CSF Biomarkers profile in siblings with Alzheimer’s disease carrying the ADAM10 nonsense mutation p.Tyr167

Background The known genetic causes of EOAD are related to increased processing of the amyloid precursor protein (APP) through the amyloidogenic pathway, with subsequent pathological accumulation of Ab peptides. A decrease in non‐amyloidogenic processing of APP through α‐secretase proteolysis is also considered a straightforward mechanism triggering AD development. The disintegrin metalloproteinase 10 (ADAM10) has been identified as the major α‐secretase in the brain and some ADAM10 gene variants have been associated with higher susceptibility to develop late‐onset disease. In this study we analyze the CSF biochemical profile of two siblings with dementia of Alzheimer type (DAT) carrying a nonsense ADAM10 prodomain mutation to assess the physiopathological effect of the mutation. Method Clinical and biomarker study of a family with DAT associated with p.Tyr167* ADAM10 mutation. CSF analysis included AD core biomarkers (Lumipulse technology, Fujirebio) as well as Western blotting of ADAM10 species and the sAPPα and sAPPb peptides. A comparison was made with normal controls (n=12) and sporadic AD cases (n=12). Result The p.Tyr167* mutation was absent from public databases and segregated with the disease. CSF samples were available for two siblings. Ab42, total tau, and phosphorylated tau biomarkers in both were consistent with AD (Erlangen score of 4). ADAM10 isoforms in CSF (full‐length ∼ 55 kDa and truncated soluble ∼ 50 kDa) were decreased by around 50% and sAPPα peptide (both 110 and 120 kDa bands) was reduced by 70%, as compared to controls. sAPPb levels showed no changes. Interestingly, the sporadic AD cases showed a similar decrease in CSF ADAM10 levels to mutants, though their sAPPα and sAPPb levels resembled those of controls. Therefore, a decreased sAPPα/sAPPβ ratio was an exclusive feature of mutant ADAM10 siblings. Conclusion The CSF biochemical profile in these siblings is consistent with α‐secretase haploinsufficiency and illustrates the role of ADAM10 in the amyloidogenic process. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model of sporadic late‐onset AD due to an age‐related down‐regulation of α‐secretase activity.