CSF ADAM10 levels in AD patients in relationship to ADAM10 gene variants

Abstract

AbstractBackgroundThe disintegrin metalloproteinase 10 (ADAM10) is the main α‐secretase acting in the non‐amyloidogenic processing of APP. Some ADAM10 gene variants (Q170H, R181G) have been associated with higher susceptibility to develop late‐onset AD and have been shown to promote AD‐type changes in mice models. We tested the hypothesis that some ADAM10 rare variants could increase the risk for AD through conferring an earlier age‐related downregulation of a‐secretase activity.Method ADAM10 gene was sequenced in 103 AD cases (78% with family history) with positive CSF biomarkers, and 96 cognitively preserved nonagenarians. ADAM10 in CSF of the AD cases was analyzed by means of ELISA (total levels) and western blot (segregated by isoforms of 50 kDa, 55 kDa, and 80 kDa) in comparison with controls and non‐AD dementia cases. We examined whether there was an increase of rare gene variants (MAF < 0.01) in the AD group and their potential association with lowers CSF protein levels.ResultRare variants were found in 15,5% of AD cases (in 23% of early‐onset versus 7,8% in late‐onset, p = 0.058) and in 12,5% of nonagenarians, and several of them were exclusive of the group. However, all were intronic variants except the Q170H change found in three AD cases and one nonagenarian. The SNP rs74016945 (3’UTR), with MAF close to 0.01, was found in 6% of the nonagenarians (OR 0.146, Fisher exact test p = 0.057). ELISA ADAM10 levels were not significantly different comparing AD cases with controls, carriers of rare variants versus non‐carriers, and did not differ consistently according to age at onset or APOE genotype. The three ADAM10 species were also similar in AD cases and controls, and did not differ according to genetic variants or age at onset.ConclusionRare ADAM10 exonic variants are uncommon in AD cases and the presence of rare intronic variants (more frequent in early versus late‐onset cases) is not associated with decreased ADAM10 levels in CSF.