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1.  Hormone therapy, dementia, and cognition: the Women's Health Initiative ten years on 
Principle findings on dementia from the Women's Health Initiative Memory Study (WHIMS) showed that conjugated equine estrogens plus medroxyprogesterone acetate (CEE/MPA) increase dementia risk in women aged 65 years and above, but not risk of mild cognitive impairment. The dementia finding was unexpected, given consistent observational evidence that associates estrogen-containing hormone therapy use with reduced risk of Alzheimer's disease. It remains controversial whether hormone use by younger postmenopausal women near the time of menopause reduces dementia risk or whether WHIMS findings should be generalized to younger women. Given the challenges of conducting a primary prevention trial to address that question, it is helpful to consider the impact of hormone therapy on cognitive test performance, particularly verbal memory, for its own sake and as a proxy for dementia risk. The WHI Study of Cognitive Aging (WHISCA) showed that CEE/MPA worsened verbal memory, whereas CEE alone had no influence on cognition. These findings have been replicated in several randomized clinical trials. The apparent negative effect of CEE/MPA on verbal memory does not appear to be age-dependent. Additional investigations are needed to understand the impact of other hormonally active compounds on dementia and cognitive outcomes.
PMCID: PMC3667708  PMID: 22612612
Alzheimer's disease; cognition; dementia; estrogen; hormone therapy; menopause; memory; progestogen; review; selective estrogen receptor modulator; women's health initiative
2.  Effects of Tamoxifen and Raloxifene on Memory and Other Cognitive Abilities: Cognition in the Study of Tamoxifen and Raloxifene 
Journal of Clinical Oncology  2009;27(31):5144-5152.
To compare the effects of two selective estrogen receptor modulators, tamoxifen and raloxifene, on global and domain-specific cognitive function.
Patients and Methods
The National Surgical Adjuvant Breast and Bowel Project's Study of Tamoxifen and Raloxifene (STAR) study was a randomized clinical trial of tamoxifen 20 mg/d or raloxifene 60 mg/d in healthy postmenopausal women at increased risk of breast cancer. The 1,498 women who were randomly assigned in STAR were age 65 years and older, were not diagnosed with dementia, and were enrolled onto the Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR) trial, beginning 18 months after STAR enrollment started. A cognitive test battery modeled after the one used in the Women's Health Initiative Study of Cognitive Aging (WHISCA) was administered. Technicians were centrally trained to administer the battery and recertified every 6 months. Analyses were conducted on all participants and on 273 women who completed the first cognitive battery before they started taking their medications.
Overall, there were no significant differences in adjusted mean cognitive scores between the two treatment groups across visits. There were significant time effects across the three visits for some of the cognitive measures. Similar results were obtained for the subset of women with true baseline measures.
Tamoxifen and raloxifene are associated with similar patterns of cognitive function in postmenopausal women at increased risk of breast cancer. Future comparisons between these findings and patterns of cognitive function in hormone therapy and placebo groups in WHISCA should provide additional insights into the effects of tamoxifen and raloxifene on cognitive function in older women.
PMCID: PMC2773473  PMID: 19770382
3.  Body Adiposity in Late Life and Risk of Dementia or Cognitive Impairment in a Longitudinal Community-Based Study 
The association between body adiposity at older ages and the development of cognitive impairment is unclear.
The association of body mass index (BMI) and waist circumference in late life with incidence of cognitive impairment was prospectively examined in a cohort study of 1,351 Latinos, aged 60–101 and residents of the Sacramento, CA, area at study baseline. The status of dementia and “cognitive impairment but not demented” (CIND) was determined at baseline and at each of five follow-up examinations by a multistage assessment protocol. Incident cases of dementia and CIND were combined (dementia/CIND) for more than 8 years of follow-up. BMI was categorized as less than 25.0, 25.0–29.9 (overweight), and 30 kg/m2 or greater (obese). Waist circumference was categorized into sex-specific tertiles.
Dementia/CIND was diagnosed in 110 (8.2%) participants. Compared with the lowest BMI category, overweight participants had a 48% decreased rate of dementia/CIND (adjusted hazard ratio [HR] = 0.52, 95% confidence interval [CI]: 0.30–0.91) and obese participants had a 61% decreased rate of dementia/CIND (HR = 0.39, 95% CI: 0.20–0.78). Rates of dementia/CIND for the middle and high tertile of waist circumference, compared with the low tertile, were 80% and 90% higher, respectively (adjusted HR = 1.8, 95% CI: 1.1–3.1, and adjusted HR = 1.9, 95% CI: 0.91–3.8).
Abdominal fat in late life appears to confer an increased risk for dementia/CIND, whereas overall obesity appears to be protective. This may reflect age-related changes in body composition and the association of visceral fat with metabolic dysregulation.
PMCID: PMC2691186  PMID: 19168781
Adiposity; Dementia; Cognitive impairment; Body mass index; Waist circumference
4.  The Cross-Sectional Relationship Between Body Mass Index, Waist-Hip Ratio and Cognitive Performance in Postmenopausal Women Enrolled in the Women's Health Initiative (WHI) 
To determine if body weight (BMI) is independently associated with cognitive function in postmenopausal women and the relationship between body fat distribution as estimated by waist-hip-ratio (WHR) and cognitive function.
Cross-sectional data analysis
Baseline data from the Women's Health Initiative (WHI) hormone trials.
8745 postmenopausal women aged 65–79 years, free of clinical evidence of dementia and completed baseline evaluation in the Women's Health Initiative (WHI) hormone trials.
Participants completed a Modified Mini-Mental State Examination (3MSE), health and lifestyle questionnaires, and standardized measurements of height, weight, body circumferences and blood pressure. Statistical analysis of associations between 3MSE scores, BMI and WHR after controlling for known confounders.
With the exception of smoking and exercise, vascular disease risk factors, including hypertension, waist measurement, heart disease and diabetes, were significantly associated with 3MSE score and were included as co-variables in subsequent analyses. BMI was inversely related to 3MSE scores, for every 1 unit increase in BMI, 3MSE decrease 0.988 (p=.0001) after adjusting for age, education and vascular disease risk factors. BMI had the most pronounced association with poorer cognitive functioning scores among women with smaller waist measurements. Among women with the highest WHR, cognitive scores increased with BMI.
Increasing BMI is associated with poorer cognitive function in women with smaller WHR. Higher WHR, estimating central fat mass, is associated with higher cognitive function in this cross-sectional study. Further research is needed to clarify the mechanism for this association.
PMCID: PMC2955186  PMID: 20646100
obesity; cognition; dementia; waist-hip ratio; women
5.  The Metabolic Syndrome and Development of Cognitive Impairment among Older Women 
Archives of neurology  2009;66(3):324-328.
Several studies support a role for cardiovascular risk factors in cognitive aging. The metabolic syndrome, a constellation of cardiovascular risk factors, is common in elderly people. A growing but conflicting body of literature suggests that the metabolic syndrome may be associated with cognitive impairment.
To investigate the association between the metabolic syndrome, and its components, and incident cognitive impairment in older women.
We prospectively determined if the metabolic syndrome and its components were associated with a 4-year risk of developing cognitive impairment (dementia, mild cognitive impairment or low global cognitive test score).
The study was conducted at 180 clinical centers in 25 countries.
A total of 4895 older women (mean age, 66.2 years) with osteoporosis who were part of an ancillary study to determine clinically relevant cognitive impairment were included in this study. These women were free of baseline cognitive impairment and had metabolic syndrome component measures.
Main Outcome Measures
Clinically significant cognitive impairment was defined to include women with clinically adjudicated dementia or MCI and women who had a Short Blessed test score greater than 6 (consistent with impairment), but whose cases were not clinically adjudicated. Logistic regression analysis was used to examine the association between presence of the metabolic syndrome and development of clinically significant cognitive impairment.
A total of 497 women (10.2%) had the metabolic syndrome, and of these, 36 (7.2%) developed cognitive impairment compared with 181 women (of 4398, 4.1%) without the syndrome (age-adjusted odds ratio, 1.66; 95% confidence interval, 1.14–2.41). The mean (SD) number of metabolic syndrome components for all women was 1.0 (1.1); 518 women (10.6%) were obese, 895 (18.3%) had hypertriglyceridemia, 1200 (24.5%) had low high-density lipoprotein cholesterol levels, 1944 (39.7%) had high blood pressure, and 381 (7.8%) had high fasting blood glucose levels. There was a 23.0% age-adjusted increase in the risk of developing cognitive impairment (odds ratio, 1.23, 95% confidence interval, 1.09–1.39), per unit increase in the number of components. Further multivariable adjustment somewhat reduced the effect.
We found an association between the metabolic syndrome and the number of components and risk of developing cognitive impairment in older women. Additional studies are needed to determine if screening and close management of these at-risk elderly women would diminish the incidence of cognitive impairment.
PMCID: PMC2685462  PMID: 19273750
dementia; metabolic syndrome; cognitive impairment
6.  Calcium and Vitamin D Supplementation and Cognitive Impairment in the Women’s Health Initiative 
Calcium and vitamin D are thought to play important roles in neuronal functioning. Studies have found associations between low serum vitamin D levels and reduced cognitive functioning, as well as high serum calcium levels and reduced cognitive functioning.
To examine the effects of vitamin D and calcium on cognitive outcomes in elderly women.
Post-hoc analysis of a randomized double-blinded placebo-controlled trial.
40 Women’s Health Initiative clinical centers across the U.S.
4143 women aged 65 years and older without probable dementia at baseline who participated in the WHI Calcium and Vitamin D trial and the Women’s Health Initiative Memory Study.
2034 women were randomized to 1000 mg of calcium carbonate combined with 400 IU of vitamin D3; 2109 women were randomized to placebo.
Primary: classifications of probable dementia or mild cognitive impairment via a 4-phase protocol that included central adjudication. Secondary: global cognitive function and individual cognitive subtests.
Mean age of participants was 71 years. During mean follow-up of 7.8 years, there were 39 cases of incident dementia among calcium plus vitamin D subjects compared to 37 cases among placebo subjects (hazard ratio=1.11, 95% CI: 0.71–1.74, p=0.64). Likewise, there were 98 cases of incident mild cognitive impairment among calcium plus vitamin D subjects compared to 108 cases among placebo subjects (hazard ratio=0.95, 95% CI: 0.72–1.25, p=0.72). There were no significant differences in incident dementia or mild cognitive impairment, or in global or domain-specific cognitive function between groups.
There was no association between treatment assignment and incident cognitive impairment. Further studies are needed to investigate the effects of vitamin D and calcium separately, on men and in other age and ethnic groups, and with other doses.
PMCID: PMC3521077  PMID: 23176129
Vitamin D; Calcium; Dementia; Cognition; Mild Cognitive Impairment
7.  Body Size and Incident Colorectal Cancer: A Prospective Study of Older Women 
Obesity is a controversial risk factor for colorectal cancer (CRC) in older women. We evaluated associations between multiple body size parameters and incident CRC in the prospective, population-based Iowa Women's Health Study (IWHS). IWHS participants, ages 55–69 years, provided data regarding height; weight; weight at ages 50, 40, 30, 18 years; hip circumference; and waist circumference at baseline (1986). Derived variables included body mass index (BMI), waist-to-hip ratio (WHR) and “overweight years” (OWYs; conceptually similar to cigarette pack-years). Incident CRC cases (n=1464) were ascertained from the State Health Registry of Iowa, through 2005. Multivariable Cox regression models were fit to estimate body size-associated CRC risks. Among 36,941 women (619,961 person-years), baseline height, weight, BMI, hip circumference, waist circumference and WHR were all positively associated with incident CRC (p trend ≤ 0.003 for each). Baseline BMI yielded the highest CRC risk estimates (obese III versus normal, RR=1.56; 95% CI=1.10–2.22; p trend < 0.001) and was more closely associated with distal than proximal tumors (p trend < 0.001 vs. 0.06). Conversely, height was more closely associated with proximal than distal tumors (p trend < 0.001 vs. 0.04). Other body size parameters were less predictive of incident CRC. These data strongly support a positive association between increased body size and CRC risk among older women. Further investigation of when increased body size has the greatest effect on CRC risk (i.e., early adulthood versus later adulthood) might also be informative, particularly with respect to defining subsite-specific pathways of colorectal carcinogenesis.
PMCID: PMC3005991  PMID: 20719902
Colorectal Cancer; Body Size; Older Women; Cohort Study
8.  Intraindividual Variability in Domain-Specific Cognition and Risk of Mild Cognitive Impairment and Dementia 
Intraindividual variability among cognitive domains may predict dementia independently of interindividual differences in cognition. A multidomain cognitive battery was administered to 2305 older adult women (mean age 74 years) enrolled in an ancillary study of the Women's Health Initiative. Women were evaluated annually for probable dementia and mild cognitive impairment (MCI) for an average of 5.3 years using a standardized protocol. Proportional hazards regression showed that lower baseline domain-specific cognitive scores significantly predicted MCI (N = 74), probable dementia (N = 45), and MCI or probable dementia combined (N = 101) and that verbal and figural memory predicted each outcome independently of all other cognitive domains. The baseline intraindividual standard deviation across test scores (IAV Cognitive Domains) significantly predicted probable dementia and this effect was attenuated by interindividual differences in verbal episodic memory. Slope increases in IAV Cognitive Domains across measurement occasions (IAV Time) explained additional risk for MCI and MCI or probable dementia, beyond that accounted for by interindividual differences in multiple cognitive measures, but risk for probable dementia was attenuated by mean decreases in verbal episodic memory slope. These findings demonstrate that within-person variability across cognitive domains both at baseline and longitudinally independently accounts for risk of cognitive impairment and dementia in support of the predictive utility of within-person variability.
PMCID: PMC3881440  PMID: 24454359
9.  Central Obesity, Leptin and Cognitive Decline: the Sacramento Area Latino Study on Aging 
Central obesity is a risk factor for cognitive decline. Leptin is secreted by adipose tissue and has been associated with better cognitive function. Aging Mexican-Americans have higher levels of obesity than Non-Hispanic Whites, but no investigations examined the relationship between leptin and cognitive decline among them or the role of central obesity in this association.
We analyzed 1480 dementia-free older Mexican-Americans who were followed over ten years. Cognitive function was assessed every 12 to 15 months with the Modified Mini Mental State Exam (3MSE) and the Spanish and English Verbal Learning Test (SEVLT).
For females with small waist circumference (≤35inches), an interquartile range (IQR) difference in leptin was associated with 35% less 3MSE errors and 22% less decline in SEVLT score over 10 years. For males with small waist circumference (≤40inches), an IQR difference in leptin was associated with 44% less 3MSE errors and 30% less decline in SEVLT score over 10 years. There was no association between leptin and cognitive decline among females or males with large waist circumference.
Leptin interacts with central obesity in shaping cognitive decline. Our findings provide valuable information about the effects of metabolic risk factors on cognitive function.
PMCID: PMC3483312  PMID: 22814127
Aging; cognition; obesity; leptin; longitudinal study; Mexican Americans
10.  The Relationship of Birth Weight With Longitudinal Changes in Body Composition in Adult Women 
Obesity (Silver Spring, Md.)  2011;20(2):463-465.
Most research on birth weight and adult health status has reported adult measures at a single time point. This study examined the relationship of self-reported birth weight to longitudinal changes in adult body composition in 587 women of the Michigan Bone Health and Metabolism Study, followed from 1992 to 2007 and aged 24–50 years at baseline. Linear mixed models were used to estimate the association between three birth weight categories and women’s 15-year changes in adult weight, height, BMI, waist and hip circumference, waist-to-hip ratio, and fat, lean, and skeletal muscle mass. Body composition measures increased in all women over the 15-year study period. At their adult baseline, high birth weight women weighed 13% more and had waist circumference and lean mass measures that were 5.51 cm and 3.91 kg larger, respectively, than normal birth weight women. No differences were observed in adult body composition between low and normal birth weight women and rates of change in the adult measures did not vary across the birth weight groups. Women heavier at birth continued to be heavier through adulthood, corroborating previous reports based on single measures of adult body composition. Research to address whether higher adult body composition in high birth weight women increases the longitudinal risk for obesity-related chronic diseases is needed.
PMCID: PMC3218298  PMID: 21617640
11.  Long Term Effects of Conjugated Equine Estrogens Therapies on Domain-Specific Cognitive Function: Results from the Women's Health Initiative Study of Cognitive Aging (WHISCA) Extension 
Conjugated equine estrogen (CEE) therapies when initiated among older women have been shown to produce small decrements in global cognitive function. We are interested whether these persist after cessation and extend to specific cognitive domains.
Randomized controlled clinical trial
Fourteen clinical centers of the Women's Health Initiative
2,304 women aged 65-80 years and free of probable dementia at enrollment
0.625 mg/day of CEE, with or without medroxyprogesterone acetate (MPA, 10 mg/day), and matching placebos
Annual administrations of a battery of cognitive tests during and following the trial
General linear models were used to compare on-trial and post-trial mean standardized test scores between treatment groups, with adjustment for baseline risk factors for cognitive impairment.
Assignment to CEE-based therapies was associated with small mean relative decrements in global and several domain-specific cognitive functions on-trial, which largely persisted through up to 4 years post-trial. The strongest statistical evidence was for global cognitive function: 0.07 standard deviation decrements both on-trial (p=0.007) and post-trial (p=0.01). Among domain specific scores, the mean relative decrements were slightly smaller, were less significant, and tended to be larger for CEE-alone therapy.
CEE-based therapies, when initiated after age 65 years, produce a small broad-based decrement in cognitive function that persists after their use is stopped. The differences in cognitive function however are small and would not be detectable or have clinical significance for an individual woman. Differences in effects among cognitive domains suggest that more than one mechanism may be involved.
PMCID: PMC2917208  PMID: 20649689
Postmenopausal hormone therapy; Cognitive function; Women's health
12.  Adiposity and Cognitive Decline in the Cardiovascular Health Study 
Neuroepidemiology  2013;40(4):274-281.
Studies relating adiposity to cognition in the elderly show conflicting results, which may be explained by the choice of adiposity measures. Thus, we studied the longitudinal associations of different adiposity measures, fat mass by bioelectrical impedance analysis (BIA), body mass index (BMI) and waist circumference (WC), with cognitive performance in the Cardiovascular Health Study.
Cognitive performance was assessed with the modified Mini Mental State Examination (3MS), the Digit Symbol Substitution Test (DSST), and a composite of both. We used linear mixed models to estimate rates of change in cognitive function scores associated with adiposity measured at baseline.
The final sample was comprised of 2,681 women (57.9%) and 1,949 men (42.1%) aged 73 ± 5.2 and 73.9 ± 5.6 years. Adiposity was associated with slower cognitive decline in most analyses. Results were similar for fat mass, BMI and WC. Higher fat-free mass was also related to slower cognitive decline. Results were similar in analyses excluding persons with cancer, smokers, and persons with short follow-up, poor self-reported health, or persons with cardiovascular disease.
Higher adiposity and higher fat-free mass in the elderly was related to better cognitive performance. This finding was not explained by confounding by pre-existing conditions.
PMCID: PMC4044822  PMID: 23445925
adiposity; fat mass; bioelectrical impedance; body mass index; waist circumference; cognition
13.  Cognitive Changes After Menopause: Influence of Estrogen 
The natural menopause is not associated with substantial cognitive change. Limited clinical trial evidence suggests that estrogen-containing hormone therapy has little effect on cognition during midlife, but prompt initiation after surgical menopause may improve aspects of memory. Among older postmenopausal women, strong clinical trial evidence demonstrates that hormone initiation does not improve cognition. More limited clinical trial evidence indicates no improvement in Alzheimer symptoms, and the Women’s Health Initiative Memory Study found an increase in dementia risk among older women. Observational findings of reduced Alzheimer risk may reflect early hormone use in younger women, or findings may be biased. Cognitive effects of selective estrogen receptor modulators are not yet well studied.
PMCID: PMC2637911  PMID: 18677155
Alzheimer disease; cognition; estrogen; memory; menopause; selective estrogen receptor modulators
14.  Cognitive Function in Normal-Weight, Overweight, and Obese Older Adults: An Analysis of the Advanced Cognitive Training for Independent and Vital Elderly Cohort 
To assess how elevated body mass index (BMI) affects cognitive function in elderly people.
Cross-sectional study.
Data for this cross-sectional study were taken from a multicenter randomized controlled trial, the Advanced Cognitive Training for Independent and Vital Elderly trial.
The analytic sample included 2,684 normal-weight, overweight, or obese subjects aged 65 to 94.
Evaluation of cognitive abilities was performed in several domains: global cognition, memory, reasoning, and speed of processing. Cross-sectional association between body weight status and cognitive functions was analyzed using multiple linear regression.
Overweight subjects had better performance on a reasoning task (β = 0.23, standard error (SE) = 0.11, P = .04) and the Useful Field of View (UFOV) measure (β = −39.46, SE = 12.95, P = .002), a test of visuospatial speed of processing, after controlling for age, sex, race, years of education, intervention group, study site, and cardiovascular risk factors. Subjects with class I (BMI 30.0–34.9 kg/m2) and class II (BMI>35.0 kg/m2) obesity had better UFOV measure scores (β = −38.98, SE = 14.77, P = .008; β = −35.75, SE = 17.65, and P = .04, respectively) in the multivariate model than normal-weight subjects. The relationships between BMI and individual cognitive domains were nonlinear.
Overweight participants had better cognitive performance in terms of reasoning and visuospatial speed of processing than normal-weight participants. Obesity was associated with better performance in visuospatial speed of processing than normal weight. The relationship between BMI and cognitive function should be studied prospectively.
PMCID: PMC2834231  PMID: 16420204
cognitive function; body mass index
15.  Subtypes of Mild Cognitive Impairment in Older Postmenopausal Women: The Women’s Health Initiative Memory Study 
Mild cognitive impairment (MCI) is a transitional state between normal cognitive functioning and dementia. A proposed MCI typology1 classifies individuals by the type and extent of cognitive impairment, yet few studies have characterized or compared these subtypes. 447 women 65 years of age and older from the Women’s Health Initiative Memory Study2 were classified into the four MCI subgroups and a ‘no impairment’ group and compared on clinical, sociodemographic, and health variables.
82.1% of participants had a cognitive deficit in at least one domain with most (74.3%) having deficits in multiple cognitive domains. Only 4.3% had an isolated memory deficit, while 21.3% had an isolated non-memory deficit. Of the 112 women who met all MCI criteria examined, the most common subtype was amnestic multi-domain MCI (42.8%) followed by non-amnestic multiple domain MCI (26.7%), non-amnestic single domain (24.1%) and amnestic single domain MCI (6.3%). Subtypes were similar with respect to education, health status, smoking, depression and pre- and on-study use of hormone therapy.
Despite the attention it receives in the literature amnestic MCI is the least common type highlighting the importance of identifying and characterizing other non-amnestic and multi-domain subtypes. Further research is needed on the epidemiology of MCI subtypes, clinical and biological differences between them and rates for conversion to dementia.
PMCID: PMC2929315  PMID: 20473134
MCI; women; WHIMS; postmenopausal; cognition; dementia; hormone therapy
16.  Adipose Tissue Fatty Acid Patterns and Changes in Anthropometry: A Cohort Study 
PLoS ONE  2011;6(7):e22587.
Diets rich in n-3 long chain polyunsaturated fatty acids (LC-PUFA), but low in n-6 LC-PUFA and 18:1 trans-fatty acids (TFA), may lower the risk of overweight and obesity. These fatty acids have often been investigated individually. We explored associations between global patterns in adipose tissue fatty acids and changes in anthropometry.
34 fatty acid species from adipose tissue biopsies were determined in a random sample of 1100 men and women from a Danish cohort study. We used sex-specific principal component analysis and multiple linear regression to investigate the associations of adipose tissue fatty acid patterns with changes in weight, waist circumference (WC), and WC controlled for changes in body mass index (WCBMI), adjusting for confounders.
7 principal components were extracted for each sex, explaining 77.6% and 78.3% of fatty acid variation in men and women, respectively. Fatty acid patterns with high levels of TFA tended to be positively associated with changes in weight and WC for both sexes. Patterns with high levels of n-6 LC-PUFA tended to be negatively associated with changes in weight and WC in men, and positively associated in women. Associations with patterns with high levels of n-3 LC-PUFA were dependent on the context of the rest of the fatty acid pattern.
Adipose tissue fatty acid patterns with high levels of TFA may be linked to weight gain, but patterns with high n-3 LC-PUFA did not appear to be linked to weight loss. Associations depended on characteristics of the rest of the pattern.
PMCID: PMC3141072  PMID: 21811635
17.  Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women's Health Initiative Memory Study 
Data on cardiovascular diseases (CVD) and cognitive decline are conflicting. Our objective was to investigate if CVD is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of CVD on cognitive functioning.
Methods and Results
Prospective follow‐up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the Women's Health Initiative Memory Study (WHIMS). CVD was determined by self‐report. For cognitive decline, we assessed the incidence of mild cognitive impairment (MCI) or probable dementia (PD) via modified mini‐mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow‐up was 8.4 years. Women with CVD tended to be at increased risk for cognitive decline compared with those free of CVD (hazard ratio [HR], 1.29; 95% CI: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (HR, 2.10; 95% CI: 1.40, 3.15 or HR, 1.97; 95% CI: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (HR 1.45; 95% CI: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without CVD. Diabetes tended to elevate the risk for MCI/PD in women with CVD. No significant trend was seen for adiposity.
CVD is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of CVD prevention for preserving cognitive functioning.
PMCID: PMC3886762  PMID: 24351701
cardiovascular diseases; cognitive decline; postmenopausal women
18.  The rationale, design, and baseline characteristics of the Women’s Health Initiative Memory Study of Younger Women (WHIMS-Y) 
Brain research  2013;1514:3-11.
The Women’s Health Initiative Memory Study-Younger (WHIMS-Y) was designed to assess the effect of prior random assignment to hormone therapy (HT) (conjugated equine estrogen (CEE) alone or CEE plus medroxyprogesterone acetate (MPA)) on global cognitive function in younger middle-aged women relative to placebo. WHIMS-Y was an ancillary study to the Women’s Health Initiative (WHI) HT trial and enrolled 1361 women who were aged 50-54 years and postmenopausal at WHI enrollment. WHIMS-Y will examine whether an average of 5.4 years of HT during early menopause has longer term protective effects on global cognitive function and if these effects vary by regimen, time between menopause and study initiation, and prior use of HT. We present the study rationale and design. We describe enrollment, adherence to assigned WHI therapy, and compare risk factor characteristics of the WHIMS-Y cohort at the time of WHI enrollment to similar aged women in the WHI HT who did not enroll in WHIMS-Y. Challenges of WHIMS-Y include lower than expected and differential enrollment. Strengths of WHIMS-Y include balance in baseline risk factors between treatment groups, standardized and masked data collection, and high rates of retention and on-trial adherence and exposure. In addition, the telephone-administered cognitive battery showed adequate construct validity. WHIMS-Y provided an unprecedented chance to examine the hypothesis that HT may have protective effects on cognition in younger postmenopausal women aged 50-54 years. Integrated into the WHI, WHIMS-Y optimized the experience of WHI investigators to ensure high retention and excellent quality assurance across sites.
PMCID: PMC3684042  PMID: 23578696
Postmenopausal hormone therapy; Cognitive function; Aging
19.  Behaviorally Supported Exercise Predicts Weight Loss in Obese Adults Through Improvements in Mood, Self-Efficacy, and Self-Regulation, Rather Than by Caloric Expenditure 
The Permanente Journal  2011;15(1):23-27.
Background: The relationship of exercise to weight loss, beyond minimal caloric expenditures possible in obese and deconditioned individuals, requires clarification.
Objective: We assessed whether changes in theory-based psychological variables associated with participation in an exercise treatment extended to psychologically based predictors of controlled eating and weight and waist-circumference reductions.
Methods: A group of 137 adults with severe obesity (mean body mass index, 42.2 kg/m2) volunteered for an exercise-support and nutrition-education treatment of 26 weeks' duration that was based on social cognitive theory. Exercise- and eating-related measures of mood, self-regulation, and self-efficacy were obtained at baseline and at treatment end, along with weight, waist circumference, and exercise volume. Analyses were also conducted separately for women participants only (n = 102).
Results: Treatment-induced changes in total mood disturbance, self-regulatory skill usage for exercise, and exercise self-efficacy were significantly related to changes in self-efficacy to control emotional eating, self-regulatory skill usage for controlled eating, and overall self-efficacy for controlled eating, respectively (p < 0.001). Changes in the eating-related measures significantly predicted changes in weight and waist circumference with adjusted R2 values from 0.15 to 0.21 and 0.28 to 0.30, respectively (p < 0.001). Post-hoc testing indicated a strong negative correlation between exercise completed and weight change (r = −0.62); however, only 12.4% of the observed weight change was accounted for through associated caloric expenditures.
Conclusion: Exercise may support weight loss primarily through psychological rather than physiological pathways. Although the models tested were viable, additional modifiable variables may further strengthen the prediction of weight and waist-circumference change and benefit weight-loss theory and treatment outcomes.
PMCID: PMC3048629  PMID: 21505614
20.  Stroke and Memory Performance in Elderly without Dementia 
Archives of neurology  2006;63(4):571-576.
There is conflicting data showing that stroke is associated with a higher risk of dementia and a more severe decline in persons with cognitive impairment. However, if cerebrovascular disease is directly related to cognitive decline in the absence of cognitive impairment or dementia remains unclear.
To examine the association between stroke and changes in cognitive function over time in elderly persons without dementia at baseline.
The results of neuropsychological tests from several intervals over a five-year-period were clustered into domains of memory, abstract/visuospatial and language in 1271 elderly without dementia or cognitive decline. Stroke was related to the slope of performance in each cognitive domain using generalized estimating equations.
Memory performance declined over time while abstract/visuospatial and language performance remained stable over the study period. Stroke was associated with a more rapid decline in memory performance, while there was no association between stroke and decline in abstract/visuospatial or language performance. The association between stroke and decline in memory performance was strongest for men and for persons without an APOE4 allele. A significant association between stroke and decline in abstract/visuospatial performance was also observed for persons without the APOE-e4 allele.
A history of stroke is related to a progressive decline in memory and abstract/visuospatial performance especially among men and those without an APOE-e4 allele.
PMCID: PMC2669794  PMID: 16606771
stroke; memory performance; cognitive performance
21.  Longitudinal Changes in Memory and Executive Functioning are Associated with Longitudinal Change in Instrumental Activities of Daily Living in older adults 
The Clinical neuropsychologist  2008;23(3):446-461.
Impaired everyday function is a diagnostic criterion for dementia, and a determinant of healthcare utilization and caregiver burden. Although many previous studies have demonstrated a cross-sectional relationships between cognition (particularly executive functions and memory) and everyday function in older adults, very little is known about longitudinal relationships between these domains. This study examined the association between longitudinal change in episodic memory (MEM) and executive functioning (EXEC) and change in everyday function. Participants were a cognitively heterogeneous group of 100 elderly persons including those with normal cognition, as well as those with mild cognitive impairment and dementia. They were followed for an average of five years. Random effects modeling showed that change in both MEM and EXEC were independently associated with rate of change in informant-rated instrumental activities of daily living (IADLs), even after controlling for age, education, and gender. Findings indicate that declines in MEM and EXEC over time make unique and independent contributions to declines in older adults’ ability to function in daily life.
PMCID: PMC2881703  PMID: 18821181
Memory; Executive functioning; Everyday Function; dementia; Alzheimer’s disease
22.  Cognitive Decline in Prodromal Alzheimer's Disease and Mild Cognitive Impairment 
Archives of neurology  2011;68(3):351-356.
To characterize the course of cognitive decline during the prodromal phase of Alzheimer's disease.
Longitudinal cohort study with up to 16 years of observation.
Older persons from two projects underwent annual clinical evaluations that included cognitive function testing and clinical classification of mild cognitive impairment, dementia, and Alzheimer's disease. At baseline, there were 2,071 individuals without dementia and 1,511 without cognitive impairment.
Main Outcome Measures
Change in previously established composite measures of global cognition and specific cognitive domains assessed in mixed-effects models that allow rate of decline to shift at specific points.
During follow-up, 462 persons developed Alzheimer's disease (20 with dementia solely due to another condition were excluded). Five to six years before the diagnosis, rate of global cognitive decline sharply accelerated by more than 15-fold. The acceleration in decline occurred slightly earlier for semantic memory (76 months before diagnosis) and working memory (75 months) than other cognitive functions. Mild cognitive impairment was also preceded by years of cognitive decline which began earlier (80 months before diagnosis) and proceeded more rapidly (annual loss of 0.102 unit) in the amnestic than nonamnestic (62 months, 0.072 unit) subtype.
Dementia due to Alzheimer's disease is preceded by about five to six years of accelerated decline in multiple cognitive functions. By contrast, little decline is evident in persons not developing Alzheimer's disease.
PMCID: PMC3100533  PMID: 21403020
23.  Cognitive decline in the elderly: an analysis of population heterogeneity 
Age and Ageing  2011;40(6):684-689.
Background: studies of cognitive ageing at the group level suggest that age is associated with cognitive decline; however, there may be individual differences such that not all older adults will experience cognitive decline.
Objective: to evaluate patterns of cognitive decline in a cohort of older adults initially free of dementia.
Design, setting and subjects: elderly Catholic clergy members participating in the Religious Orders Study were followed for up to 15 years. Cognitive performance was assessed annually.
Methods: performance on a composite global measure of cognition was analysed using random effects models for baseline performance and change over time. A profile mixture component was used to identify subgroups with different cognitive trajectories over the study period.
Results: from a sample of 1,049 participants (mean age 75 years), three subgroups were identified based on the distribution of baseline performance and change over time. The majority (65%) of participants belonged to a slow decline class that did not experience substantial cognitive decline over the observation period [−0.04 baseline total sample standard deviation (SD) units/year]. About 27% experienced moderate decline (−0.19 SD/year), and 8% belonged to a class experiencing rapid decline (−0.57 SD/year). A subsample analysis revealed that when substantial cognitive decline does occur, the magnitude and rate of decline is correlated with neuropathological processes.
Conclusions: in this sample, the most common pattern of cognitive decline is extremely slow, perceptible on a time scale measured by decades, not years. While in need of cross validation, these findings suggest that cognitive changes associated with ageing may be minimal and emphasise the importance of understanding the full range of age-related pathologies that may diminish brain function.
PMCID: PMC3199215  PMID: 21890481
aged; 80 and over; cognition disorders; longitudinal study; elderly
24.  Adiposity Predicts Cognitive Decline in Older Persons with Diabetes: A 2-Year Follow-Up 
PLoS ONE  2010;5(4):e10333.
The mechanisms related to cognitive impairment in older persons with Type 2 diabetes (DM) remains unclear. We tested if adiposity parameters and body fat distribution could predict cognitive decline in older persons with DM vs. normal glucose tolerance (NGT).
693 older persons with no dementia were enrolled: 253 with DM in good metabolic control; 440 with NGT (age range:65–85 years). Longitudinal study comparing DM and NGT individuals according to the association of baseline adiposity parameters (body mass index (BMI), waist-hip-ratio (WHR), waist circumference (WC) and total body fat mass) to cognitive change (Mini Mental State Examination (MMSE), a composite score of executive and attention functioning (CCS) over time.
At baseline, in DM participants, MMSE correlated with WHR (β = −0.240; p = 0.043), WC (β = −0.264; p = 0.041) while CCS correlated with WHR (β = −0.238; p = 0.041), WC (β = −0.326; p = 0.013) after adjusting for confounders. In NGT subjects, no significant correlations were found among any adiposity parameters and MMSE, while CCS was associated with WHR (β = −0.194; p = 0.036) and WC (β = −0.210; p = 0.024). Participants with DM in the 3rd tertile of total fat mass showed the greatest decline in cognitive performance compared to those in 1st tertile (tests for trend: MMSE(p = 0.007), CCS(p = 0.003)). Logistic regression models showed that 3rd vs. 1st tertile of total fat mass, WHR, and WC predicted an almost two-fold decline in cognitive function in DM subjects at 2nd yr (OR 1.68, 95%IC 1.08–3.52).
Total fat mass and central adiposity predict an increased risk for cognitive decline in older person with DM.
PMCID: PMC2859057  PMID: 20428239
25.  Generalization of adiposity genetic loci to US Hispanic women 
Nutrition & Diabetes  2013;3(8):e85-.
Obesity is a public health concern. Yet the identification of adiposity-related genetic variants among United States (US) Hispanics, which is the largest US minority group, remains largely unknown.
To interrogate an a priori list of 47 (32 overall body mass and 15 central adiposity) index single-nucleotide polymorphisms (SNPs) previously studied in individuals of European descent among 3494 US Hispanic women in the Women's Health Initiative SNP Health Association Resource (WHI SHARe).
Cross-sectional analysis of measured body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) were inverse normally transformed after adjusting for age, smoking, center and global ancestry. WC and WHR models were also adjusted for BMI. Genotyping was performed using the Affymetrix 6.0 array. In the absence of an a priori selected SNP, a proxy was selected (r2⩾0.8 in CEU).
Six BMI loci (TMEM18, NUDT3/HMGA1, FAIM2, FTO, MC4R and KCTD15) and two WC/WHR loci (VEGFA and ITPR2-SSPN) were nominally significant (P<0.05) at the index or proxy SNP in the corresponding BMI and WC/WHR models. To account for distinct linkage disequilibrium patterns in Hispanics and further assess generalization of genetic effects at each locus, we interrogated the evidence for association at the 47 surrounding loci within 1 Mb region of the index or proxy SNP. Three additional BMI loci (FANCL, TFAP2B and ETV5) and five WC/WHR loci (DNM3-PIGC, GRB14, ADAMTS9, LY86 and MSRA) displayed Bonferroni-corrected significant associations with BMI and WC/WHR. Conditional analyses of each index SNP (or its proxy) and the most significant SNP within the 1 Mb region supported the possible presence of index-independent signals at each of these eight loci as well as at KCTD15.
This study provides evidence for the generalization of nine BMI and seven central adiposity loci in Hispanic women. This study expands the current knowledge of common adiposity-related genetic loci to Hispanic women.
PMCID: PMC3759132  PMID: 23978819
obesity; Hispanic; women; genetics; generalization

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