APOE ε4 carriage is associated with olfactory-hippocampal tract functional connectivity

Olfactory dysfunction often emerges before cognitive symptoms and may signal early vulnerability to neurodegenerative processes. This study examined whether genetic risk, specifically the presence of the epsilon 4 allele in apolipoprotein E, is associated with altered functional connectivity between the hippocampus and olfactory regions. Resting-state functional imaging data from 126 participants (mean age = 71.8 years, SD = 6.9; 67 females) across a range of clinical stages were analyzed. Functional connectivity was computed between the hippocampus and four olfactory-related regions: anterior piriform cortex, posterior piriform cortex, olfactory bulb, and olfactory tract. Multiple regression models assessed whether genetic risk, age, sex, and clinical diagnosis predicted connectivity strength. Genetic risk was significantly associated with increased connectivity between the hippocampus and the olfactory tract (model R² = 0.12). A nominal APOE ε4 effect was also observed in the olfactory bulb, although the overall model did not reach significance, while no significant effects were observed in the piriform cortex regions. Clinical diagnosis was not a significant predictor of connectivity in any region. These results suggest that genetic risk is linked to early functional reorganization in specific olfactory-hippocampal pathways, particularly the olfactory tract, independent of clinical progression. The olfactory-hippocampal network may serve as a sensitive target for detecting early brain changes associated with neurodegenerative risk.