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

Jan Bressler, Thomas H. Mosley, Alan Penman, Rebecca F. Gottesman, Beverly Gwen Windham, David S Knopman, Lisa M. Wruck, Eric Boerwinkle

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Fingerprint

Atherosclerosis
Alzheimer Disease
Alleles
African Americans
Cognition
Word Processing
Genome-Wide Association Study
Executive Function
Single Nucleotide Polymorphism
Dementia
Linear Models
Genotype
Education

Keywords

  • Alzheimer's disease
  • Association study
  • Cognition
  • Genetic epidemiology

ASJC Scopus subject areas

  • Genetics(clinical)
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

Cite this

Genetic variants associated with risk of Alzheimer's disease contribute to cognitive change in midlife : The Atherosclerosis Risk in Communities Study. / Bressler, Jan; Mosley, Thomas H.; Penman, Alan; Gottesman, Rebecca F.; Windham, Beverly Gwen; Knopman, David S; Wruck, Lisa M.; Boerwinkle, Eric.

In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 2016.

Research output: Contribution to journalArticle

@article{5c96fc6f7e764aeb84f900504cdc38ee,
title = "Genetic variants associated with risk of Alzheimer's disease contribute to cognitive change in midlife: The Atherosclerosis Risk in Communities Study",
abstract = "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.",
keywords = "Alzheimer's disease, Association study, Cognition, Genetic epidemiology",
author = "Jan Bressler and Mosley, {Thomas H.} and Alan Penman and Gottesman, {Rebecca F.} and Windham, {Beverly Gwen} and Knopman, {David S} and Wruck, {Lisa M.} and Eric Boerwinkle",
year = "2016",
doi = "10.1002/ajmg.b.32509",
language = "English (US)",
journal = "American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics",
issn = "1552-4841",
publisher = "Wiley-Liss Inc.",

}

TY - JOUR

T1 - Genetic variants associated with risk of Alzheimer's disease contribute to cognitive change in midlife

T2 - The Atherosclerosis Risk in Communities Study

AU - Bressler, Jan

AU - Mosley, Thomas H.

AU - Penman, Alan

AU - Gottesman, Rebecca F.

AU - Windham, Beverly Gwen

AU - Knopman, David S

AU - Wruck, Lisa M.

AU - Boerwinkle, Eric

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Association study

KW - Cognition

KW - Genetic epidemiology

UR - http://www.scopus.com/inward/record.url?scp=84995768110&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84995768110&partnerID=8YFLogxK

U2 - 10.1002/ajmg.b.32509

DO - 10.1002/ajmg.b.32509

M3 - Article

C2 - 27781389

AN - SCOPUS:84995768110

JO - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics

JF - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics

SN - 1552-4841

ER -