Neural Underpinnings of Olfactory Dysfunction across Parkinson’s and Alzheimer’s Spectra

Olfactory dysfunction is a frequent yet understudied feature of neurodegenerative spectrum disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). To disentangle the neural substrates of hyposmia across disease spectra, we examined 222 participants from the Parkinson’s and Alzheimer’s disease Dimensional Neuroimaging Initiative cohort. Participants were classified according to the presence of cognitive disturbance, movement disorder, or both. Olfactory testing disclosed that cognitive disturbance and movement disorder were independently associated with hyposmia, and having both cognitive disturbance and movement disorder was associated with severe hyposmia. Whole-brain voxel-based morphometry revealed that hyposmia was associated with atrophy in the medial temporal lobe (MTL) in individuals with cognitive disturbance, whereas an artificial intelligence-based segmentation model identified olfactory bulb atrophy in those with movement disorder. Regression analysis and structural equation modeling further confirmed that the MTL and olfactory bulb volume contributed to olfactory performance through distinct processes. Individuals with cognitive disturbance and movement disorder had atrophy in both the MTL and olfactory bulb (“double hit”). We identified dual processes underlying hyposmia in the AD and PD spectra: a process linking MTL degeneration to cognitive disturbance and a process linking olfactory bulb degeneration to movement disorder. Our transdiagnostic approach enhances strategy in identifying specific neural correlates underlying hyposmia, lending support to the development of biomarkers for early intervention in AD and PD.