Functional Connectivity between the Resting-State Olfactory Network and the Hippocampus in Alzheimer's Disease

Olfactory impairment is associated with prodromal Alzheimer's disease (AD) and is a risk factor for the development of dementia. AD pathology is known to disrupt brain regions instrumental in olfactory information processing, such as the primary olfactory cortex (POC), the hippocampus, and other temporal lobe structures. This selective vulnerability suggests that the functional connectivity (FC) between the olfactory network (ON), consisting of the POC, insula and orbital frontal cortex (OFC) (Tobia et al., 2016), and the hippocampus may be impaired in early stage AD. Yet, the development trajectory of this potential FC impairment remains unclear. Here, we used resting-state functional magnetic resonance imaging (rs-fMRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to investigate FC changes between the ON and hippocampus in four groups: aged-matched cognitively normal (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and AD. FC was calculated using low frequency fMRI signal fluctuations in the ON and hippocampus (Tobia et al., 2016). We found that the FC between the ON and the right hippocampus became progressively disrupted across disease states, with significant differences between EMCI and LMCI groups. Additionally, there were no significant differences in gray matter hippocampal volumes between EMCI and LMCI groups. Lastly, the FC between the ON and hippocampus was significantly correlated with neuropsychological test scores, suggesting that it is related to cognition in a meaningful way. These findings provide the first in vivo evidence for the involvement of FC between the ON and hippocampus in AD pathology. Results suggest that functional connectivity (FC) between the olfactory network (ON) and hippocampus may be a sensitive marker for Alzheimer's disease (AD) progression, preceding gray matter volume loss.