APP and Alzheimer disease: Genetic analyses of families with late-onset AD revealed two rare mutations (Q170H and R181G) in the pro-domain of ADAM10 that attenuated its α-secretase activity and shifted APP processing toward β-secretase–mediated cleavage with a 2–3-fold increase in Aβ levels, enhanced Aβ plaque load, and reactive gliosis (49, 50).