Cellular redox status is linked to olfactory alterations in cognitive decline.

Growing evidence demonstrates that olfactory dysfunction and disease-related pathology in the olfactory areas occur early in Alzheimer's disease (AD), which is the most common neurodegenerative disorder. Oxidative stress is strongly linked to AD-associated changes in the brain, yet very little is known about redox homeostasis in the peripheral olfactory tissues, and its link to olfactory dysfunction associated with early AD. The olfactory mucosa (OM), located at the rooftop of the nasal cavity is the primary organ for olfaction through odorant detection and transmission of these signals to the brain via the olfactory nerves. This study collected patient-derived biopsies of the OM from cognitively healthy donors, individuals with mild cognitive impairment (MCI) and AD. Shotgun proteomics of the biopsies provided new insights into the molecular mechanisms associated with early AD and olfactory dysfunction, which was assessed by odor identification testing. Furthermore, microRNA sequencing and quantitative analyses of electron carriers, cofactors and glutathione from the biopsy-derived primary cells of the OM were used to link these findings to cellular redox status. The results revealed mitochondrial changes and alterations to cellular defense against oxidative stress, specifically the potentially dampened NRF2 pathway, in MCI and AD OM, which were linked to impairments in odor identification. Understanding the early cellular and molecular changes occurring in the olfactory system and olfaction could aid in the early identification of individuals at risk of developing AD and pathophysiological changes of the OM in AD.