Amyloidogenic nanoplaque levels are increased in the cerebrospinal fluid in Alzheimer’s disease: Biomarkers (non‐neuroimaging) / Novel biomarkers

Background The aggregation of amyloid β (Aβ) is a central step in Alzheimer’s disease (AD) pathogenesis according to the amyloid cascade hypothesis. Measures of misfolded or aggregated Aβ are attractive biomarkers for AD, as they could potential reflect an important disease step. Newly, a Thioflavin‐T Fluorescence Correlation Spectroscopy (ThT‐FCS) assay has been developed that allows the quantification of amyloidogenic aggregates, hereby nanoplaques, with single‐molecule sensitivity. Thus far, no study has evaluated the association between cerebrospinal fluid (CSF) nanoplaque levels and core CSF biomarkers of AD. Method CSF was collected from 118 individuals assessed for cognitive complaints at the Oslo University Hospital Memory Clinic. Levels of CSF core biomarkers: Aβ 42 , total tau (T‐tau) and phosphorylated tau (P‐tau) were evaluated with ELISA assays (Innotest kits). The CSF nanoplaque concentration was quantified using the ThT‐FCS analysis. All patients received research diagnoses, and were AT(N)‐classified based on all available biomarkers (fluid‐ and imaging biomarkers). Result Sixty‐eight patients were clinically diagnosed with possible or probable AD, and 50 patients were diagnosed with other cognitive disorders. Sixty‐five patients were classified as A+ (on the Alzheimer’s continuum) and 53 patients were classified as A‐ (normal AD biomarkers or non‐AD pathologic changes). Nanoplaque levels were significantly increased in patients with clinically diagnosed possible or probable AD as compared to memory clinic patients with other cognitive disorders, P = .02. Nanoplaque concentration was also significantly increased in A+ patients as compared to A‐, P = .04. CSF nanoplaque levels were inversely correlated with CSF Aβ 42 levels (r = − 0.2, P = .03), but did not correlate with CSF T‐ or P‐tau levels. Conclusion CSF concentrations of nanoplaques can be quantified with single‐molecule sensitivity using the ThT‐FCS assay. Increased nanoplaque levels are related to the Alzheimer’s continuum and clinical AD, and correlate inversely with levels of Aβ 42 monomers/small oligomers determined by immunoassays. The association between this potential biomarker and disease stage should be further explored.