Pathology of early-onset Alzheimer's disease cases bearing the Thr113-114ins presenilin-1 mutation

Most cases of familial presenile Alzheimer's disease are caused by mutation s in the presenilin-1 (PSEN-1) gene, most of these mutations being missense mutations. A mutation in the splice donor site of intron 4 of PSEN-1 has b een described recently which results in aberrant splicing of PSEN-1 mRNA, c ausing insertion of an additional amino acid, Thr113-114ins, into the prote in. We studied the neuropathology of four cases bearing this mutation in an attempt to clarify the pathology of this hereditary form of Alzheimer's di sease and to determine whether it differs from other familial forms of the disease. The disease presented as a progressive cognitive decline, myoclonu s and seizures developing later in the disease, a feature common to PSEN-li nked Alzheimer's disease. The course of the disease was relatively rapid, d eath occurring approximately 6 years after onset, Pathology in the intron 4 cases demonstrated a severe Alzheimer's disease pathology with abundant de position of beta -amyloid (A beta) 1-42 senile plaques and the formation of neurofibrillary tangles. Amyloid angiopathy was present in these cases and was readily demonstrated by A beta 1-40 staining, particularly in the cere bellum. Cases with the intron 4 mutation appear clinically and pathological ly similar to other cases of early-onset Alzheimer's disease bearing PSEN-1 mutations.