Comprehensive Search for Alzheimer Disease Susceptibility

Arch Neurol. 2012 Aug 6:1-10. doi: 10.1001/archneurol.2012.2052. [Epub ahead of print]

Comprehensive Search for Alzheimer Disease Susceptibility Loci in the APOE Region.

Jun G, Vardarajan BN, Buros J, Yu CE, Hawk MV, Dombroski BA, Crane PK, Larson EB, Mayeux R, Haines JL, Lunetta KL, Pericak-Vance MA, Schellenberg GD, Farrer LA; Alzheimer’s Disease Genetics Consortium.

Abstract

OBJECTIVE To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523). DESIGN Conditional logistic regression models and survival analysis.

SETTING Fifteen genome-wide association study data sets assembled by the Alzheimer’s Disease Genetics Consortium.

PARTICIPANTS Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls.

MAIN OUTCOME MEASURES Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer’s Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls.

RESULTS In models adjusting for APOE ϵ4, no SNPs in the entire region were significantly associated with AAO at P < .001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ϵ3/ϵ3 subjects.

CONCLUSIONS APOE alleles ϵ2, ϵ3, and ϵ4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.

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