AS250 - Genetic Contributions to Cognitive Decline in Normal and Pathological Aging in Older Postmenopausal Women and Modification by Hormone Therapy

Investigator Names and Contact Information

Ira Driscoll, PhD;


Genetic research is expected to aid in the definition and treatment of disease. The neural mechanisms by which genetic variation increases risk for a disease have long been elusive, as genes do not encode directly for clinical manifestations of the disease. Through this proposal, we will determine the extent to which genetic variability in the four candidate genes explains variability in cognitive function.   Follow-up studies in the WHIMS and WHIMS-MRI cohorts suggest that the adverse effects of HT in older women may be most pronounced in a subgroup of women who already had low cognitive performance at WHI baseline (Espeland et al., 2004). The WHIMS-MRI study (under review) suggests that CEE-based HT may be associated with greater brain atrophy, specifically in frontal and hippocampal regions, among women aged 65 years or older, and that the adverse effects may be most pronounced in women already experiencing cognitive impairment.  Since women with low cognitive function at baseline appear to be the most vulnerable to adverse effects of HT on global cognition and brain volumes, the results of this proposal will determine whether these genetic polymorphisms contribute to the risk for cognitive decline and the risk for adverse effects of HT in older women. The genetic analyses proposed herein may provide critical insights about genetic contributors to age-related cognitive decline in general and to vulnerability to the adverse effects of HT in particular.  The identification of genes involved in cognitive decline and in vulnerability to HT in older women would be major breakthroughs in our current understanding of the effects of HT on cognitive performance; dementia risk and brain atrophy in older postmenopausal women and could lead to new approaches to prevention and treatment of cognitive impairment.
We propose to investigate specific candidate genes that may be associated with cognitive decline and dementia, using existing follow-up data and DNA samples from WHIMS (N = 7479) and WHISCA (total N = 2302) participants in the randomized clinical trial of hormone therapy (HT) of the Women’s Health Initiative (WHI).  The main scientific goals of this study are to investigate associations of four specific genetic polymorphisms and cognitive decline in the WHIMS and WHISCA samples and to determine whether HT (with and without progestin) modifies these associations.  A secondary goal is to investigate associations between these polymorphisms and brain structure, including ischemic lesion volumes and measures of frontal lobe and hippocampal atrophy, and whether the HT-associated frontal and hippocampal atrophy found in the WHIMS-MRI study is modified by genotype.  The strengths of this proposal lie in longitudinal examinations of a large, well-characterized, multi-site study sample investigated within the context of a randomized clinical trial, the availability of valid MRI scans for a large sample of 1403 women, and advanced genetic methodology.  The findings will provide important insights into genetic risk factors for cognitive decline and brain changes in older women and will provide information on whether HT modifies the expression of these risk factors.  As marked cognitive decline is an intermediate phenotype for dementia, greater understanding of the role of genetic and hormonal modifiers, alone and in combination, may also provide new insights into treatment strategies to ameliorate or delay cognitive decline and dementia in women. 
Primary Aims:
1.     To measure single nucleotide polymorphisms (SNP) and haplotype variation in four candidate genes (APOE, BDNF, COMT, and KIBRA) (84 SNPs) with reported involvement in specific aspects of cognition and to investigate their associations with cognitive decline and impairment.
2.     To determine whether HT modifies the associations between genetic polymorphisms in these four candidate genes and global and specific cognitive decline in the WHIMS/WHISCA.
Secondary Aims:
3.     To investigate the relationship between candidate gene (APOE, BDNF, COMT, and KIBRA) variations and incidence of mild cognitive impairment (MCI) and dementia.
4.      To determine whether genetic variations in the APOE, COMT, KIBRA and BDNF genes that are associated with cognitive decline are associated with total brain, hippocampal and frontal lobe volumes.     
5.       To determine whether potential associations between APOE and brain volume measures are modified by HT.
Summary of Central hypothesis: Genetic variations in the APOE, COMT, KIBRA, and BDNF candidate genes are associated with variability in the rates of cognitive decline, and the associations between these polymorphisms and cognitive decline are influenced by HT.  WHIMS findings indicate that adverse effects of HT on cognitive function and brain volumes in older women are most pronounced in women with low baseline cognitive performance.  Thus, genetic risk factors may be one mechanism leading to the greater vulnerability of some women to the adverse effects of HT on cognitive function and brain atrophy.    

Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, Hsia J, Margolis KL, Hogan PE, Wallace R, Dailey M, Freeman R, Hays J (2004). Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA 291:2959-2968.