PRESENILE ALZHEIMER DEMENTIA CHARACTERIZED BY AMYLOID ANGIOPATHY AND LARGE AMYLOID CORE TYPE SENILE PLAQUES IN THE APP 692ALA-]GLY MUTATION

Mutations at codons 717 and 670/671 in the amyloid precursor protein ( APP) are rare genetic causes of familial Alzheimer's disease (AD). A m utation at codon 693 of APP has also been described as the genetic def ect in hereditary cerebral hemorrhage with amyloidosis of the Dutch ty pe (HCHWA-D). We have reported a APP692Ala-->Gly (Flemish) mutation as a cause of intracerebral hemorrhage and presenile dementia diagnosed as probable AD in a Dutch family. We now describe the post-mortem exam ination of two demented patients with the APP692 mutation. The neuropa thological findings support the diagnosis of AD. Leptomeningial and pa renchymal vessels showed extensive deposition of AP amyloid protein. N umerous senile plaques consisted of large AP amyloid cores, often meas uring more than 30 mu m in diameter and were surrounded by a fine mesh work of dystrophic neurites, In addition, there were a large number of paired helical filaments in pyramidal neurons and dystrophic neurites . Our findings show that the APP692 mutation leads to morphological ab normalities that are similar to AD, but the morphology of senile plaqu es is clearly distinct from that described in sporadic and chromosome 14-linked AD patients, in patients with APP717 mutations causing famil ial, presenile AD and in patients with the APP693 mutation causing HCH WA-D.