The Association Between Genetic Variants in SORL1 and Alzheimer Disease in an Urban, Multiethnic, Community-Based Cohort

Abstract

Context-Variants in 3′ and 5′ regions of SORL1, the neuronal sorting protein-related receptor, were recently found to be associated with late onset familial and sporadic Alzheimer's disease in several datasets that were selected for familial aggregation or were ethnically diverse or clinic-based selected series. Objective-To investigate the association between Alzheimer's disease and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic community-based population. Design & Setting-We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older, residing in northern Manhattan. Participants-There were 296 patients with probable Alzheimer's disease and 428 healthy elderly controls. The participants were of African American (34%), Caribbean Hispanic (51%) or non-Hispanic whites (15%).

SORL1 is Genetically Associated with Neuropathologically Characterized Late-Onset Alzheimer's Disease

“…In our samples, association signals were located in both LD regions (Fig. 1), which is consistent with previous studies [5,18,20]. As suggested by Rogaeva et al [5] and others [18,20], allelic heterogeneity obviously exists in the SORL1 region.…”

“…1), which is consistent with previous studies [5,18,20]. As suggested by Rogaeva et al [5] and others [18,20], allelic heterogeneity obviously exists in the SORL1 region. Given the two rough LD structures and the presence of three recombination hot spots within SORL1 (Fig.…”

SORL1 is Genetically Associated with Neuropathologically Characterized Late-Onset Alzheimer's Disease

“…In our samples, association signals were located in both LD regions (Fig. 1), which is consistent with previous studies [5,18,20]. As suggested by Rogaeva et al [5] and others [18,20], allelic heterogeneity obviously exists in the SORL1 region.…”

“…1), which is consistent with previous studies [5,18,20]. As suggested by Rogaeva et al [5] and others [18,20], allelic heterogeneity obviously exists in the SORL1 region. Given the two rough LD structures and the presence of three recombination hot spots within SORL1 (Fig.…”

Candidate gene analysis for Alzheimer's disease in adults with Down syndrome

“…Our results extend previous findings of a relationship between SNPs in candidate genes located on chromosome 21 and chromosomes other than 21 and risk of AD in adults with DS (Jones et al, 2013; Lee et al, 2007a; Liu et al, 2008; Margallo-Lana et al, 2004; Mok et al, 2014; Patel et al, 2011; Wegiel et al, 2008, 2011). Our analysis revealed that multiple SNPs in APP within a 100kb region on 21q21.3 were associated with AD in adults with DS at gene-wise level.…”

Whole Exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer Disease

“…While qualifying variants were present in only 0.27% of patients, only a single variant was found among 13,232 controls, and the single control carrier upon a post hoc cognitive evaluation was identified to have a diagnosis of mild cognitive impairment. These results confirm and greatly extend those from sequencing studies in familial and sporadic early onset Alzheimer’s disease 19–21 , familial AD families 24, 26, 33 and investigations within clinical settings. The resulting impact of the loss-of-function variants in SORL1 on recycling of the amyloid precursor protein and the amyloid β protein make this pathway an attractive target for the development of therapies.…”

SORL1 is Genetically Associated with Neuropathologically Characterized Late-Onset Alzheimer's Disease

“…In our samples, association signals were located in both LD regions (Fig. 1), which is consistent with previous studies [5,18,20]. As suggested by Rogaeva et al [5] and others [18,20], allelic heterogeneity obviously exists in the SORL1 region.…”

“…1), which is consistent with previous studies [5,18,20]. As suggested by Rogaeva et al [5] and others [18,20], allelic heterogeneity obviously exists in the SORL1 region. Given the two rough LD structures and the presence of three recombination hot spots within SORL1 (Fig.…”

Candidate gene analysis for Alzheimer's disease in adults with Down syndrome

“…Our results extend previous findings of a relationship between SNPs in candidate genes located on chromosome 21 and chromosomes other than 21 and risk of AD in adults with DS (Jones et al, 2013; Lee et al, 2007a; Liu et al, 2008; Margallo-Lana et al, 2004; Mok et al, 2014; Patel et al, 2011; Wegiel et al, 2008, 2011). Our analysis revealed that multiple SNPs in APP within a 100kb region on 21q21.3 were associated with AD in adults with DS at gene-wise level.…”

Whole Exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer Disease

“…While qualifying variants were present in only 0.27% of patients, only a single variant was found among 13,232 controls, and the single control carrier upon a post hoc cognitive evaluation was identified to have a diagnosis of mild cognitive impairment. These results confirm and greatly extend those from sequencing studies in familial and sporadic early onset Alzheimer’s disease 19–21 , familial AD families 24, 26, 33 and investigations within clinical settings. The resulting impact of the loss-of-function variants in SORL1 on recycling of the amyloid precursor protein and the amyloid β protein make this pathway an attractive target for the development of therapies.…”

SORL1 is Genetically Associated with Neuropathologically Characterized Late-Onset Alzheimer's Disease

“…In our samples, association signals were located in both LD regions (Fig. 1), which is consistent with previous studies [5,18,20]. As suggested by Rogaeva et al [5] and others [18,20], allelic heterogeneity obviously exists in the SORL1 region.…”

“…1), which is consistent with previous studies [5,18,20]. As suggested by Rogaeva et al [5] and others [18,20], allelic heterogeneity obviously exists in the SORL1 region. Given the two rough LD structures and the presence of three recombination hot spots within SORL1 (Fig.…”

Candidate gene analysis for Alzheimer's disease in adults with Down syndrome

“…Our results extend previous findings of a relationship between SNPs in candidate genes located on chromosome 21 and chromosomes other than 21 and risk of AD in adults with DS (Jones et al, 2013; Lee et al, 2007a; Liu et al, 2008; Margallo-Lana et al, 2004; Mok et al, 2014; Patel et al, 2011; Wegiel et al, 2008, 2011). Our analysis revealed that multiple SNPs in APP within a 100kb region on 21q21.3 were associated with AD in adults with DS at gene-wise level.…”

Whole Exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer Disease

“…While qualifying variants were present in only 0.27% of patients, only a single variant was found among 13,232 controls, and the single control carrier upon a post hoc cognitive evaluation was identified to have a diagnosis of mild cognitive impairment. These results confirm and greatly extend those from sequencing studies in familial and sporadic early onset Alzheimer’s disease 19–21 , familial AD families 24, 26, 33 and investigations within clinical settings. The resulting impact of the loss-of-function variants in SORL1 on recycling of the amyloid precursor protein and the amyloid β protein make this pathway an attractive target for the development of therapies.…”