Olfactory decline tracks central‐to‐peripheral spread of tau pathology in Alzheimer's disease

INTRODUCTION: Olfactory decline often precedes cognitive symptoms in Alzheimer's disease (AD) and is linked to tau pathology. Yet, whether tau aggregates start in peripheral olfactory structures or spread from central regions remains debated. METHODS: We analyzed 34 post mortem human olfactory bulb (OB) and 2 neuroepithelium (ONE) samples across Braak stages, combined with ex vivo nasal swabs and standardized olfactory testing in 88 clinically characterized participants. RESULTS: Tau aggregates appeared in the anterior olfactory nucleus layer of the OB from Braak stage III, spreading to peripheral layers only in late stages. Olfactory identification declined in the preclinical phase and was linked to central tau pathology. Discrimination worsened during the prodromal stage, while threshold impairment appeared only in dementia, reflecting the anatomical progression of tau pathology. DISCUSSION: This anatomical-functional link supports a central-to-peripheral spread of tau pathology in the olfactory system, with stage-specific deficits suggesting targeted smell tests as early AD biomarkers.