Adachi, Y.; Katori, K.; Ishiyama, S.; Morikawa, S.; Saito, T.; Saido, T. C.; Ikegaya, Y.; Takeuchi, H.

Background Olfactory impairment often precedes cognitive decline in Alzheimer\'s disease (AD). Recent studies suggest odor specificity in olfactory deficits during early AD stages, making olfactory tests a promising tool for early diagnosis. However, the mechanisms underlying olfactory impairment remain unclear, complicating the identification of optimal odorants for diagnostic purposes. Objective In this study, we assessed olfactory sensitivity in a knock-in mouse model of Alzheimer\'s disease (AppNL-G-F mice) that recapitulates key features of human AD pathology. Methods To evaluate odor detection thresholds, we employed an olfactory assay that leverages innate behavior without requiring associative learning. Six odorants representing distinct functional groups were tested in wild-type (WT) and AppNL-G-F mice at 2 and 4 months of age. Results AppNL-G-F mice exhibited odorant-specific hyposmia at 4 months of age, coinciding with amyloid deposition in cortical and subcortical regions but preceding measurable cognitive deficits. Unexpectedly, at an earlier stage (2 months), these mice showed odorant-specific hyperosmia to ester odorants, which transitioned to hyposmia by 4 months, indicating dynamic, age-dependent alterations in olfactory sensitivity as AD pathology progresses. Conclusions Our findings demonstrate that odorant-specific olfactory testing could serve as a promising diagnostic tool for early-stage AD, providing insights into the mechanisms underlying olfactory dysfunction in neurodegenerative diseases.