Trajectory of olfactory cortex degeneration from normal cognition to Alzheimer's disease: Insights from multimodal neuroimaging

The olfactory cortex is among the earliest brain regions affected by Alzheimer's disease (AD), with olfactory deficits frequently preceding cognitive decline. This study aimed to characterize the functional and structural degeneration trajectory of the olfactory cortex from normal cognition (NC) to mild cognitive impairment (MCI) and eventually to AD using multimodal neuroimaging techniques. A total of 105 participants (28 with NC, 35 with MCI, and 42 with AD) were subjected to olfactory University of Pennsylvania Smell Identification Test (UPSIT) and cognitive e.g., Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) assessments. This was followed by olfactory task–based functional magnetic resonance imaging (fMRI; olfactory activation), resting-state fMRI amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo), and structural MRI gray matter volume (GMV) and white matter volume (WMV) in 12 olfactory-related regions of interest. Group comparisons using one-way analysis of variance/Kruskal–Wallis and multivariate logistic regression analyses were performed to identify stage-specific imaging biomarkers and evaluate diagnostic performance. From the NC to MCI and then to AD groups, a consistent pattern of declining olfactory activation values, GMV, and WMV, coupled with increased ALFF and ReHo in olfactory subregions, was observed. Moreover, corresponding decreases in olfactory and cognitive scores were noted. Our multivariate logistic regression models yielded the following classification performance: NC versus MCI right primary olfactory cortex (POC) olfactory activation, right insula olfactory activation, left POC GMV, left insula ReHo, right amygdala ALFF, and MMSE scores achieved 90.5 % accuracy; MCI versus AD (left hippocampal GMV, left insula ReHo, and MMSE scores) reached 94.8 % accuracy; and NC versus AD (left hippocampal GMV and UPSIT scores) achieved 92.9 % accuracy. Our findings delineate a spatiotemporal progression of olfactory cortex degeneration, with early POC alterations in MCI evolving into widespread atrophy and functional dysregulation in AD. Multimodal MRI metrics and logistic modeling yield highly accurate stage classification, underscoring their potential as sensitive biomarkers for early AD detection and monitoring. • Integration of olfactory task–based functional magnetic resonance imaging (fMRI), resting-state fMRI, and structural MRI systematically traces the trajectory of olfactory cortex degeneration from normal cognition to mild cognitive impairment and eventually to Alzheimer's disease (AD). • Multivariate logistic regression models combining clinical and imaging metrics yielded exceptional diagnostic accuracy (90.5 %–94.8 %), demonstrating the clinical potential of olfactory-based biomarkers. • Early degeneration in the primary olfactory cortex offers measurable changes, supporting its role as a sensitive imaging biomarker for the early detection of AD.