Clinical data strongly support olfactory impairment as an early indicator of neurodegenerative diseases (ND), including Alzheimer’s disease. In AD patients, neurofibrillary tangles (NFTs) have been identified in the entorhinal cortex and olfactory bulbs, both crucial in olfactory information processing. We therefore investigated the hypothesis that typical ND lesions could appear early in olfactory system regions.We used a tauopathy mouse model (PS19 mice) expressing the human tau protein (1N4R) carrying the P301S mutation. PS19 mice develop NFTs-like inclusions at six months, leading to progressive neurodegeneration at eight months. Immunohistochemistry and western blots were performed on brain samples to evidence the expression of hyperphosphorylated human tau protein (pTau). Specific olfactory regions such as the olfactory epithelium (OE) and bulbs (OB) were investigated to correlate tau profiles with data obtained in CNS regions.Detection of pathological pTau (Ser202, Thr205) was observed in PS19 mice. In the OE, pTau was detected in the olfactory neurons within the middle stratum as early as 1.5 month. In the OB, pTau was expressed in the olfactory nerve layer. Tau lesions were found in the piriform and entorhinal cortex from 6 months, along with the CA3 region and dentate gyrus in the hippocampus. We hypothesize that pTau may appear early in the OE and subsequently spread to the CNS following neuroanatomical pathways, like the olfactory or perforant pathways. These findings highlight: (i) the prognostic potential of the OE region in the tauopathy diagnosis and (ii) its likely contribution to the pathology progression in the CNS.