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

Abstract

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-β (Aβ), the key biomarker of AD, in patient nasal discharge using proteomic analysis. Then, we profiled the significant differences in Aβ 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 Aβ 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 Aβ 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 Aβ*56 and 15-mer AβO, respectively. The longitudinal cohort study confirmed that the cognitive decline of mild AD patients with high nasal discharge Aβ*56 levels advanced to the moderate stage within three years. Our clinical evidence strongly supports the view that the presence of oligomeric Aβ proteins in nasal discharge is a potential surrogate biomarker of AD and an indicator of cognitive decline progression.

Olfactory neuropathology in Alzheimer's disease: a sign of ongoing neurodegeneration

“…Hence nasal fluid from the OE may feasibly contain high-throughput biological material information which mirrors AD pathological changes in the olfactory system ( 37 ) that could be linked to the OE. The composition of oligomerized Aβ proteins in nasal discharge is also closely correlated with cognitive function during AD progression ( 73 ). Thus, nasal-fluid biomarkers could prove to be a candidate sourcing tool in AD similar to cerebrospinal fluid and plasma biomarkers.…”

Disease specific alterations in the olfactory mucosa of patients with Alzheimer’s disease

“…Our findings reveal that OM cells can produce and secrete Aβ1-40 and Aβ1-42, with AD patient cells secreting significantly more Aβ1-42 than cognitively healthy control cells. Prior literature demonstrates that the nasal mucosa or nasal secretions of AD patients also exhibit increased levels of Aβ 4,[6][7][8]17 . Furthermore, the amount of Aβ1-42 in the nasal area of transgenic Tg2576 mice modelling AD positively correlates with Aβ1-42 deposition in their brain 18 .…”

“…However, late-onset AD (LOAD) is the most common disease form and the major risk gene for this is APOE, the ε4 allele of which confers a 12-fold increase in disease risk in homozygous carriers 3 Nasal secretions of LOAD patients contain elevated amounts of Aβ and phosphorylated tau [4][5][6] .…”

“…Nasal secretions of LOAD patients contain elevated amounts of Aβ and phosphorylated tau 4–6 . Post mortem histological analysis of AD OM have revealed increased Aβ aggregation in the apical surface of the epithelium and intracellular Aβ has been detected in anosmic LOAD patients 7 .…”

“…Nasal secretions of LOAD patients contain elevated amounts of Aβ and phosphorylated tau 7–9 , indicative of pathological processes occurring in the nasal cavity. Post mortem histological analysis of AD OM have revealed immunostaining for filamentous tau inside neurites and in neuronal soma, resembling intracellular neurofibrillary tangles, in cells close to the OM basal membrane 10 .…”