Comprehensive Search for Alzheimer Disease Susceptibility Loci in the APOE Region

Jun, Gyungah; Vardarajan, Badri N.; Buros, Jacqueline L.; Yu, Chang; Hawk, Michele; Dombroski, Beth A.; Crane, Paul K.; Larson, Eric B.; Mayeux, Richard; Haines, Jonathan L.; Lunetta, Kathryn L.; Pericak‐Vance, Margaret A.; Schellenberg, Gerard D.; Farrer, Lindsay A.

doi:10.1001/archneurol.2012.2052

Cited by 104 publications

(107 citation statements)

References 37 publications

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“…Roses et al [33][34][35][36] reported that longer lengths of rs10524523 are associated with a higher risk for LOAD; for APOE-3/4 patients who developed LOAD after 60 years of age, individuals with long poly T repeats (19-39 nucleotides) linked to APOE-3 develop LOAD on an average of 7 years earlier than individuals with shorter poly T repeats (11-16 nucleotides) linked to APOE-3 [33,34,37]. Apparently, these results could not be replicated by other authors [46][47][48][49]. In our case, we clearly found that patients harboring the APOE-4/4-L/L cluster developed dementia at an earlier age (<70 yrs) than their counterparts with other genotypes.…”

Section: Discussionmentioning

confidence: 89%

“…A poly T repeat in an intronic polymorphism (rs10524523) (intron 6) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in AD [31][32][33][34][35][36][37][38][39][40][41][42][43][44], and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms [32][33][34][35][36][37]45], although the latter assumption needs replication due to contradictory results [36,[46][47][48][49]. A fixed-effect meta-analysis approach showed that rs4420638 at the TOMM40/APOE/APOC1 gene locus is associated with longevity [50,51].…”

Section: Introductionmentioning

confidence: 99%

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APOE-TOMM40 in the Pharmacogenomics of Dementia

Cacabelos

Goldgaber²,

Àlex³

et al. 2013

J Pharmacogenomics Pharmacoproteomics

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

APOE-TOMM40 in the Pharmacogenomics of Dementia

Cacabelos

Goldgaber²,

Àlex³

et al. 2013

J Pharmacogenomics Pharmacoproteomics

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“…These results together with the study by Bertram et al [22] in 2008 made CD33 the only gene (except for APOE) with significance in GWASs in AD with both case-control and family-based approaches [34]. Using GWAS datasets, Jun et al [35] looked into the APOE region and found no association of SNPs in this region with AD or AAO after adjusting for APOE status, suggesting that APOE could explain all the genetic risk in the APOE region. Wijsman et al conducted the largest combined GWAS among familial LOAD pedigrees so far, in which CUGBP2 reached genome-wide significance among APOEe4 homozygotes and the association of BIN1 and CLU was successfully replicated [36].…”

Section: Abundant Genetic Risk Factors Uncovered By Gwassmentioning

confidence: 82%

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

Shen

Jia

2016

Neurosci. Bull.

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Genome-wide association studies (GWASs) have revealed a plethora of putative susceptibility genes for Alzheimer's disease (AD). With the sole exception of the APOE gene, these AD susceptibility genes have not been unequivocally validated in independent studies. No single novel functional risk genetic variant has been identified. In this review, we evaluate recent GWASs of AD, and discuss their significance, limitations, and challenges in the investigation of the genetic spectrum of AD.

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“…7,8,30,31 Null or even conflicting findings have also been reported. [9][10][11]32,33 Using annual cognitive data from .1,000 community-based older white Americans who were e3/3 homozygous, we examined the effect of the 9523 variant on late-life cognitive decline, We found that the e3/3 in linkage to 9523-S/S is associated with faster decline in cognition compared with the linkage to either S/VL or VL/VL. The effect is driven primarily by episodic and semantic memory.…”

mentioning

confidence: 99%

TOMM40 ′523 variant and cognitive decline in older persons with APOE ε3/3 genotype

Lutz

Wilson

et al. 2017

Neurology

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Objective: To interrogate a poly-T variant (rs10524523, 9523) in TOMM40, a gene adjacent to the APOE gene on chromosome 19, in older persons with APOE e3/3 homozygosity for association with cognitive decline, the clinical hallmark of Alzheimer disease (AD).Methods: Data came from participants in 2 cohort studies of aging and dementia who underwent annual clinical evaluations for up to 21 years. APOE and TOMM409523 genotypes were determined from DNA from blood or brain samples. Linear mixed models compared the rates of decline in cognition among APOE e3/3 carriers with different 9523 genotypes.Results: The 1,170 APOE e3/3 homozygotes were of European ancestry, were free of dementia at baseline, and had an average age of 78.5 years at baseline. Three major genotypes at the 9523 variant were linked to APOE e3/3; 26.5% had 2 short poly-Ts (S/S), 48.5% had 1 short and 1 very long poly-T (S/VL), and 24.0% had 2 very long poly-Ts (VL/VL). Participants with '523-S/S had faster decline in global cognition than participants with '523-S/VL or VL/VL (p 5 0.002). The same association was observed for episodic memory (p , 0.001) and semantic memory (p 5 0.003) but not for working memory, perceptual speed, or visuospatial ability. Conclusions:Our data reveal an association of APOE e3/3-TOMM409523 haplotypes with cognitive decline in community-based older persons such that the S/S poly-T genotype is related to faster cognitive decline, primarily in the domains of episodic and semantic memory.

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Comprehensive Search for Alzheimer Disease Susceptibility Loci in the APOE Region

Cited by 104 publications

References 37 publications

APOE-TOMM40 in the Pharmacogenomics of Dementia

APOE-TOMM40 in the Pharmacogenomics of Dementia

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

TOMM40 ′523 variant and cognitive decline in older persons with APOE ε3/3 genotype

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