title: Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family.
abstract: OBJECTIVE
  To report, for the first time, a large autosomal dominant Alzheimer disease (AD) family in which the APP A713T mutation is present in the homozygous and heterozygous state. To date, the mutation has been reported as dominant, and in the heterozygous state associated with familial AD and cerebrovascular lesions.
  
  
  METHODS
  The family described here has been genealogically reconstructed over 6 generations dating back to the 19th century. Plasma β-amyloid peptide was measured. Sequencing of causative AD genes was performed.
  
  
  RESULTS
  Twenty-one individuals, all but 1 born from 2 consanguineous unions, were studied: 8 were described as affected through history, 5 were studied clinically and genetically, and 8 were asymptomatic at-risk subjects. The A713T mutation was detected in the homozygous state in 3 patients and in the heterozygous state in 8 subjects (6 asymptomatic and 2 affected).
  
  
  CONCLUSIONS
  Our findings, also supported by the β-amyloid plasma assay, confirm (1) the pathogenic role of the APP A713T mutation, (2) the specific phenotype (AD with cerebrovascular lesions) associated with this mutation, and (3) the large span of age at onset, not influenced by APOE, TOMM40, and TREM2 genes. No substantial differences concerning clinical phenotype were evidenced between heterozygous and homozygous patients, in line with the classic definition of dominance. Therefore, in this study, AD followed the classic definition of a dominant disease, contrary to that reported in a previously described AD family with recessive APP mutation. This confirms that genetic AD may be considered a disease with dominant and recessive traits of inheritance.
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Conidi
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Bernardi
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Puccio
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Smirne
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Muraca
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Sabrina A M
authors.initials: SA
authors.lastname: Curcio
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Colao
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Piscopo
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Gallo
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Anfossi
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Frangipane
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Clodomiro
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Mirabelli
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Vasso
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cupidi
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Giusi
authors.initials: G
authors.lastname: Torchia
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Di Lorenzo
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Mandich
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Confaloni
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
authors.forename: Raffaele G
authors.initials: RG
authors.lastname: Maletta
authors.affiliation: From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy. bruni@arn.it.
authors.forename: Amalia C
authors.initials: AC
authors.lastname: Bruni
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor