Genome-Wide Association Study of Dementia in a Community-Based Sample of Older Subjects

Congratulations to Dr. Steven DeKosky on the publication of “Genome-Wide Association Study of Dementia in a Community-Based Sample of Older Subjects,” which appears in the June 16th issue of Alzheimer’s & Dementia:  The Journal of the Alzheimer’s Assocation.




Dementia broadly describes conditions that affect a person’s memory, cognition, and behavior with Alzheimer’s disease (AD) being the most common cause. AD affects millions of people in the U.S. and around the world causing a significant financial burden and placing significant stress on caretakers. AD is a complex disease influenced by both the environment and genetics, however, much of the genetic component remains unaccounted for. The purpose of this work was to use genome-wide association analyses to detect genetic associations with incident AD in a sample of older adults age 75 and above.


We performed a genome-wide association study (GWAS) on the genome-wide genotyped and imputed data (14,113,004 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia cases (mean age ± sd = 84.64±3.95) and 2,206 non-demented subjects (mean age ± sd = 84.55±3.23).


The established association of APOE*4 with AD was confirmed in this community-based sample of older subjects (OR = 2.22; P = 9.36E-14). In addition, a genome-wide significant novel locus on chromosome 12 was observed near FAR2 and CCDC91 genes (OR = 3.31; P = 1.66E-08). Sex-stratified analyses showed a stronger association of APOE*4 with AD in females (P = 1.74E-10) than in males (P = 2.43E-05). In males, a novel SNP on chromosome 1 near LOC729987 and SNX7 genes reached genome-wide significance (OR = 4.51; P = 3.72E-08). Of the known AD genes, SNPs near or at TREM2, NME8/EPDR1, MS4A6A/MS4A4E, PICALM, APH1B, and PLCG2 showed nominal significance.


The use of community-based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case-control studies. Replication of these signals and further study of these regions and genes will help to provide a clearer picture for their role in AD.