Candidate Gene for the Chromosome 1 Familial Alzheimer's Disease Locus

Levy‐Lahad, Ephrat; Wasco, Wilma; Poorkaj, Parvoneh; Romano, Donna M.; Oshima, Junko; Pettingell, Warren H.; Yu, Chang; Jondro, Paul D.; Schmidt, Stephen D.; Wang, Kai; Crowley, Annette C.; Fu, Ying Hui; Guénette, Suzanne Y.; Galas, David J.; Nemens, Ellen; Wijsman, Ellen M.; Bird, Thomas D.; Schellenberg, Gerard D.; Tanzi, Rudolph E.

doi:10.1126/science.7638622

Cited by 2,312 publications

(1,181 citation statements)

References 18 publications

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“…AD affects 5.4 million Americans, and one of three elderly Americans will die with some form of AD‐type dementia. Genetic studies have identified a number of mutations in the APP gene (chromosome 21) and two homologous genes, PSEN1 (chromosome 14) and PSEN2 (chromosome 1), that appear to be causative in the early (familial) form of AD (Goate et al., 1991; Levy‐Lahad et al., 1995; Rogaev et al., 1995; Sherrington et al., 1995). Familial AD is much rarer than general ADs, which are prevalent after the age of about 65 years (Charlesworth, 1996).…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E region molecular signatures of Alzheimer's disease

et al. 2018

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SummaryAlthough the APOE region is the strongest genetic risk factor for Alzheimer's diseases (ADs), its pathogenic role remains poorly understood. Elucidating genetic predisposition to ADs, a subset of age‐related diseases characteristic for postreproductive period, is hampered by the undefined role of evolution in establishing molecular mechanisms of such diseases. This uncertainty is inevitable source of natural‐selection–free genetic heterogeneity in predisposition to ADs. We performed first large‐scale analysis of linkage disequilibrium (LD) structures characterized by 30 polymorphisms from five genes in the APOE 19q13.3 region (BCAM,NECTIN2,TOMM40,APOE, and APOC1) in 2,673 AD‐affected and 16,246 unaffected individuals from five cohorts. Consistent with the undefined role of evolution in age‐related diseases, we found that these structures, being highly heterogeneous, are significantly different in subjects with and without ADs. The pattern of the difference represents molecular signature of AD comprised of single nucleotide polymorphisms (SNPs) from all five genes in the APOE region. Significant differences in LD in subjects with and without ADs indicate SNPs from different genes likely involved in AD pathogenesis. Significant and highly heterogeneous molecular signatures of ADs provide unprecedented insight into complex polygenetic predisposition to ADs in the APOE region. These findings are more consistent with a complex haplotype than with a single genetic variant origin of ADs in this region.

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Section: Introductionmentioning

confidence: 99%

Apolipoprotein E region molecular signatures of Alzheimer's disease

et al. 2018

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“…2 Phenotypically, it is known that at least 30% of individuals with PD develop dementia 5,6 and that age has been described as a major predisposing factor for the development of cognitive impairment. 7 Accordingly, we sought to assess the contribution of genetic factors known to be involved in dementias such as AD [8][9][10][11] or FTD 2,[12][13][14] to the PD phenotype.…”

Section: Introductionmentioning

confidence: 99%

Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease

et al. 2015

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Many individuals with Parkinson's disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency o5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer's disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aβ mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G4A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G4A (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.

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“…Sequence analysis predicts integral membrane proteins, that contain seven putative transmembrane domains, a short hydrophilic amino-and carboxyl-terminal tail, and a large hydrophilic loop between the sixth and seventh membrane-spanning domain. All of the reported mutations that result in early-onset Alzheimer's disease are missense mutations, 24 in PSI [5 11] and two in PS2 [12,13], or mutations that affect the splicing without affecting the coding of the protein [14] and this has led to the hypothesis that they may result in a gain of (mis)function. This view is also consistent with a recent report describing that an intron polymorphism in the PSI gene is related to approx.…”

Section: Introductionmentioning

confidence: 99%

Characterization of human presenilin 1 using N‐terminal specific monoclonal antibodies: Evidence that Alzheimer mutations affect proteolytic processing

et al. 1996

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The majority of cases of early-onset familial Alzheimer disease are caused by mutations in the recently identified presenilin 1 (PS1) gene, located on chromosome 14. PS1, a 467 amino acid protein, is predicted to be an integral membrane protein containing seven putative transmembrane domains and a large hydrophilic loop between the sixth and seventh membranespanning domain. We produced 7 monoclonal antibodies that react with 3 non-overlapping epitopes on the N-terminal hydrophilic tail of PS1. The monoclonal antibodies can detect the full-size PS1 at Mr 47 000 and a more abundant Mr 28 000 product in membrane extracts from human brain and human cell lines. PC12 cells transiently transfected with PS1 constructs containing two different Alzheimer mutations fail to generate the 28 kDa degradation product in contrast to PC12 cells transfected with wild-type PS1. Our results indicate that missense mutations in this form of familial Alzheimer disease may act via a mechanism of impaired proteolytic processing of PS1.

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Candidate Gene for the Chromosome 1 Familial Alzheimer's Disease Locus

Cited by 2,312 publications

References 18 publications

Apolipoprotein E region molecular signatures of Alzheimer's disease

Apolipoprotein E region molecular signatures of Alzheimer's disease

Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease

Characterization of human presenilin 1 using N‐terminal specific monoclonal antibodies: Evidence that Alzheimer mutations affect proteolytic processing

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