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A candidate gene study of risk for dementia in older, postmenopausal women: Results from the Women's Health Initiative Memory Study. Int J Geriatr Psychiatry 2019 May;34(5):692-699



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Pubmed Central ID




Scopus ID

2-s2.0-85062720937   8 Citations


OBJECTIVE: While a number of single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) or cognitive impairment have been identified, independent replications remain the only way to validate proposed signals. We investigated SNPs in candidate genes associated with either cognitive impairment or AD pathogenesis and their relationships with probable dementia (PD) in the Women's Health Initiative Memory Study (WHIMS).

METHODS: We analyzed 96 SNPs across five genes (APOE/TOMM40, BDNF, COMT, SORL1, and KIBRA) in 2857 women (ages ≥65) from the WHIMS randomized trials of hormone therapy using a custom Illumina GoldenGate assay; 19% of the sample were MCI (N = 165) or PD (N = 387), and the remaining 81% were free of cognitive impairment. SNP associations were evaluated for PD in non-Hispanic whites adjusting for age and HT using logistic regression under an additive genetic model.

RESULTS: One SNP (rs157582), located in the TOMM40 gene nearby APOE, was associated with the PD phenotype based on a P value accounting for multiple comparisons. An additional 12 SNPs were associated with the PD phenotype at P ≤ 0.05 (APOE: rs405509, rs439401; TOMM40: rs8106922, and KIBRA: rs4320284, rs11740112, rs10040267, rs13171394, rs6555802, rs2241368, rs244904, rs6555805, and rs10475878). Results of the sensitivity analyes excluding MCI were similar, with addition of COMT rs737865 and BDNF rs1491850 (P ≤ 0.05).

CONCLUSIONS: Our results in older women provide supporting evidence that the APOE/TOMM40 genes confer dementia risk and extend these findings to COMT, BDNF, and KIBRA. Our findings may lead to a better understanding of the role these genes play in cognition and cognitive impairment.

Author List

Driscoll I, Snively BM, Espeland MA, Shumaker SA, Rapp SR, Goveas JS, Casanova RL, Wactawski-Wende J, Manson JE, Rossom R, Brooks J, Hernandez DG, Singleton AB, Resnick SM


Joseph S. Goveas MD Professor in the Psychiatry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alzheimer Disease
Apolipoproteins E
Brain-Derived Neurotrophic Factor
Catechol O-Methyltransferase
Cognitive Dysfunction
Genetic Predisposition to Disease
Intracellular Signaling Peptides and Proteins
LDL-Receptor Related Proteins
Membrane Transport Proteins
Middle Aged
Polymorphism, Single Nucleotide
Women's Health