Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum.

To determine the prevalence of early-onset Alzheimer disease (EOAD) and of autosomal dominant forms of EOAD (ADEOAD), we performed a population-based study in the city of Rouen (426,710 residents). EOAD was defined as onset of disease at age <61 years, and ADEOAD was defined as the occurrence of at least three EOAD cases in three generations. Using these stringent criteria, we calculated that the EOAD and ADEOAD prevalences per 100,000 persons at risk were 41.2 and 5.3, respectively. We then performed a mutational analysis of the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) in 34 families with ADEOAD ascertained in France. In 19 (56%) of these families, we identified 16 distinct PSEN1 missense mutations, including 4 (Thr147Ile, Trp165Cys, Leu173Trp, and Ser390Ile) not reported elsewhere. APP mutations, including a novel mutation located at codon 715, were identified in 5 (15%) of the families. In the 10 remaining ADEOAD families and in 9 additional autosomal dominant Alzheimer disease families that did not fulfill the strict criteria for ADEOAD, no PSEN1, PSEN2, or APP mutation was identified. These results show that (1) PSEN1 and APP mutations account for 71% of ADEOAD families and (2) nonpenetrance at age <61 years is probably infrequent for PSEN1 or APP mutations.

[1]  Y. Agid,et al.  Evidence for apolipoprotein E epsilon 4 association in early-onset Alzheimer's patients with late-onset relatives. , 1995, American journal of medical genetics.

[2]  A. Goate,et al.  Exploring the etiology of Alzheimer disease using molecular genetics. , 1997, JAMA.

[3]  Nick C Fox,et al.  Incomplete penetrance of familial Alzheimer's disease in a pedigree with a novel presenilin-1 gene mutation , 1996, The Lancet.

[4]  P. S. St George-Hyslop,et al.  A presenilin‐1 mutation in a Japanese family with Alzheimer's disease and distinctive abnormalities on cranial MRI , 1997, Neurology.

[5]  J. Rommens,et al.  Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant. , 1996, Human molecular genetics.

[6]  Miguel Ángel Martínez,et al.  No founder effect in three novel Alzheimer's disease families with APP 717 Val-->Ile mutation. Clerget-darpoux. French Alzheimer's Disease Study Group. , 1996, Journal of medical genetics.

[7]  J. Haines,et al.  Apolipoprotein E genotype in patients with alzheimer's disease: Implications for the risk of dementia among relatives , 1995, Annals of neurology.

[8]  M McNamara,et al.  A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. , 1997, Annals of neurology.

[9]  V. Lehtinen,et al.  Prevalence of severe dementia in Finland , 1985, Neurology.

[10]  J. Rinne,et al.  The Glu318Gly mutation of the presenilin‐1 gene does not necessarily cause Alzheimer's disease , 1998, Annals of neurology.

[11]  M. Adams,et al.  A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene , 1995, Neuroreport.

[12]  Nick C Fox,et al.  Chromosome 14 familial Alzheimer’s disease: the clinical and neuropathological characteristics of a family with a leucine→serine (L250S) substitution at codon 250 of the presenilin 1 gene , 1998, Journal of neurology, neurosurgery, and psychiatry.

[13]  A. Myers,et al.  E280A PS‐1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles , 1997, Human mutation.

[14]  Miguel Ángel Martínez,et al.  De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. French Alzheimer's Disease Study Group. , 1998, Journal of medical genetics.

[15]  A. Patel,et al.  Presenilins and early-onset familial Alzheimer's disease. , 1997, Neuroreport.

[16]  A Hofman,et al.  Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. , 1998, Human molecular genetics.

[17]  M. Cruts,et al.  Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. , 1995, Human molecular genetics.

[18]  A. Hofman,et al.  The Glu318Gly substitution in presenilin 1 is not causally related to Alzheimer disease. , 1999, American journal of human genetics.

[19]  B. Dubois,et al.  Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. , 1995, Human molecular genetics.

[20]  Y. Agid,et al.  A large pedigree with early-onset Alzheimer's disease , 1995, Neurology.

[21]  A. Paetau,et al.  A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1 , 1998, Nature Medicine.

[22]  Nick C Fox,et al.  Clinicopathological features of familial Alzheimer's disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic factor. , 1997, Brain : a journal of neurology.

[23]  Y. Ikejiri,et al.  A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy , 1997, Neuroscience Letters.

[24]  M. Bullido,et al.  Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer's disease , 1998, Neuroscience Letters.

[25]  K P Offord,et al.  Prevalence of medically diagnosed dementia in a defined United States population , 1989, Neurology.

[26]  D. Campion,et al.  Unusual phenotypic alteration of β amyloid precursor protein (βAPP) maturation by a new Val-715 → Met βAPP-770 mutation responsible for probable early-onset Alzheimer’s disease , 1999 .

[27]  Lars Lannfelt,et al.  A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early-onset Alzheimer's disease , 1997, Neuroscience Letters.

[28]  D. Campion,et al.  Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[29]  L. Thal,et al.  Early‐onset Alzheimer's disease with a presenilin‐1 mutation at the site corresponding to the volga German presenilin‐2 mutation , 1997, Annals of neurology.

[30]  G. Schellenberg,et al.  Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene , 1998, Human mutation.

[31]  D. T. Vernier,et al.  Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. , 1990, Journal of lipid research.

[32]  J. Growdon,et al.  A novel presenilin‐1 mutation: Increased β‐amyloid and neurofibrillary changes , 1997 .

[33]  L. Lannfelt,et al.  Wide range of disease onset in a family with Alzheimer disease and a His163Tyr mutation in the presenilin-1 gene. , 1998, Archives of Neurology.

[34]  Hans Förstl,et al.  Missense mutations of the PS‐1/S182 gene in german early‐onset Alzheimer's disease patients , 1996, Annals of neurology.

[35]  J. Hardy,et al.  Screening for mutations in the open reading frame and promoter of the beta-amyloid precursor protein gene in familial Alzheimer's disease: identification of a further family with APP717 Val-->Ile. , 1992, Human molecular genetics.

[36]  B. Dubois,et al.  Characteristics of familial aggregation in early-onset Alzheimer's disease: evidence of subgroups. , 1995, American journal of medical genetics.

[37]  J. Buxbaum,et al.  A novel Polish presenilin‐1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years , 1998, NeuroReport.

[38]  Y. Agid,et al.  Apolipoprotein E ϵ4 Allele and Familial Aggregation of Alzheimer Disease , 1998 .

[39]  J. Hardy,et al.  Two novel (M233T and ρ278T) presenilin‐1 mutations in early‐onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin‐1 mutations with a novel phenotype , 1997, Neuroreport.

[40]  N. Cairns,et al.  A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease. , 1998, American journal of human genetics.

[41]  B. Schoenberg,et al.  Severe dementia. Prevalence and clinical features in a biracial US population. , 1985, Archives of neurology.

[42]  Rudolph E Tanzi,et al.  Presenilins and Alzheimer's disease , 1997, Current Opinion in Neurobiology.

[43]  A. Hofman,et al.  Apolipoprotein E4 allele in a population–based study of early–onset Alzheimer's disease , 1994, Nature Genetics.