Genetic variants associated with risk of Alzheimer's disease contribute to cognitive change in midlife: The Atherosclerosis Risk in Communities Study

Am J Med Genet B Neuropsychiatr Genet. 2017 Apr;174(3):269-282. doi: 10.1002/ajmg.b.32509. Epub 2016 Oct 26.


Alzheimer's disease (AD) is the most common form of dementia and is characterized by impairment in memory, behavioral changes, and gradual loss of autonomy. Since there is a long latent period prior to diagnosis, the aim of this study was to determine whether twenty single nucleotide polymorphisms identified in genome-wide association analyses of AD are associated with cognitive change in 8,320 white and 2,039 African-American middle-aged adults enrolled in the prospective Atherosclerosis Risk in Communities (ARIC) study. Cognition was evaluated using the Delayed Word Recall Test (DWRT; verbal memory), Digit Symbol Substitution Test (DSST; processing speed), and Word Fluency Test (WFT; executive function). General linear models were used to assess mean differences in 6-year change in test scores among individuals categorized by genotype after adjusting for age, gender, and years of education. Addition of the minor allele for rs670139 (MS4A4E), rs9331896 (CLU), and rs12155159 (NME8) was nominally associated with change on the DWRT, DSST, and WFT, respectively, in whites. The ZCWPW1 (rs1476679) and CDS33 (rs3865444) variants were nominally associated with change on the DWRT and WFT in African-Americans. For rs670139 and rs9331896 the association was only significant in individuals bearing at least one APOE ϵ4 allele in stratified analyses. An unweighted genetic risk score aggregating the risk alleles for 15 polymorphisms was not associated with change in cognitive function. Although the AD-associated genetic variants appear to have small effects on early cognitive change, replication will be required to establish whether there is a discernible influence on cognitive status in midlife. © 2016 Wiley Periodicals, Inc.

Keywords: Alzheimer's disease; association study; cognition; genetic epidemiology.

MeSH terms

  • African Americans / genetics
  • African Continental Ancestry Group / genetics
  • Alleles
  • Alzheimer Disease / complications
  • Alzheimer Disease / genetics*
  • Atherosclerosis / complications
  • Atherosclerosis / genetics
  • Atherosclerosis / psychology
  • Clusterin / genetics
  • Cognition
  • Cognition Disorders / genetics
  • Dementia / genetics
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Variation / genetics
  • Genome-Wide Association Study / methods
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Memory
  • Middle Aged
  • Neuropsychological Tests
  • Polymorphism, Single Nucleotide / genetics
  • Prospective Studies
  • Risk Factors
  • Thioredoxins / genetics


  • CLU protein, human
  • Clusterin
  • MS4A4E protein, human
  • Membrane Proteins
  • NME8 protein, human
  • Thioredoxins