Altered olfactory adaptation of primary olfactory cortex-hippocampus-parietal lobe in Alzheimer's disease continuum:...

Olfactory adaptation, the progressive reduction of neural responses to repeated odor stimulation, is closely linked to cognitive function and is altered in Alzheimer's disease (AD). However, its evolution across biomarker-defined stages and relationship with plasma p-tau217 remain unclear. We studied 168 participants classified by plasma p-tau217: cognitively normal (p-tau217-NC, n = 37; p-tau217+NC, n = 8), subjective cognitive decline (p-tau217-SCD, n = 57; p-tau217+SCD, n = 16), and mild cognitive impairment (p-tau217-MCI, n = 40; p-tau217+MCI, n = 10). Odor-induced fMRI with four concentrations (0.032%, 0.1%, 0.32%, 1.0%) presented in a fixed ascending order, although concentration effects could not be fully separated from time-related factors and other confounders, to assess activation in the primary olfactory cortex (POC), hippocampus (HP), and parietal lobe (PL). Receiver operating characteristic (ROC) analyses were performed using logistic regression models. In NC groups, adaptation emerged at 0.1% and 0.32% odor conditions. In p-tau217-SCD, POC adaptation was delayed to 1.0% odor condition, HP was largely preserved, and PL was dysregulated. p-tau217+SCD and MCI groups showed delayed and dysregulated adaptation across all regions. Odor adptations were associated with plasma p-tau217 levels and olfactory memory (p_unc 〈 0.05, p_FDR 〉 0.05). Furthermore, plasma p-tau217 partially mediated the relationship between adaptation-related alterations and olfactory memory. ROC analyses indicated that olfactory adaptation may distinguished individuals across disease stages, require further confirmation in independent cohorts. These findings reveal that impaired olfactory adaptation may represent an early signature associated with AD continuum, particularly in SCD and p-tau217-positive stages.