Longitudinal profiling of oligomeric Aβ in human nasal discharge reflecting cognitive decline in probable Alzheimer's disease

Despite clinical evidence indicating a close relationship between olfactory dysfunction and Alzheimer's disease (AD), further investigations are warranted to determine the diagnostic potential of nasal surrogate biomarkers for AD. In this study, we first identified soluble amyloid-beta (A beta), the key biomarker of AD, in patient nasal discharge using proteomic analysis. Then, we profiled the significant differences in A beta oligomers level between patient groups with mild or moderate cognitive decline (n=39) and an age-matched normal control group (n=21) by immunoblot analysis and comparing the levels of A beta by a self-standard method with interdigitated microelectrode sensor systems. All subjects received the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and the Global Deterioration Scale (GDS) for grouping. We observed higher levels of A beta oligomers in probable AD subjects with lower MMSE, higher CDR, and higher GDS compared to the normal control group. Moreover, mild and moderate subject groups could be distinguished based on the increased composition of two oligomers, 12-mer A beta *56 and 15-mer A beta O, respectively. The longitudinal cohort study confirmed that the cognitive decline of mild AD patients with high nasal discharge A beta *56 levels advanced to the moderate stage within three years. Our clinical evidence strongly supports the view that the presence of oligomeric A beta proteins in nasal discharge is a potential surrogate biomarker of AD and an indicator of cognitive decline progression.