Olfactory Function in Preclinical Alzheimer's Disease: A Multi-Cohort Study

Introduction: Olfactory impairment is an early feature of Alzheimer's disease (AD). However, it is unclear if olfactory performance reflects early pathological changes during preclinical AD and/or predicts subsequent clinical progression among characterized cognitively normal (CN) individuals. We aimed to determine whether odor identification differs by amyloid status, relates to medial temporal lobe (MTL) tau burden and morphometry, and predicts longitudinal conversion to mild cognitive impairment (MCI). Methods: We analyzed data from 257 cognitively normal (CN) older adults enrolled in PREVENT-AD (n = 217) and UCLouvain (n = 40), including 76 amyloid-positive (CN A+) and 181 amyloid-negative participants (CN A−). Participants completed olfactory testing, underwent tau-PET imaging, and structural MRI. Results: CN A+ participants had significantly lower odor identification performance than CN A− participants, with no evidence of cohort heterogeneity. Tau-PET associations with odor identification differed by cohort. After whole-brain FDR correction and exclusion of extreme values, parahippocampal tau burden was negatively associated with odor identification score in UCLouvain ([18F]MK-6240), an association that was not found in PREVENT-AD ([18F]flortaucipir). No morphometric association survived multiple comparison correction. In 250 participants with longitudinal follow-up, each 10-percentage-point higher odor identification score was associated with a 16% lower hazard of incident MCI, independent of baseline global cognition and APOE ϵ4-carrier status. Discussion: Odor identification was lower in preclinical AD and associated with incident MCI independently of baseline global cognition and APOE ϵ4-carrier status. Its association with parahippocampal tau burden differed between cohorts, supporting further investigation using harmonized imaging methods.