Clinical, neuropathologic, and biochemical profile of the amyloid precursor protein I716F mutation

We report the clinical, pathologic, and biochemical characteristics of the recently described amyloid precursor protein (APP) I716F mutation. We present the clinical findings of individuals carrying the APP I716F mutation and the neuropathologic examination of the proband. The mutation was found in a patient with Alzheimer disease with onset at the age of 31 years and death at age 36 years and who had a positive family history of early-onset Alzheimer disease. Neuropathologic examination showed abundant diffuse amyloid plaques mainly composed of amyloid-β42 and widespread neurofibrillary pathology. Lewy bodies were found in the amygdala. Chinese hamster ovary cells transfected with this mutation showed a marked increase in the amyloid-β42/40 ratio and APP C-terminal fragments and a decrease in APP intracellular domain production, suggesting reduced APP proteolysis by γ-secretase. Taken together, these findings indicate that the APP I716F mutation is associated with the youngest age of onset for this locus and strengthen the inverse association between amyloid-β42/40 ratio and age of onset. The mutation leads to a protein that is poorly processed by γ-secretase. This loss of function may be an additional mechanism by which some mutations around the γ-secretase cleavage site lead to familial Alzheimer disease. Copyright © 2009 by the American Association of Neuropathologists, Inc.