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Estrogen receptor genotype and risk of cognitive impairment in elders: findings from the Health ABC study.

ABSTRACT: OBJECTIVE:To determine whether variants in the estrogen receptors 1 (alpha) and 2 (beta) (ESR1 and ESR2) genes are associated with cognitive impairment in non-demented elderly men and women. BACKGROUND:Several single nucleotide polymorphisms (SNPs) on ESR1 and ESR2 genes have been associated with a range of hormone sensitive diseases such as breast cancer and osteoporosis. Genetic variations in ESR may also influence cognitive aging but are less studied, especially among men. METHODS:We studied 2527 participants enrolled in an ongoing prospective study of community-dwelling elders. Four SNPs from ESR1 and four from ESR2 were analyzed. We measured cognitive function with the Modified Mini-Mental Status Examination (3MS) at baseline and biannually; cognitive impairment was defined as a decline of five or more points over 4 years. We calculated odds of developing cognitive impairment across SNPs using gender-stratified logistic regression and adjusted analyses for age, education, baseline 3MS score and in addition for race. RESULTS:One thousand three hundred and forty-three women (mean age 73.4) and 1184 men (mean age 73.7) comprised our cohort. Among women, after multivariate adjustment, two of the ESR1 SNPs (rs8179176, rs9340799) and two of the ESR2 SNPs (rs1256065, rs1256030) were associated with likelihood of developing cognitive impairment, although the association for rs8179176 was of trend level significance. In men, one of the ESR1 SNPs (rs728524) and two of the ESR2 (rs1255998, rs1256030) were associated with cognitive impairment. Further adjustment for race attenuated the results somewhat. There was no association between any ESR SNP and level of bioavailable estradiol but testosterone level did vary among two of the SNPs (p<0.05). CONCLUSION:We found that among non-demented community elders, several SNPs in the ESR1 and ESR2 genes were associated with risk of developing cognitive impairment. These findings suggest that estrogen receptor genetic variants may play a role in cognitive aging.

SUBMITTER: Yaffe K

PROVIDER: S-EPMC2826192 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Estrogen receptor genotype and risk of cognitive impairment in elders: findings from the Health ABC study.

Yaffe Kristine K Lindquist Karla K Sen Saunak S Cauley Jane J Ferrell Robert R Penninx Brenda B Harris Tamara T Li Rongling R Cummings Steven R SR

Neurobiology of aging 20070921 4

<h4>Objective</h4>To determine whether variants in the estrogen receptors 1 (alpha) and 2 (beta) (ESR1 and ESR2) genes are associated with cognitive impairment in non-demented elderly men and women.<h4>Background</h4>Several single nucleotide polymorphisms (SNPs) on ESR1 and ESR2 genes have been associated with a range of hormone sensitive diseases such as breast cancer and osteoporosis. Genetic variations in ESR may also influence cognitive aging but are less studied, especially among men.<h4>M ...[more]

PMID: 17889406

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Project description:BackgroundOne of the more profound features of systemic lupus erythematosus (SLE) is that females have a 9:1 prevalence of this disease over males. Up to 80% of SLE patients have cognitive defects or affective disorders. The mechanism of CNS injury responsible for cognitive impairment is unknown. We previously showed that ER? deficiency significantly reduced renal disease and increased survival in lupus-prone mice. We hypothesized that ER? deficiency would be similarly protective in the brain, and that ER? may play a role in modulating blood-brain barrier (BBB) integrity and/or neuroinflammation in lupus-prone mice.MethodsMRL/lpr ER?+/+ and ER?KO mice (n?=?46) were ovariectomized, received 17?-estradiol pellets, and underwent radial arm water maze (WRAM) and novel object recognition (NOR) testing starting at eight weeks of age. Mice were sacrificed and brains were hemisected and processed for either immunohistochemistry, or hippocampus and parietal cortex dissection for Western blotting.ResultsMRL/lpr ER?KO mice (n?=?21) performed significantly better in WRAM testing than wild-type MRL/lpr mice (n?=?25). There was a significant reduction in reference memory errors (P <0.007), working memory errors (P <0.05), and start arm errors (P <0.02) in ER?KO mice. There were significant differences in NOR testing, particularly total exploration time, with ER? deficiency normalizing behavior. No significant differences were seen in markers of tight junction, astrogliosis, or microgliosis in the hippocampus or cortex by Western blot, however, there was a significant reduction in numbers of Iba1+ activated microglia in the hippocampus of ER?KO mice, as evidenced by immunohistochemietry (IHC).ConclusionER? deficiency provides significant protection against cognitive deficits in MRL/lpr mice as early as eight weeks of age. Additionally, the significant reduction in Iba1+ activated microglia in the MRL/lpr ER?KO mice was consistent with reduced inflammation, and may represent a biological mechanism for the cognitive improvement observed.

Project description:BackgroundObesity and cognitive impairment prevalence increases as age increases. Recent growing evidence finds links between obesity and cognitive impairment in older adults. However, the association between the two is controversial. This study aims to identify obesity marker trajectory patterns, and to assess whether these patterns are associated with cognitive impairment and cognitive decline during a 10-year follow-up period among community-dwelling older adults.MethodsA total of 626 older adults aged 65 and older were involved in the study, with at least two repeated measurements at baseline, one-year or 10-year follow-up. Cognitive function was measured through the Mini Mental State Examination. Obesity markers included body mass index, waist circumference, waist-to-hip (WHR), fat mass (FM), and abdominal fat (AF) measured by dual-energy X-ray absorptiometry. Multivariate logistic regression analyses were performed to estimate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of cognitive impairment and cognitive decline for obesity marker trajectory patterns.ResultsAfter a 10-year follow-up, 168 older adults with incident cognitive impairment and 156 with rapid cognitive decline were defined as the top 25th percentile of cognitive decline. Four distinct trajectory groups of obesity markers were identified. In multivariate logistic regression analyses, a low likelihood of cognitive impairment was observed in the consistently high-level group from FM trajectory (ORs = 0.41, 95% CI = 0.20-0.85); the high-level U-shaped group from WHR trajectory (0.43, 0.22-0.84); and the median-level flat inverse U-shaped, consistently high-level, and low-level flat U-shaped groups from AF trajectory (0.44, 0.26-0.77; 0.33, 0.18-0.61; 0.39, 0.18-0.82). In addition, a low likelihood of rapid decline was found in the low-level, slightly increasing trend group from WHR trajectory (0.43, 0.22-0.85).ConclusionFM and AF trajectories with consistent high levels and WHR trajectory with high level with U-shaped group are associated with low risks of incident cognitive impairment in older adults. Similarly, WHR trajectory with a low but slowly increasing trend is associated with a decreased risk of cognitive decline.

Dataset Information

Estrogen receptor genotype and risk of cognitive impairment in elders: findings from the Health ABC study.

Publications

Estrogen receptor genotype and risk of cognitive impairment in elders: findings from the Health ABC study.

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