THE CYSTATIN-C GENE IS NOT LINKED TO EARLY-ONSET FAMILIAL ALZHEIMERS-DISEASE

The APP717 mutations discovered in only a few early onset Alzheimer's disease (AD) families have confirmed the genetic heterogeneity of this disorder. To identify the other gene(s) involved in the disease we se lected the protease inhibitor, Cystatin-C, as a candidate gene. Cystat in-C is an amyloidogenic protein causing hereditary cerebral haemorrha ge with amyloidosis - Icelandic type (HCHWA-1). It is localised with t he beta-amyloid peptide in the arterial walls of AD brains. We have an alysed the segregation of a polymorphic marker in this gene in 8 early onset AD families. Two early onset families showed clear non-segregat ion of the marker with the disease. When the 8 families are analysed t ogether (assuming only one other gene is involved), they present exclu sion linkage criteria. These data indicate that Cystatin-C is not the site of the defect in 2 families and is not likely to be in the other families analysed. We conclude that the deposition of Cystatin-C in AD is a secondary event in the disease process, and that this gene is no t pathogenic in familial AD.