Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692)

Several mutations in the amyloid precursor protein (APP) gene may lead to e ither Alzheimer's disease or cerebral haemorrhage due to congophilic amyloi d angiopathy (CAA). A single family is known in which both types of patholo gy are expressed because of a missense mutation at codon 692 of the APP gen e (APP692). Here we describe the clinical and pathological expression of AP P692 in eight patients with the mutation. Furthermore, 21 first-degree rela tives with an a priori risk of 50% of being a carrier were tested for the A PP692 mutation and studied for presymptomatic signs by neurological examina tion, neuropsychological testing and brain MRI. Patients with APP692 presen ted with haemorrhage, dementia or both. The dementia in patients with the A PP692 mutation was compatible with Alzheimer's disease both clinically and neuropathologically. Of the 21 healthy relatives at 50% risk, five carried the APP692 mutation. The presymptomatic carriers showed a subtle, non-signi ficant impairment of cognitive function compared with relatives without APP 692. A significant increase in the number of periventricular and subcortica l white matter lesions at young age was seen in presymptomatic carriers (me an age 26.4 years). The findings of this study suggest that a single (genet ic) mechanism may underlie the pathology of Alzheimer's disease and CAA. Th ese diseases are manifested subclinically by white matter pathology. Furthe r insight into the relationship between CAA and Alzheimer's disease may pro vide clues about the aetiology of Alzheimer's disease.