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ADAM10 and ADAM17, members of the membrane-bound disintegrin metalloproteinase (ADAM) family, act as α-secretases in the non-amyloidogenic processing of the amyloid precursor protein. While alterations in ADAM10, the primary α-secretase, have been reported in Alzheimer’s disease (AD), with certain controversy between studies, ADAM17 changes remain less understood. Both enzymes display a complex pattern of expression that includes immature zymogen and mature full-length, assigned as the active form, and soluble cleaved species. We reported for the first time that ADAM10 is present in human cerebrospinal fluid (CSF), and levels of the full-length and soluble fragments decrease in samples from AD patients. ADAM10 and ADAM17 levels were determined in human samples from frontal cortex (Brodmann areas 9/10) from histopathologically-confirmed AD cases (n = 16) and non-dementia controls (n = 13), and in CSF from individuals with cognitive symptoms and an AD-consistent biomarker profile (n = 20) and from controls with normal biomarker parameters (n = 18). Levels were also assessed in SH-SY5Y cells differentiated to neurons, after 48 h of 3 µM Aβ42 treatment. Protein species were resolved by electrophoresis followed by quantitative fluorescent western blotting. Significant differences between AD and control groups were evaluated using Student’s unpaired t-test or the Mann–Whitney U test, as appropriate. We confirm the significant reduction in levels of mature and soluble ADAM10 species in lumbar CSF of AD patients. We also validate in postmortem AD brain the decrease in mature species of ADAM10 with no change in the levels of its zymogen nor mRNA transcript, suggesting a post-translational dysregulation in the production of active protein. In contrast, ADAM17 levels remained unchanged in both brain and CSF samples, highlighting a differential regulation between these two α-secretases in AD pathology. In SH-SY5Y-differentiated neurons, treatment with Aβ42 also led to a specific reduction in mature ADAM10, implicating Aβ in the disruption of ADAM10 maturation. Our study links a compromise in α-secretase to AD pathology. It demonstrates a selective reduction of the mature forms of ADAM10 in AD that may contribute to an impaired non-amyloidogenic APP processing. Aβ42 appears to be a key modulator of this dysfunction, suggesting that ADAM10 downregulation may be an early event in AD pathogenesis. The results don’t evidence any major role for ADAM17 in AD pathogenesis.