: Increased FCs in SCD indicated a significant compensatory neural mechanism for the disrupted FCs in MCI, leading to an apparent normal olfactory function in SCD participants. Moreover, the findings suggest that olfactory deficits may be associated with cognitive decline rather than solely impaired olfactory sensory processing. As such olfactory deficits could be a proxy for cognitive decline in AD and the altered FCs could aid in the early detection of individuals at high risk for preclinical AD.