~ Pergamon 0197-0186(94) E0017-N Neurochem. Int. Vol. 25, No. 1, pp. 81 84, 1994 Copyright ~) 1994 ElsevierScienceLtd Printed in Great Britain. All rights reserved 01974) 186/94 $7.00+ 0.00 MOLECULAR GENETICS OF ALZHEIMER'S DISEASE IN ITALIAN FAMILIES SANDRO SORBI*, BENEDETTA NACMIAS, MARZIA MORTILLA, PAOLO FORLEO, SILVIA PIACENTINI and LUIGI AMADUCCI Department of Neurological and Psychiatric Sciences, University of Florence, 50134 FIorence~ Italy (Received l November 1993 ; aecepted 15 December 1993) Abstract--We screened 11 families from different regions of Italy by direct sequencing of exon 17 of the APP gene. Two unrelated families carried the APPvl7 mutation segregating with the disease. These two families originate from two Italian regions which are considered genetically separate. Published studies have demonstrated the presence of the APPT~7Val ~ Ile mutation in kindreds of British or Japanese origin with early onset familial Alzheimer's disease. These data suggest that the APP7t 7 mutation is not confined to islander families which may share common founders. From the molecular genetic point of view we also did linkage analysis. Several families, in fact, have not shown a linkage with chromosome 21 and the resolution of this dilemma required investigation of those pedigrees both with additional markers from chromosome 21 and with markers from other chromosomes. At least 7 families with early onset familial Alz- heimer's disease (EOFAD) (Goate et al., 1991) seg- regating with APP717 mutations have been reported, four of British origin and three Japanese (Naruse et al., 1991 ; Yoshioka et al., 1991 ; Fidani et al., 1992; Karlinsky et al., 1992). To date, this mutation has been absent from pedigrees of any other ethnic origin, It has been suggested that the clustering of cases on two island nations argues for the existence of a common founder in each country (St George-Hyslop et al., 1992a). Several early and late onset families and spor- adic cases have been screened for the APP717 mutation (St George-Hyslop et al., 1992 ; Chartier-Harlin et al., 1991 ; Schellenberg et al., 1991 ; Van Dujin et al., 1991 ; Tanzi et al., 1992 ; Kamino et al., 1992) with negative results suggesting that the APP717 is a very rare mu- tation (below 1% of EOFAD cases). We have studied 11 well characterized early onset Italian FAD families by restriction enzyme analysis and direct sequenc- ing and we have found two families with the APP7, mutation (Sorbi et al., 1993). These families are the first two APP717 mutated Caucasian families not of British or islander origin. In order to identify the chromosomal location of *Author to whom all correspondence should be addressed: Sandro Sorbi, M.D., Department of Neurological and Psychiatric Sciences, University of Florence, Viale Mor- gagni 85, 50134 Florence, Italy. 81 novel FAD genes we collaborated with Dr P. H. St. George-Hyslop, University of Toronto, screening for linkage to chromosome 14 that contains several puta- tive candidate genes (serine proteases including cathepsin G, serine protease inhibitors including ~l- antichymotrypsin and molecular chaperons such as HSP70). Pedigree data Eleven families with autopsy proven autosomal dominant EOFAD were studied. Clinical diagnosis of Alzheimer's disease (AD) was assigned as described elsewhere (Bracco et al., 1992), fulfilled the NIH- NINCDS criteria and was confirmed in each family at autopsy. None of the investigated families, and particularly FLOi2 and FLO13 which carry the APP717 mutation, are linked by genealogy. FLOI2 is from central Italy with eight affected members in the last three generations. In this family the first clinical signs included some psychotic features such as para- noid delusion and thought disorders followed by the appearance of disorders of memory and other cog- nitive functions. The mean duration of the illness was 8 years. Post mortem examination of two brains showed typical AD neuropathological findings. FLO13 is a kindred from southern Italy with eight members with AD in the last three generations. Neuro- psychological assessment of affected members showed