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Background: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long‐term follow‐up in the WHI clinical trials. Methods: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1–2, and 3–4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high‐cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status. Results: After a >20‐year mortality follow‐up, a higher MetS score (3–4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)–positive, progesterone receptor (PR)–negative cancers (p =.03), 53% more deaths after breast cancer (p <.001), and 44% higher breast cancer mortality (p =.03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER‐positive, PR‐positive cancers (p <.001), more total breast cancers (p <.001), and more deaths after breast cancer (p <.001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m2; p <.001). Conclusions: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies. Metabolic syndrome and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. [ABSTRACT FROM AUTHOR]

Objective: In the 5.3‐year randomized, 2 × 2 factorial, double‐blind, placebo‐controlled Vitamin D and Omega‐3 Trial (VITAL), vitamin D supplementation reduced autoimmune disease (AD) incidence (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.61–0.99). Omega‐3 (n‐3) fatty acid supplementation showed a statistically nonsignificant reduction (HR 0.85, 95% CI 0.67–1.08). We aimed to confirm further AD cases arising during and after randomization and assess sustained effects with two years of postintervention observation. Methods: Of the 12,786 men aged ≥50 and 13,085 women aged ≥55 initially randomized, we observed surviving and willing participants for two more years. We continued to confirm annual participant‐reported new AD by medical record review. Cox models calculated HRs for all confirmed incident AD, (and secondary endpoints, including probable cases, and individual ADs), during the observational and randomized periods. Results: A total of 21,592 participants (83.5%) were observed for two more years; 514 participants developed incident confirmed AD (236 since prior report), of whom 255 had been randomized to vitamin D versus 259 to vitamin D placebo (HR 0.98 [95% CI 0.83–1.17] at 7 years). AD was confirmed in 234 participants initially randomized to n‐3 fatty acids versus 280 randomized to its placebo (HR 0.83 [95% CI 0.70–0.99] at 7 years). Of newly confirmed cases, 65 had onset during randomization; their inclusion changed randomized results as follows: HR 0.85 (95% CI 0.70–1.04) for vitamin D and HR 0.87 (95% CI 0.71–1.06) for n‐3 fatty acids. Conclusion: Two years after trial termination, the protective effects of 2000 IU/day of vitamin D dissipated, but 1,000 mg/day of n‐3 fatty acids had a sustained effect in reducing AD incidence. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Apolipoprotein E4 (APOE4) carriers' tendency toward hypercholesterolemia may contribute to Alzheimer's disease (AD) risk through oxysterols, which traverse the blood‐brain barrier. METHODS: Relationships between baseline plasma oxysterols, APOE status, serum lipids, and cognitive impairment risk were examined in 328 postmenopausal women from the Women's Health Initiative Memory Study. Women were followed for 25 years or until incident dementia or cognitive impairment. RESULTS: Levels of 24(S)‐hydroxycholesterol (24‐OHC), 27‐hydroxycholesterol (27‐OHC), and 24‐OHC/27‐OHC ratio did not differ by APOE status (p's > 0.05). Higher 24‐OHC and 27‐OHC were associated with higher total, low density lipoprotein (LDL), non‐high density lipoprotein (HDL), remnant, LDL/HDL, and total/HDL cholesterol and triglycerides (p's < 0.05). Higher 24‐OHC/27‐OHC was associated with greater dementia risk (hazard ratio = 1.51, 95% confidence interval:1.02‐2.22), which interaction analyses revealed as significant for APOE3 and APOE4+, but not APOE2+ carriers. DISCUSSION: Less favorable lipid profiles were associated with higher oxysterol levels. A higher ratio of 24‐OHC/27‐OHC may contribute to dementia risk in APOE3 and APOE4+ carriers. [ABSTRACT FROM AUTHOR]

Background: Elevated psychosocial stress has been linked with accelerated biological aging, including composite DNA methylation (DNAm) markers that predict aging‐related outcomes ("epigenetic age"). However, no study has examined whether stressful life events (SLEs) are associated with epigenetic age acceleration in postmenopausal women, an aging population characterized by increased stress burden and disease risk. Methods: We leveraged the Women's Health Initiative, a large muti‐ancestry cohort of postmenopausal women with available psychosocial stress measures over the past year and epigenomic data. SLEs and social support were ascertained via self‐report questionnaires. Whole blood DNAm array (450 K) data were used to calculate five DNAm‐based predictors of chronological age, health span and life span, and telomere length (HorvathAge, HannumAge, PhenoAge, GrimAge, DNAmTL). Results: After controlling for potential confounders, higher SLE burden was significantly associated with accelerated epigenetic aging, as measured by GrimAge (β: 0.34, 95% CI: 0.08, 0.59) and DNAmTL (β: −0.016, 95% CI: −0.028, −0.004). Exploratory analyses showed that SLEs‐GrimAge associations were stronger in Black women as compared to other races/ethnicities and in those with lower social support levels. In women with lower social support, SLEs‐DNAmTL associations showed opposite association in Hispanic women as compared to other race/ethnicity groups. Conclusions: Our findings suggest that elevated stress burden is associated with accelerated epigenetic aging in postmenopausal women. Lower social support and/or self‐reported race/ethnicity may modify the association of stress with epigenetic age acceleration. These findings advance understanding of how stress may contribute to aging‐related outcomes and have important implications for disease prevention and treatment in aging women. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease (AD) and AD‐related dementias (ADRD) are leading causes of death among older adults in the United States. Efforts to understand risk factors for prevention are needed. METHODS: Participants (n = 146,166) enrolled in the Women's Health Initiative without AD at baseline were included. Diabetes status was ascertained from self‐reported questionnaires and deaths attributed to AD/ADRD from hospital, autopsy, and death records. Competing risk regression models were used to estimate the cause‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) for the prospective association of type 2 diabetes mellitus (T2DM) with AD/ADRD and non‐AD/ADRD mortality. RESULTS: There were 29,393 treated T2DM cases and 8628 AD/ADRD deaths during 21.6 (14.0–23.5) median (IQR) years of follow‐up. Fully adjusted HRs (95% CIs) of the association with T2DM were 2.94 (2.76–3.12) for AD/ADRD and 2.65 (2.60–2.71) for the competing risk of non‐AD/ADRD mortality. DISCUSSION: T2DM is associated with AD/ADRD and non‐AD/ADRD mortality. Highlights: Type 2 diabetes mellitus is more strongly associated with Alzheimer's disease (AD)/AD and related dementias (ADRD) mortality compared to the competing risk of non‐AD/ADRD mortality among postmenopausal women.This relationship was consistent for AD and ADRD, respectively.This association is strongest among participants without obesity or hypertension and with younger age at baseline, higher diet quality, higher physical activity, higher alcohol consumption, and older age at the time of diagnosis of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background: Several metabolites are individually related to incident type 2 diabetes (T2D) risk. We prospectively evaluated a novel T2D‐metabolite pattern with a risk of progression to T2D among high‐risk women with a history of gestational diabetes mellitus (GDM). Methods: The longitudinal Nurses' Health Study II cohort enroled 116,429 women in 1989 and collected blood samples from 1996 to 1999. We profiled plasma metabolites in 175 incident T2D cases and 175 age‐matched controls, all with a history of GDM before the blood draw. We derived a metabolomics score from 21 metabolites previously associated with incident T2D in the published literature by scoring according to the participants' quintile (1–5 points) of each metabolite. We modelled the T2D metabolomics score categorically in quartiles and continuously per 1 standard deviation (SD) with the risk of incident T2D using conditional logistic regression models adjusting for body mass index at the blood draw, and other established T2D risk factors. Results: The percentage of women progressing to T2D ranged from 10% in the bottom T2D metabolomics score quartile to 78% in the highest score quartile. Adjusting for established T2D risk factors, women in the highest quartile had more than a 20‐fold greater diabetes risk than women in the lowest quartile (odds ratios [OR] = 23.1 [95% CI = 8.6, 62.1]; p for trend<0.001). The continuous T2D metabolomics score was strongly and positively associated with incident T2D (adjusted OR = 2.7 per SD [95% CI = 1.9, 3.7], p < 0.0001). Conclusions: A pattern of plasma metabolites among high‐risk women is associated with a markedly elevated risk of progression to T2D later in life. [ABSTRACT FROM AUTHOR]

Background: Caregiving is commonly undertaken by older women. Research is mixed, however, about the impact of prolonged caregiving on their health, well‐being, and mortality risk. Using a prospective study design, we examined the association of caregiving with mortality in a cohort of older women. Methods: Participants were 158,987 postmenopausal women aged 50–79 years at enrollment into the Women's Health Initiative (WHI) who provided information on current caregiving status and caregiving frequency at baseline (1993–1998) and follow‐up (2004–2005). Mortality was ascertained from baseline through March of 2019. Cox regression with caregiving status defined as a time‐varying exposure was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for mortality, adjusting for sociodemographic factors, smoking, and history of diabetes, hypertension, cardiovascular disease (CVD), and cancer. Stratified analyses explored whether age, race‐ethnicity, depressive symptoms, frequency of caregiving, optimism, and living status modified the association between caregiver status and mortality. Results: At baseline, 40.7% of women (mean age 63.3 years) self‐identified as caregivers. During a mean 17.5‐year follow‐up, all‐cause mortality (50,526 deaths) was 9% lower (multivariable‐adjusted HR = 0.91, 95% CI: 0.89–0.93) in caregivers compared to non‐caregivers. The inverse association between caregiving and all‐cause mortality did not differ according to caregiving frequency or when stratified by age, race‐ethnicity, depressive symptoms, optimism, or living status (interaction p > 0.05, all). Caregiving was inversely associated with CVD and cancer mortality. Conclusion: Among postmenopausal women residing across the United States, caregiving was associated with lower mortality. Studies detailing the type and amount of caregiving are needed to further determine its impact on older women. See related editorial by Dillon et al in this issue. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Whether apolipoprotein E's (APOE's) involvement in lipid metabolism contributes to Alzheimer's disease (AD) risk remains unknown. METHODS: Incident probable dementia and cognitive impairment (probable dementia+mild cognitive impairment) were analyzed in relation to baseline serum lipids (total, low‐density lipoprotein [LDL], high‐density lipoprotein [HDL], non‐HDL cholesterol, total‐to‐HDL, LDL‐to‐HDL, remnant cholesterol, and triglycerides) using Mendelian randomization in 5358 postmenopausal women from the Women's Health Initiative Memory Study. We also examined associations of baseline dietary cholesterol and fat with lipids based on APOE status. RESULTS: After an average of 11.13 years, less favorable lipid levels related to greater dementia and cognitive impairment risk. Dementia (odds ratio [OR] = 3.13; 95% confidence interval [CI]: 2.31 to 4.24) and cognitive impairment (OR = 2.38; 95% CI: 1.85 to 3.06) risk were greatest in relation to higher remnant cholesterol levels. Greater cholesterol consumption related to poorer lipids in APOE4+ compared to APOE3 carriers. DISCUSSION: APOE4+ carriers consuming more cholesterol had less favorable lipids, which were associated with greater dementia and cognitive impairment risk. Highlights: Less favorable serum lipids were associated with higher dementia incidence.Mendelian randomization findings suggest causality between lipids and dementia.Lipid levels in older women may be clinical indicators of dementia risk.APOE4 carriers had poorest lipid profiles in relation to cholesterol consumption.APOE risk for dementia may be modifiable through lipid management. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We assessed the effects of multivitamin‐mineral and cocoa extract supplementation on incident mild cognitive impairment (MCI) and all‐cause probable dementia. METHODS: COSMOS‐Mind (N = 2262), a 2 × 2 factorial, randomized‐controlled clinical trial administered a telephone‐based cognitive battery at baseline and annually for 3 years. Incidence rates of MCI, and separately dementia, were compared among treatment arms with proportional hazards regression. RESULTS: Over 3 years, 110 incident MCI and 14 incident dementia cases were adjudicated. Incidence rates did not vary by assignment to multivitamin‐mineral or cocoa extract (all p's ≥ 0.05); however, statistical power was low. When participants assigned to multivitamin‐mineral versus placebo converted to MCI, their scores for global cognition (p = 0.03) and executive function (p < 0.001) were higher and had declined less relative to the previous year (p = 0.03 for global cognition; p = 0.004 for executive function). DISCUSSION: Multivitamin‐mineral therapy may provide cognitive resilience, countering conversion to MCI, but not significantly reduce its incidence over 3 years. Highlights: Multivitamin‐mineral supplementation did not reduce risks for cognitive impairment.Cocoa extract supplementation did not reduce risks for cognitive impairment.Multivitamin‐mineral supplementation slowed cognitive declines for incident mild cognitive impairment. [ABSTRACT FROM AUTHOR]

Low circulating vitamin D levels are more prevalent in Black than White individuals. We analyzed the Women's Health Initiative (WHI) calcium plus vitamin D (CaD) randomized clinical trial extended follow‐up data to evaluate associations between calcium plus vitamin D supplementation and incident cancer, cardiovascular disease (CVD), and cause‐specific mortality endpoints among Black women. Intent‐to‐treat analysis was performed. Among 3325 Black women in the CaD trial who were randomized into either daily calcium (1000 mg of calcium carbonate) plus vitamin D (400 IU D3) or placebos for an average of 7 years, there were 813 deaths, 588 incident cancers, and 837 CVD events during an average of 15.7 years of follow up (52 230 total person‐years). Using Cox's proportional hazards models, we calculated hazard ratios and their confidence intervals for outcomes ascertained during the trial period, posttrial follow‐up period and overall periods combined. We found that total mortality, cause‐specific mortality, and total cancer incidence were almost identical between CaD and placebo groups. These results suggest that calcium plus vitamin D supplementation does not reduce risks of cancer, CVD, or other major causes of death in Black women overall and, thus, other medical, behavioral or social interventions should be considered to narrow health disparities related to these outcomes. However, other finer endpoints, such as colorectal cancer, warrants further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Physical activity (PA) is prospectively inversely associated with dementia risk, but few studies examined accelerometer measures of PA and sitting with rigorously‐adjudicated mild cognitive impairment (MCI) and dementia risk. Methods: We examined the associations of accelerometer measures (PA and sitting) with incident MCI/probable dementia in the Women's Health Initiative (n = 1277; mean age = 82 ± 6 years) Results: Over a median follow‐up of 4.2 years, 267 MCI/probable dementia cases were identified. Adjusted Cox regression HRs (95% CI) across moderate‐to‐vigorous PA (MVPA) min/d quartiles were 1.00 (reference), 1.28 (0.90 to 1.81), 0.79 (0.53 to 1.17), and 0.69 (0.45 to 1.06); P‐trend = 0.01. Adjusted HRs (95% CI) across steps/d quartiles were 1.00 (reference), 0.73 (0.51 to 1.03), 0.64 (0.43 to 0.94), and 0.38 (0.23 to 0.61); P‐trend < 0.001. The HR (95% CI) for each 1‐SD increment in MVPA (31 min/d) and steps/d (1865) were 0.79 (0.67 to 0.94) and 0.67 (0.54 to 0.82), respectively. Sitting was not associated with MCI/probable dementia. Discussion: Findings suggest ≥ moderate intensity PA, particularly stepping, associates with lower MCI and dementia risk. Highlights: Few studies have examined accelerometer‐measured physical activity, including steps, and sitting with incident ADRD.Moderate‐to‐vigorous physical activity and steps, but not light physical activity or sitting, were inversely associated with lower ADRD risk.Among older women, at least moderate intensity physical activity may be needed to reduce ADRD risk. [ABSTRACT FROM AUTHOR]

Background: Few studies have examined accelerometer‐measured physical activity and incident breast cancer (BC). Thus, this study examined associations between accelerometer‐measured vector magnitude counts per 15 seconds (VM/15s) and average daily minutes of light physical activity (LPA), moderate‐to‐vigorous PA (MVPA), and total PA (TPA) and BC risk among women in the Women's Health Accelerometry Collaboration (WHAC). Methods: The WHAC comprised 21,089 postmenopausal women (15,375 from the Women's Health Study [WHS]; 5714 from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study [OPACH]). Women wore an ActiGraph GT3X+ on the hip for ≥4 days and were followed for 7.4 average years to identify physician‐adjudicated in situ (n = 94) or invasive (n = 546) BCs. Multivariable stratified Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for tertiles of physical activity measures in association with incident BC overall and by cohort. Effect measure modification was examined by age, race/ethnicity, and body mass index (BMI). Results: In covariate‐adjusted models, the highest (vs. lowest) tertiles of VM/15s, TPA, LPA, and MVPA were associated with BC HRs of 0.80 (95% CI, 0.64–0.99), 0.84 (95% CI, 0.69–1.02), 0.89 (95% CI, 0.73–1.08), and 0.81 (95% CI, 0.64–1.01), respectively. Further adjustment for BMI or physical function attenuated these associations. Associations were more pronounced among OPACH than WHS women for VM/15s, MVPA, and TPA; younger than older women for MVPA; and women with BMI ≥30 than <30 kg/m2 for LPA. Conclusion: Greater levels of accelerometer‐assessed PA were associated with lower BC risk. Associations varied by age and obesity and were not independent of BMI or physical function. In a study of over 20,000 US postmenopausal women, higher levels of accelerometer‐measured physical activity were associated with lower risk of breast cancer. Associations varied by age and obesity and were not independent of body mass index or physical function. [ABSTRACT FROM AUTHOR]

Introduction: Dietary supplements are touted for cognitive protection, but supporting evidence is mixed. COSMOS‐Mind tested whether daily administration of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin‐mineral (MVM) versus placebo improved cognition in older women and men. Methods: COSMOS‐Mind, a large randomized two‐by‐two factorial 3‐year trial, assessed cognition by telephone at baseline and annually. The primary outcome was a global cognition composite formed from mean standardized (z) scores (relative to baseline) from individual tests, including the Telephone Interview of Cognitive Status, Word List and Story Recall, Oral Trail‐Making, Verbal Fluency, Number Span, and Digit Ordering. Using intention‐to‐treat, the primary endpoint was change in this composite with 3 years of cocoa extract use. The pre‐specified secondary endpoint was change in the composite with 3 years of MVM supplementation. Treatment effects were also examined for executive function and memory composite scores, and in pre‐specified subgroups at higher risk for cognitive decline. Results: A total of 2262 participants were enrolled (mean age = 73y; 60% women; 89% non‐Hispanic White), and 92% completed the baseline and at least one annual assessment. Cocoa extract had no effect on global cognition (mean z‐score = 0.03, 95% CI: ‐0.02 to 0.08; P =.28). Daily MVM supplementation, relative to placebo, resulted in a statistically significant benefit on global cognition (mean z = 0.07, 95% CI 0.02 to 0.12; P =.007), and this effect was most pronounced in participants with a history of cardiovascular disease (no history: 0.06, 95% CI 0.01 to 0.11; history: 0.14, 95% CI ‐0.02 to 0.31; interaction, nominal P =.01). Multivitamin‐mineral benefits were also observed for memory and executive function. The cocoa extract by MVM group interaction was not significant for any of the cognitive composites. Discussion: Cocoa extract did not benefit cognition. However, COSMOS‐Mind provides the first evidence from a large, long‐term, pragmatic trial to support the potential efficacy of a MVM to improve cognition in older adults. Additional work is needed to confirm these findings in a more diverse cohort and to identify mechanisms to account for MVM effects. Highlights: COSMOS‐Mind was a large simple pragmatic randomized clinical trial in older adults conducted by mail and telephone.The trial used a two‐by‐two factorial design to assess treatment effects of two different interventions within a single large study.We found no cognitive benefit of daily cocoa extract administration (containing 500 mg flavanols) for 3 years.Daily multivitamin‐mineral (MVM) supplementation for 3 years improved global cognition, episodic memory, and executive function in older adults.The MVM benefit appeared to be greater for adults with cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Research has suggested optimism is associated with healthy aging and exceptional longevity, but most studies were conducted among non‐Hispanic White populations. We examined associations of optimism to longevity across racial and ethnic groups and assessed healthy lifestyle as a possible mediating pathway. Methods: Participants from the Women's Health Initiative (N = 159,255) completed a validated measure of optimism and provided other demographic and health data at baseline. We evaluated associations of optimism with increments in lifespan using accelerated failure time models, and with likelihood of exceptional longevity (survival to age ≥90) using Poisson regression models. Causal mediation analysis explored whether lifestyle‐related factors mediated optimism‐lifespan associations. Results: After covariate adjustment, the highest versus lowest optimism quartile was associated with 5.4% (95% confidence interval [CI] = 4.5, 6.4%) longer lifespan. Within racial and ethnic subgroups, these estimates were 5.1% (95%CI = 4.0, 6.1%) in non‐Hispanic White, 7.6% (95%CI = 3.6, 11.7%) in Black, 5.4% (95%CI = −0.1, 11.2%) in Hispanic/Latina, and 1.5% (95% CI = −5.0, 8.5) in Asian women. A high proportion (53%) of the women achieved exceptional longevity. Participants in the highest versus lowest optimism quartile had greater likelihood of achieving exceptional longevity (e.g., full sample risk ratio = 1.1, 95%CI = 1.1, 1.1). Lifestyle mediated 24% of the optimism‐lifespan association in the full sample, 25% in non‐Hispanic White, 10% in Black, 24% in Hispanic/Latina, and 43% in Asian women. Conclusions: Higher optimism was associated with longer lifespan and a greater likelihood of achieving exceptional longevity overall and across racial and ethnic groups. The contribution of lifestyle to these associations was modest. Optimism may promote health and longevity in diverse racial and ethnic groups. Future research should investigate these associations in less long‐lived populations. See related Editorial by Cobert et al. and article by Jeffrey M. Levine in this issue. [ABSTRACT FROM AUTHOR]

Background: Women have higher rates of hypertension at the time of menopausal transition than men. Although elevated systolic and diastolic blood pressures (SBP and DBP) are risk factors for white matter (WM) injury both in women and men, WM hyperintensities (WMH), a marker of WM injury, are more common in women than in men after the age of 60. Thus, women may be vulnerable to the effects of elevated BP on WM integrity during menopausal transition. We investigated the association of BP in recently postmenopausal women with good cardiovascular health with WMH volume assessed 13 years later. Method: Women (n = 212; median age = 67; range 58‐72), who were previously enrolled in a multi‐site randomized menopausal hormone therapy trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59). Participants who were on antihypertensive medications at KEEPS baseline were excluded from the analysis (n = 34). Approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions, WM integrity was assessed with automated WMH volume measurements from 3D‐FLAIR MRI. Associations of baseline SBP and DBP with logWMH volume measured 13 years later were tested by linear regression analyses. Model 1 was adjusted for age, study site, and total intracranial volume. Model 2 was adjusted for covariates of model 1, triglycerides, low density lipoproteins, and waist/hip ratio. Result: The median SBP was 116 (range 83‐158) and DBP was 74 (range 56‐98). Higher SBP was associated with greater WMH volume (model 1:p = 0.005; model 2:p = 0.005). Similarly, higher DBP was associated with greater WMH volume (model 1:p = 0.008; model 2:p = 0.006) (Figure 1). Neither menopausal hormone therapies versus placebo, nor having high/low SBP (≥120/<120) modified these associations. Voxel‐based analyses demonstrate the association of BPs with the spatial distribution of WMHs (Figure 2). Conclusion: Higher BPs in recently menopausal women were associated with greater WM injury more than a decade later after adjusting for CVD risk factors. Early postmenopausal stage is a critical time for BP control in women, which may reduce the risk of WM injury later in life. [ABSTRACT FROM AUTHOR]

A relatively high healthy lifestyle index (HLI) score, representing a healthy diet, participation in moderate to vigorous physical exercise, no smoking, low to no alcohol intake and a normal body mass index, has been associated with a reduced risk of invasive breast cancer. However, no study has shown an association between the HLI and the risk of ductal carcinoma in situ of the breast (DCIS), which is considered to be a nonobligate precursor of invasive breast cancer. We evaluated this association in a prospective cohort of 132 230 postmenopausal women, aged 50 to 79 years, recruited between 1993 and 1998 across the United States and enrolled in the Women's Health Initiative study. The HLI score was created and categorized into quartiles. During an average follow‐up of 15.4 years, 2035 DCIS cases were ascertained. Multivariable‐adjusted Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of HLI with the risk of DCIS. Women in the highest HLI quartile had a lower DCIS risk than those in the lowest quartile (HR4thQT = 0.80, 95% CI, 0.70‐0.92) and this association was stronger in women with a family history of breast cancer (HR4thQT = 0.70, 95% CI, 0.52‐0.93), and for ER+/PR+ DCIS (HR4thQT = 0.66, 95% CI, 0.52‐0.83). These findings suggest that there is an inverse association between HLI and risk of DCIS, and suggest that the adoption of a healthy lifestyle might lower the risk of DCIS. [ABSTRACT FROM AUTHOR]

Introduction:: Few large, randomized trials have evaluated marine n-3 supplements and cognition in healthy older adults. Methods:: Healthy community-dwelling participants aged 60+ years (mean [standard deviation] = 70.9 [5.8] years) in VITAL (randomized trial of n-3 fats [1 g/day, including 840 mg of eicosapentaenoic acid + docosahexaenoic acid] and vitamin D) were included: 3424 whose cognition was assessed by phone (VITAL-Cog; eight neuropsychological tests; 2.8 years) and 794 evaluated in person (CTSC-Cog; nine tests; 2.0 years). The primary outcome was a global score (average of test z-scores) of change over two assessments. We used multivariable-adjusted linearmixed models; substudyspecific results weremeta-analyzed. Results: :We observed no significant effect of n-3 supplementation: the mean difference in annual rate of cognitive change for the n-3 versus placebo group was -0.01 standard units (95% confidence interval [CI]: -0.02, 0.003) in VITAL-Cog and -0.002 (95% CI: -0.04, 0.03) in CTSC-Cog; the pooled difference was -0.01 (95% CI: -0.02, 0.003; P = .15). Discussion:: Marine n-3 supplementation (1 g/day) did not confer cognitive benefits over 2 to 3 years in community-dwelling older adults. [ABSTRACT FROM AUTHOR]

BACKGROUND: The IBIS/Tyrer‐Cuzick model is used clinically to guide breast cancer screening and prevention, but was developed primarily in non‐Hispanic White women. Little is known about its long‐term performance in a racially/ethnically diverse population. METHODS: The Women's Health Initiative study enrolled postmenopausal women from 1993‐1998. Women were included who were aged <80 years at enrollment with no prior breast cancer or mastectomy and with data required for IBIS/Tyrer‐Cuzick calculation (weight; height; ages at menarche, first birth, and menopause; menopausal hormone therapy use; and family history of breast or ovarian cancer). Calibration was assessed by the ratio of observed breast cancer cases to the number expected by the IBIS/Tyrer‐Cuzick model (O/E; calculated as the sum of cumulative hazards). Differential discrimination was tested for by self‐reported race/ethnicity (non‐Hispanic White, non‐Hispanic Black, Hispanic, Asian or Pacific Islander, and American Indian or Alaskan Native) using Cox regression. Exploratory analyses, including simulation of a protective single‐nucleotide polymorphism (SNP), rs140068132 at 6q25, were performed. RESULTS: During follow‐up (median 18.9 years, maximum 23.4 years), 6783 breast cancer cases occurred among 90,967 women. IBIS/Tyrer‐Cuzick was well calibrated overall (O/E ratio = 0.95; 95% CI, 0.93‐0.97) and in most racial/ethnic groups, but overestimated risk for Hispanic women (O/E ratio = 0.75; 95% CI, 0.62‐0.90). Discrimination did not differ by race/ethnicity. Exploratory simulation of the protective SNP suggested improved IBIS/Tyrer‐Cuzick calibration for Hispanic women (O/E ratio = 0.80; 95% CI, 0.66‐0.96). CONCLUSIONS: The IBIS/Tyrer‐Cuzick model is well calibrated for several racial/ethnic groups over 2 decades of follow‐up. Studies that incorporate genetic and other risk factors, particularly among Hispanic women, are essential to improve breast cancer–risk prediction. The IBIS/Tyrer‐Cuzick model, which is used to guide clinical decision‐making about breast cancer prevention and screening, was found to perform well for most postmenopausal women in the Women's Health Initiative study. However, studies incorporating genetic and other risk factors, particularly for Hispanic women, should be prioritized to improve clinical breast cancer–risk prediction. [ABSTRACT FROM AUTHOR]

Background: Higher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results. Method: Women with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)). Result: Higher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p≤0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p<0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure). Conclusion: Higher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life. [ABSTRACT FROM AUTHOR]

Background: Few randomized clinical trials (RCTs) have investigated the effect of multivitamin‐mineral supplementation (MVM) on cognitive change among community‐dwelling older adults and effects remain untested using detailed in‐person, gold‐standard neuropsychological assessments; thus, we tested the effect of daily MVM vs. placebo on cognitive function among older adults enrolled in the in‐clinic component of COSMOS (COcoa Supplement and Multivitamin Outcomes Study). Furthermore, we conducted a meta‐analysis of the findings from the three COSMOS cognition studies: COSMOS‐Clinic (n = 603 for the detailed in‐person cognitive assessments), COSMOS‐Mind (n = 2262 for telephonic‐based cognitive assessments); and COSMOS‐Web (n = 3562 for computer‐based cognitive assessments) to provide a robust evaluation of the effects of MVM on cognition. Methods: COSMOS is a 2×2 factorial RCT of cocoa extract supplements (Mars Edge; containing 500 mg/day flavanols) and/or MVM (Haleon, as Centrum Silver) for cardiovascular and cancer prevention. In COSMOS‐Clinic, n = 573 of n = 603 COSMOS‐Clinic participants completed all cognitive tests at baseline; n = 492 completed all cognitive tests at both baseline and 2‐year follow‐up. The primary outcome was global cognitive score [averaging z‐scores of 11 tests: general cognition (the Modified Mini‐Mental State), episodic memory (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] word list learning and delayed recall tests; East Boston Memory Test immediate and delayed recall trials), CERAD word list recognition, and executive function/attention (two fluency tests; Trail Making Tests A and B; digit span backwards)]. Episodic memory and executive function/attention were examined separately. Finally, we used random‐effects models to meta‐analyze the findings of three COSMOS cognition studies. Results: In COSMOS‐Clinic, we observed a signal for effect of MVM vs. placebo on improvement in global cognition over two years (mean difference = 0.06, 95% confidence interval [CI]: ‐0.003, 0.12). MVM vs. placebo led to significant improvement in episodic memory (mean difference = 0.11, 95% CI: 0.001, 0.23) but not in executive function/attention (mean difference = 0.04, 95% CI: ‐0.04, 0.11). The meta‐analysis of three COSMOS studies showed significant benefits of MVM on global cognition and episodic memory (will be presented in detail). Conclusion: Daily MVM compared to placebo showed improvement in global cognition and episodic memory over 2 years among community‐dwelling older adults. [ABSTRACT FROM AUTHOR]

Background: COSMOS‐Mind, a large, randomized placebo‐controlled pragmatic trial in older adults, recently reported that daily supplementation with multivitamin‐mineral, but not cocoa extract, benefited global cognition. We assessed effects of these supplements on prespecified secondary outcomes of mild cognitive impairment (MCI) and all‐cause dementia (DM). We also assessed treatment‐related cognitive trajectories leading to conversion to MCI or dementia. Method: COSMOS‐Mind (N = 2262) administered a telephone‐based cognitive battery at baseline and annually for 3 years. Proxies of participants meeting criteria for suspected cognitive impairment based on a cognitive screener (TICSm) were interviewed. An expert panel adjudicated cognitive status. Incidence rates of MCI, and separately DM, were compared among arms with proportional hazards regression. Changes in cognitive trajectories leading to MCI and DM were assessed with linear models. Result: At baseline, adjudication for suspected cognitive impairment was triggered for 419 (20%) participants, yielding adjudications of 217 (10%) MCI and 4 (0.2%) DM cases. During follow‐up, triggers were less frequent in the MVM than placebo arms: hazard ratio = 0.73 (p = 0.04). Across 3 years, 110 incident MCI and 14 incident DM cases were adjudicated. Incidence rates of these outcomes did not vary by assignment to multivitamin‐mineral or cocoa extract (all p≥0.05), however statistical power was low. Incident MCI was associated with a marked decline in cognitive function from the previous year (p<0.001). When participants assigned to multivitamin‐mineral versus placebo converted to MCI, their scores for global cognition (p = 0.03) and executive function (p<0.001) were higher and had declined less relative to the previous year (p = 0.03 for global cognition; p = 0.004 for executive function). Daily cocoa extract use did not attenuate cognitive decline leading up to MCI. Conclusion: COSMOS‐Mind does not provide evidence that cocoa extract or multivitamin‐mineral therapy lowers risk of incident MCI or DM. Multivitamin‐mineral therapy, but not cocoa extract, may provide cognitive resilience countering conversion to MCI. [ABSTRACT FROM AUTHOR]

Background: Triple‐negative breast cancer (TNBC) has a high recurrence risk and poor clinical outcomes. Associations between metabolic syndrome (MetS) risk components and mortality in postmenopausal women with TNBC were examined in the Women's Health Initiative. Methods: Five hundred forty‐four postmenopausal women were diagnosed with nonmetastatic TNBC. Baseline risk components included a high waist circumference (≥88 cm), high blood pressure, hypercholesterolemia, and diabetes. Groups were categorized by the number of MetS risk components: none, 1 or 2, or 3 or 4. Hazard ratios (HRs) and 95% confidence intervals (CIs) across groups were computed with multivariable adjusted Cox models. Outcomes included breast cancer–specific mortality and breast cancer overall mortality (breast cancer followed by death from any cause). Variables in the multivariable model included age at TNBC diagnosis; race/ethnicity; income; education; clinical/observational trial status; history of oral contraceptive, hormone, and/or statin use; cancer stage; and chemotherapy and/or radiation treatment status. Results: Of the 544 participants with TNBC, 33% had no MetS risk components (n = 178), 59% had 1 or 2 risk components (n = 323), and 8% had 3 or 4 risk components (n = 43). After a median follow‐up from diagnosis of 8.3 years, multivariable results showed that women with 3 or 4 risk components had a nonsignificantly higher risk of breast cancer mortality (HR, 2.05; 95% CI, 0.94‐4.47 trend P =.114) and a significantly higher risk of overall mortality (HR, 2.13; 95% CI, 1.22‐3.71; trend P =.006) versus women with 0 risk components. Conclusions: Postmenopausal women with TNBC and 3 or 4 MetS risk components have a nonsignificantly higher breast cancer mortality risk and a significantly higher overall mortality risk, likely because of negative influences of metabolic risk factors on several causes of death. Postmenopausal women with 3 or 4 metabolic risk components who are diagnosed with triple‐negative breast cancer have higher breast cancer–specific and overall mortality rates. [ABSTRACT FROM AUTHOR]

Background and purpose: Among stroke patients, low serum 25‐hydroxyvitamin D predicts poor outcomes. In mice, higher omega‐3 (n‐3) fatty acid intake diminishes brain damage after stroke. In this study, we tested whether vitamin D or n‐3 fatty acids supplementation prior to stroke reduces the risk of functional limitations and physical disability after stroke. Methods: We used data from VITAL (the VITamin D and OmegA‐3 TriaL) which randomized middle‐aged and older men and women without cardiovascular disease to vitamin D3 (2000 IU/day) and/or marine n‐3 fatty acids (1 g/day) and followed them for incident stroke events. Individuals experiencing a non‐fatal stroke were mailed questionnaires assessing functional limitations (the physical performance scale adapted from Nagi) and physical disability (the modified Katz Activities of Daily Living and Rosow‐Breslau Functional Health scales). We used logistic regression to analyze associations between randomized treatment and limitations on each scale. Results: A total of 290 individuals experienced their first stroke during the trial, of whom 197 stroke survivors completed the stroke outcomes questionnaire a median of 1.4 years after diagnosis. We observed no associations between randomized treatment to vitamin D and functional limitations (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.52, 1.97) or physical disability (Rosow‐Breslau scale: OR 0.92, 95% CI 0.50, 1.67; Katz scale: OR 1.03, 95% CI 0.31, 3.42). Those randomized to n‐3 fatty acids had a non‐significantly lower risk of functional limitations (OR 0.55, 95% CI 0.28, 1.09) and physical disability (Rosow‐Breslau scale: OR 0.56, 95% CI 0.31, 1.02; Katz sclae: OR 0.32, 95% CI 0.50, 1.67). Conclusion: Vitamin D or omega‐3 fatty acid supplementation prior to stroke did not result in significantly improved post‐stroke outcomes. [ABSTRACT FROM AUTHOR]

Background: Cardiometabolic abnormalities are a leading cause of death among women, including women with cancer. Methods: This study examined the association between prediagnosis cardiovascular health and total and cause‐specific mortality among 12,076 postmenopausal women who developed local‐ or regional‐stage invasive cancer in the Women's Health Initiative (WHI). Cardiovascular risk factors included waist circumference, hypertension, high cholesterol, and type 2 diabetes. Obesity‐related cancers included breast cancer, colorectal cancer, endometrial cancer, kidney cancer, pancreatic cancer, ovarian cancer, stomach cancer, liver cancer, and non‐Hodgkin lymphoma. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for important predictors of survival. Results: After a median follow‐up of 10.0 years from the date of the cancer diagnosis, there were 3607 total deaths, with 1546 (43%) due to cancer. Most participants (62.9%) had 1 or 2 cardiometabolic risk factors, and 8.1% had 3 or 4. In adjusted models, women with 3 to 4 risk factors (vs none) had a higher risk of all‐cause mortality (HR, 1.99; 95% CI, 1.73‐2.30), death due to cardiovascular disease (CVD) (HR, 4.01; 95% CI, 2.88‐5.57), cancer‐specific mortality (HR, 1.37; 95% CI, 1.1‐1.72), and other‐cause mortality (HR, 2.14; 95% CI, 1.70‐2.69). A higher waist circumference was associated with greater all‐cause mortality (HR, 1.17; 95% CI, 1.06‐1.30) and cancer‐specific mortality (HR, 1.22; 95% CI, 1.04‐1.42). Conclusions: Among postmenopausal women diagnosed with cancer in the WHI, cardiometabolic risk factors before the cancer diagnosis were associated with greater all‐cause, CVD, cancer‐specific, and other‐cause mortality. These results raise hypotheses regarding potential clinical intervention strategies targeting cardiometabolic abnormalities that require future prospective studies for confirmation. Lay Summary: This study uses information from the Women's Health Initiative (WHI) to find out whether cardiac risk factors are related to a greater risk of dying among older women with cancer. The WHI is the largest study of medical problems faced by older women in this country.The results show that women who have 3 or 4 risk factors are more likely to die of any cause, heart disease, or cancer in comparison with women with no risk factors.It is concluded that interventions to help to lower the burden of cardiac risk factors can have an important impact on survivorship among women with cancer. Among postmenopausal women with select early‐stage cancers associated with metabolic syndrome, a higher number of cardiometabolic abnormalities is associated with a significantly higher risk of overall death in addition to a higher risk of death due to cancer, heart disease, and other causes. These findings highlight a major gap in the care of patients with cancer and the need for improved efforts by public health systems to improve cancer survivorship. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES: Exposure to air pollution may contribute to both increasing depressive symptoms and decreasing episodic memory in older adulthood, but few studies have examined this hypothesis in a longitudinal context. Accordingly, we examined the association between air pollution and changes in depressive symptoms (DS) and episodic memory (EM) and their interrelationship in oldest‐old (aged 80 and older) women. DESIGN: Prospective cohort data from the Women's Health Initiative Memory Study‐Epidemiology of Cognitive Health Outcomes. SETTING: Geographically diverse community‐dwelling population. PARTICIPANTS: A total of 1,583 dementia‐free women aged 80 and older. MEASUREMENTS: Women completed up to six annual memory assessments (latent composite of East Boston Memory Test and Telephone Interview for Cognitive Status) and the 15‐item Geriatric Depression Scale (GDS‐15). We estimated 3‐year average exposures to regional particulate matter with aerodynamic diameter below 2.5 μm (PM2.5) (interquartile range [IQR] = 3.35 μg/m3) and gaseous nitrogen dioxide (NO2) (IQR = 9.55 ppb) at baseline and during a remote period 10 years earlier, using regionalized national universal kriging. RESULTS: Latent change structural equation models examined whether residing in areas with higher pollutant levels was associated with annual changes in standardized EM and DS while adjusting for potential confounders. Remote NO2 (β =.287 per IQR; P =.002) and PM2.5 (β =.170 per IQR; P =.019) exposure was significantly associated with larger increases in standardized DS, although the magnitude of the difference, less than 1 point on the GDS‐15, is of questionable clinical significance. Higher DS were associated with accelerated EM declines (β = −.372; P =.001), with a significant indirect effect of remote NO2 and PM2.5 exposure on EM declines mediated by DS. There were no other significant indirect exposure effects. CONCLUSION: These findings in oldest‐old women point to potential adverse effects of late‐life exposure to air pollution on subsequent interplay between DS and EM, highlighting air pollution as an environmental health risk factor for older women. [ABSTRACT FROM AUTHOR]

The relationship between vitamin D status or supplementation and cancer outcomes has been examined in several meta‐analyses. To address remaining knowledge gaps, we conducted a systematic overview and critical appraisal of pertinent meta‐analyses. For meta‐analyses of trials, we assessed their quality using AMSTAR‐2 (A Measurement Tool to Assess Systematic Reviews), strength of associations using umbrella review methodology and credibility of evidence using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) criteria. Meta‐analyses of observational studies reported inverse associations of 25OHD with risk of cancer incidence and cancer mortality and, particularly for colorectal cancer, fulfilled some of Bradford‐Hill's causation criteria. In meta‐analyses of trials, vitamin D supplementation did not affect cancer incidence. However, we found credible evidence that vitamin D supplementation reduced total cancer mortality risk, with five out of six meta‐analyses reporting a relative risk (RR) reduction of up to 16%: RR, 0.84 (95% CI, 0.74–0.95). The strength of the association, however, was classified as weak. This was true among meta‐analyses of high, moderate, and lower quality (AMSTAR‐2–rated). Trials did not include large numbers of vitamin D‐deficient participants; many tested relatively low doses and lacked sufficiently powered data on site‐specific cancers. In conclusion, meta‐analyses show that, although observational evidence indicates that low vitamin D status is associated with a higher risk of cancer outcomes, randomized trials show that vitamin D supplementation reduces total cancer mortality, but not cancer incidence. However, trials with larger proportions of vitamin D‐insufficient participants and longer durations of follow‐up, plus adequately powered data on site‐specific common cancers, would provide further insight into the evidence base. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Objective: Knee pain from osteoarthritis is frequent in the adult population. Prior trials have had conflicting results concerning the therapeutic effects of vitamin D on knee pain, and few trials have investigated marine Omega‐3 fatty acids (n‐3 FA). Methods: In the double‐blind, placebo‐controlled Vitamin D and Omega‐3 Trial (VITAL), 25,871 US adults were randomized in a 2‐by‐2 factorial design to receive vitamin D or n‐3 FA. We identified a subgroup with chronic knee pain prior to randomization and assessed knee pain at baseline and annually during follow‐up using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (graded on a 0–100 scale, where 100 indicates worst symptoms). Repeated measures modeling was used to test the effect of randomized treatment on WOMAC pain scores over follow‐up after adjustment for age and sex. Analyses were repeated for WOMAC function and stiffness. Results: This study included 1,398 participants who returned at least one knee pain questionnaire. The mean age was 67.7 years, 66% were women, and the mean ± SD WOMAC pain score was 37 ± 19. The mean ± SD follow‐up time was 5.3 ± 0.7 years. WOMAC pain did not differ between the active vitamin D group and the vitamin D placebo group or between the active n‐3 FA group and the n‐3 FA placebo group at any time point during follow‐up. Linear time‐by‐treatment interactions were not significant for either treatment (vitamin D, P = 0.41; n‐3 FA, P = 0.77). Vitamin D and n‐3 FA supplementation did not significantly affect WOMAC function or stiffness scores over time. Conclusion: Our findings indicate that vitamin D and n‐3 FA supplementation for a mean of 5.3 years does not reduce knee pain or improve function or stiffness in a large sample of US adults with chronic knee pain. [ABSTRACT FROM AUTHOR]

Background: Research on menopausal hormone therapy (MHT) for the reduction/prevention of cognitive decline or Alzheimer's disease has been inconsistent. The Women's Health Initiative Memory Study (WHIMS) revealed elevated incident cognitive impairment for women starting MHT after age >65 with oral conjugated equine estrogens (o‐CEE) treatment, especially among women with diabetes. Subsequently, the Cognitive and Affective substudy of the Kronos Early Estrogen Prevention Study (KEEPS‐Cog) found that MHT initiated soon after menopause caused neither cognitive benefit nor harm. Waist‐to‐hip ratio (WHR) is a measure of central adiposity and a surrogate marker for insulin resistance/prediabetes. To explore effects of MHT in insulin‐resistant states, in younger women, we analyzed WHR as a predictor of cognitive response to MHT in KEEPS‐Cog. Methods: KEEPS‐Cog randomized women less than 36‐months postmenopause to oCEE, transdermal 17‐β‐estradiol (tE2) or placebo for 48 months. Cognitive tests, completed at baseline, 18, 36, and 48 months post‐randomization were summarized as factor scores representing four cognitive domains: verbal learning and memory (VLM), auditory attention and working memory (AAWM), visual attention and executive function (VAEF), and speeded language and mental flexibility (SLMF). WHR, measured at screening and months 12, 36, and 48 was modeled as a time‐varying moderator of MHT on cognitive function over time. Education was included as a time‐invariant covariate. Results: WHR decreased throughout the study in both the tE2 and oCEE groups compared to placebo. WHR was also inversely associated with all cognitive parameters at baseline. The inverse relationship of WHR on SLMF was significant at baseline and month 18, but decreased at month 48. The inverse relationship of WHR on VLM increased significantly over time. Models including interaction effects were significant for oCEE x WHR effects at months 18, 36, and 48 on SLMF, indicating better performance in MHT vs placebo arms. No other interaction effects were significant. Conclusions: WHR decreased with MHT, and was consistently associated with VLM through 4 years of MHT. Further, women on oCEE performed better on SLMF tasks at a given WHR. Differences between KEEPS‐Cog and WHIMS findings may be related to the timing of MHT administration, and effects on central adiposity/insulin resistance/prediabetes. [ABSTRACT FROM AUTHOR]

BACKGROUND Coffee and tea are two of the most widely consumed beverages worldwide and have been associated with reduced risk of mortality in some studies. However, it is unknown whether consumption of these beverages is associated with survival to an advanced age. OBJECTIVE To examine associations of coffee and tea consumption with survival to age 90 years. DESIGN Prospective cohort study among participants from the Womenʼs Health Initiative, recruited during 1993 to 1998 and followed up until March 31, 2018. SETTING The setting included 40 US clinical centers. PARTICIPANTS A racially and ethnically diverse cohort of 27,480 older women, aged 65 to 81 years at baseline. MEASUREMENTS Women were classified as having either survived to age 90 years or died before this age. Consumption of caffeinated and decaffeinated coffee and caffeinated tea was assessed at baseline and categorized as 0, 1, 2 to 3, or 4 or more cups/day. Associations of coffee and tea consumption with survival to age 90 years were examined using logistic regression models adjusted for sociodemographic characteristics, lifestyle behaviors, dietary quality, and chronic disease history. RESULTS: A total of 14,659 (53.3%) women survived to age 90 years during follow‐up. Caffeinated coffee, decaffeinated coffee, or caffeinated tea consumption was not significantly associated with survival to age 90 years after adjusting for confounders. Findings did not significantly vary by smoking, body mass index, or race/ethnicity. CONCLUSION: No amount of coffee or tea consumption was associated with late‐age survival among older women. These findings may be reassuring to older women who consume coffee and tea as part of their daily diets but do not support drinking these beverages to achieve longevity. [ABSTRACT FROM AUTHOR]

Breast cancer has been suggested to potentially have prenatal origins. We examined associations between birth weight, body mass index (BMI) at four‐time points over 25 years of adulthood, and risk of postmenopausal breast cancer, with emphasis on whether the association between birth weight and risk of breast cancer was mediated by weight and height changes over the adult life course. Postmenopausal women (n = 70,397) aged 50–79 years without breast cancer at enrollment (1993–1998) were followed up to 25 years. Weight and height were measured at baseline. Birth weight, and weights at ages 18, 35 and 50 were self‐reported. Breast cancer cases were centrally adjudicated. Compared to women with birth weight of 6–8 pounds, women with birth weight of <6 pounds had lower risk of breast cancer (HR = 0.88 95% CI: 0.79–0.99). 44% and 21% of the relationship between birth weight and breast cancer risk was mediated by adult height and weight at baseline, respectively. Birth weight of 8 pounds or more was not associated with risk of postmenopausal breast cancer. Weight gain in adulthood was associated with increased risk of breast cancer regardless of time periods. In conclusion, lower birthweight was associated with lower risk of postmenopausal breast cancer, and this reduction in risk was significantly mediated by childhood or adolescent growth, especially by adult height. Our data suggest that reaching and maintaining a healthy weight during adulthood is key in the prevention of breast cancer. What's new? Higher birthweight is associated with increased risk of breast cancer, especially in premenopausal women. In this study, the authors analyzed the effect of adult weight and height on the association between birthweight and postmenopausal breast cancer. They enrolled 70,397 postmenopausal women and monitored their breast cancer incidence over a 25‐year follow up. Women under 6 pounds at birth had reduced cancer risk, but more than 40% of this effect was mediated by adult height. High birthweight was not associated with postmenopausal breast cancer risk. Adult weight gain was associated with increased risk, regardless of birthweight. [ABSTRACT FROM AUTHOR]

Although supplemental vitamin D is used to promote bone health in the general population, data from randomized controlled trials (RCTs) have been inconsistent. We determined whether daily, vitamin D3 supplementation improves bone mineral density (BMD) and/or structure. VITamin D and OmegA‐3 TriaL (VITAL) is a double‐blind, placebo‐controlled RCT of supplemental vitamin D3 (2000 IU/d) and/or omega‐3 fatty acids (1 g/d) in 25,871 adults nationwide. This ancillary study included a subcohort of 771 participants (men ≥50 and women ≥55 years; not taking bone active medications) evaluated at baseline and at 2‐year follow‐up (89% retention). Total 25(OH)D levels were measured by liquid chromatography tandem mass spectrometry (Quest Diagnostics, San Juan Capistrano, CA, USA). Free 25(OH)D (FVD) levels were measured using the ELISA assay by Future Diagnostics Solutions BV (Wijchen, Netherlands). Primary endpoints were 2‐year changes in areal (a) BMD at the spine, hip, and whole body determined by dual‐energy X‐ray absorptiometry (DXA). Secondary endpoints were 2‐year changes in volumetric (v) BMD and cortical thickness at the radius and tibia assessed by peripheral quantitative computed tomography. Supplemental vitamin D3 versus placebo had no effect on 2‐year changes in aBMD at the spine (0.33% versus 0.17%; p = 0.55), femoral neck (−0.27% versus −0.68%; p = 0.16), total hip (−0.76% versus −0.95%; p = 0.23), or whole body (−0.22% versus −0.15%; p = 0.60), or on measures of bone structure. Effects did not vary by sex, race/ethnicity, body mass index, or 25(OH)D levels. Among participants with baseline FVD levels below the median (<14.2 pmol/L), there was a slight increase in spine aBMD (0.75% versus 0%; p = 0.043) and attenuation in loss of total hip aBMD (−0.42% versus −0.98%; p = 0.044) with vitamin D3. Whether baseline FVD levels help to identify those more likely to benefit from supplementation warrants further study. Supplemental vitamin D3 versus placebo for 2 years in general healthy adults not selected for vitamin D insufficiency did not improve BMD or structure. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Objectives: Relatively few APOE ε4+ carriers survive to old age (age 80+) without cognitive impairment (CI); thus, little is known about distinguishing characteristics of resilient APOE ε4+ carriers. Herein, we describe the sociodemographic characteristics of a large sample of resilient APOE ε4+ women from the Women's Health Initiative Memory Study (WHIMS) and compare them to noncarriers and APOE ε4+ women who developed CI before age 80.Methods: Women were recruited for clinical trials evaluating postmenopausal hormone therapy and incidence of dementia. During posttrial follow-up, cognitive status was adjudicated annually. Among 5716 women, we compared groups by APOE ε4 status using logistic regression, covarying for treatment, demographics, lifestyle, cardiovascular and physical function, well-being, and self-rated general health.Results: Among 557 APOE ε4+ women, those who survived to age 80+ without CI had higher baseline self-rated general health (odds ratio [OR]: 1.02; 95% confidence interval [CI], 1.01-1.04) and cognitive scores (OR: 1.18; 95% CI, 1.12-1.25) than those who did not reach age 80 without CI. Baseline high total cholesterol and low-density lipoprotein (LDL) levels were similar across APOE ε4+ groups but were higher compared with APOE ε4- women. Among women who survived to 80+ without CI, more APOE ε4+ women had a history of high total cholesterol (P = .003) and LDL cholesterol (OR: 1.01; 95% CI, 1.00-1.01). There were no differences in hypertension, diabetes, or other vascular risk factors in APOE ε4+ women compared with noncarriers.Conclusions: Results highlight the importance of baseline cognitive function and general health for late-life cognition among ε4+ women. [ABSTRACT FROM AUTHOR]

Background: Epigenetic age acceleration (AgeAccel) indicates faster biological aging relative to chronological age and has been independently associated with several age‐related outcomes. However, the cross‐sectional and longitudinal associations of AgeAccel with global cognitive function is understudied. Method: We therefore studied 734 women (mean±SD baseline age = 70.3±4 years; 7.9% Black, 3.5% Hispanic/Latina, 88.6% White) who were free of cognitive impairment at the baseline examination of the Women's Health Initiative (WHI) Memory Study (WHIMS,≥65 years enrolled in the WHI Hormone Therapy clinical trials between 1993‐1998). We measured global cognitive function annually with the Modified Mini Mental State Examination (3MS) through 2007 and the modified Telephone Interview for Cognitive Status (TICS‐m) from 2008‐2021. We measured extrinsic AgeAccel [EEAA] intrinsic AgeAccel [IEAA], AgeAccelPheno, and AgeAccelGrim in blood collected at baseline. AgeAccel measures were derived from chronological age and white blood cell counts (EEAA and IEAA), phenotypic age (AgeAccelPheno), or mortality (AgeAccelGrim). We estimated cross‐sectional AgeAccel‐3MS score associations in linear regression models and longitudinal AgeAccel‐3MS and TICS‐m score associations in linear mixed effects (LME) models adjusting for age, educational attainment, race, ethnicity, marital status, alcohol use, smoking, body mass index, comorbidities, hormone trial group assignment and physical activity. Result: AgeAccel measures were not cross‐sectionally associated with 3MS scores or longitudinally associated with 3MS or TICS‐m scores over a mean (SD) follow‐up of 6.4 (2.0) and 17.2 (3.6) years, respectively. Cross‐sectional AgeAccel‐3MS associations (95% confidence intervals) per 1‐year increment in AgeAccel were ‐0.03 (‐0.08, 0.02) for EEAA, ‐0.01 (‐0.08, 0.05) for IEAA, ‐0.02 (‐0.07, 0.03) for AgeAccelPheno, and 0 (‐0.10, 0.10) for AgeAccelGrim. Corresponding annual 3MS changes per 1‐year increment in AgeAccel were 0 (‐0.01, 0.01) for EEAA, 0 (‐0.01, 0.01) for IEAA, 0 (‐0.01, 0.01) for AgeAccelPheno, and 0 (‐0.02, 0.02) for AgeAccelGrim. Annual TICS‐m changes per 1‐year increment in AgeAccel were 0.01 (‐0.01, 0.03) for EEAA, 0 (‐0.02, 0.02) for IEAA, ‐0.01 (‐0.02, 0.01) for AgeAccelPheno, and 0.01 (‐0.02, 0.04) for AgeAccelGrim. Conclusion: Blood‐based AgeAccel measures were not significantly associated with global cognitive function among older women. Larger studies are needed to further examine AgeAccel‐global cognitive function associations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The optimal approach to osteoporosis screening and treatment in postmenopausal women is unclear. We compared (i) the United States Preventive Services Task Force (USPSTF) and Osteoporosis Canada osteoporosis screening strategies; and (ii) the National Osteoporosis Foundation (NOF) and Canadian treatment strategies. We used data from the prospective Women's Health Initiative Observational Study and Clinical Trials of women aged 50 to 79 years at baseline (n = 117,707 followed for self‐reported fractures; n = 8134 in bone mineral density [BMD] subset). We determined the yield of the screening and treatment strategies in identifying women who experienced major osteoporotic fractures (MOFs) during a 10‐year follow‐up. Among women aged 50 to 64 years, 23.1% of women were identified for BMD testing under the USPSTF strategy and 52.3% under the Canadian strategy. For women ≥65 years, 100% were identified for testing under the USPSTF and Canadian strategies, 35% to 74% were identified for treatment under NOF, and 16% to 37% were identified for treatment under CAROC (range among 5‐year age subgroups). Among women who experienced MOF during follow‐up, the USPSTF strategy identified 6.7% of women 50 to 54 years‐old and 49.5% of women 60 to 64 years‐old for BMD testing (versus 54.4% and 60.6% for the Canadian strategy, respectively). However, the specificity of the USPSTF strategy was higher than that of the Canadian strategy among women 50 to 64 years‐old. Among women who experienced MOF during follow‐up, sensitivity for identifying women as treatment candidates was lowest for both strategies in women aged 50 to 64 (NOF 10% to 38%; CAROC 1% to 15%) and maximal in 75‐year‐old to 79‐year‐old women (NOF 82.8%; 51.6% CAROC); specificity declined with advancing age and was lower with the NOF compared to the CAROC strategy. Among women aged 50 to 64 years, the screening and treatment strategies examined had low sensitivity for identifying those who subsequently experience MOF; sensitivity was higher among women ≥65 years than among younger women. New screening and treatment algorithms are needed. © 2018 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2‐pathway rather than the competing 16‐pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty‐four women in a WHIOS case–control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses were conducted for each metabolite, hydroxylation pathway (2‐, 4‐, or 16‐pathway) and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E + P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2‐methoxyestrone, 4‐methoxyestrone and unconjugated estriol). The relative concentrations of 2‐ and 4‐pathway EM did not differ between the MHT users (2‐pathway EM comprised 15% and 4‐pathway EM <2% of the total), but 16‐pathway EM were lower in E alone users (p = 0.036). Ratios of 2‐ and 4‐pathway EM compared to 16‐pathway EM were significantly higher in E alone compared to E + P users. Similar but not significant patterns were observed in CEE‐alone and CEE + MPA users. Our data suggest that compared to E + P users, women using E alone have more extensive metabolism via the 2‐ vs. the competing 16‐pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI. What's new? The Women's Health Initiative discovered that women taking conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) together increased their risk of breast cancer, but surprisingly, taking CEE alone reduced the risk of cancer. Here, the authors investigate the mechanism involved. To trace the pathway of CEE metabolism, they measured 15 different estrogen metabolites, using serum from women in the WHI Observational Study. In women taking estrogen alone, they found more activity in the "2‐pathway" over the "16‐pathway" of estrogen metabolism, which leads to reduced cancer risk. Those taking estrogen and progestin together showed more activity in the "16‐pathway," associated with higher cancer risk. [ABSTRACT FROM AUTHOR]

Background: Although obesity is an established risk factor for postmenopausal breast cancer, the results of weight loss and breast cancer studies are inconsistent. Therefore, we evaluated associations between weight change and breast cancer risk in postmenopausal women in the Women's Health Initiative Observational Study. Methods: Postmenopausal women (n = 61,335) who had no prior breast cancer and a normal mammogram had body weight and height measured and body mass index (BMI) calculated at baseline and year 3. Weight change at year 3 was categorized as stable (<5%), loss (≥5%), or gain (≥5%) with further assessment of weight loss intentionality by self‐report. Multivariable Cox proportional hazard regression models were used to evaluate relationships between weight change and subsequent breast cancer incidence. Results: During a mean follow‐up of 11.4 years with 3061 incident breast cancers, women with weight loss (n = 8175) had a significantly lower risk of breast cancer compared with women whose weight remained stable (n = 41,139) (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.78‐0.98; P =.02) with no interaction by BMI. Adjustment for mammography did not alter findings (HR, 0.88; 95% CI, 0.78‐0.99) with no significant difference by weight loss intentionality. Weight gain (≥5%) (n = 12,021) was not associated with breast cancer risk (HR, 1.02; 95% CI, 0.93‐1.11) but was associated with higher triple‐negative breast cancer incidence (HR, 1.54; 95% CI, 1.16‐2.05). Conclusions: Postmenopausal women who lose weight have lower breast cancer risk than those with stable weight. These findings suggest that postmenopausal women who lose weight may reduce their breast cancer risk. A large prospective study of postmenopausal women reveals that women with a weight loss of ≥5% are at lower risk for invasive breast cancer compared with women who have stable weight. [ABSTRACT FROM AUTHOR]

Background and Aim: Gallstone disease has been related to a higher prevalence and incidence of chronic conditions, such as dyslipidemia, obesity, and cardiovascular disease (CVD). However, limited data are available regarding whether gallstone disease is related to mortality. Methods: We examined the relationship of a history of gallstone disease and risk of death, using Cox proportional hazards regression analysis, among 86 030 women from the Nurses' Health Study and 43 949 men from the Health Professionals Follow‐up Study. Results: During the up‐to 32 years of follow‐up, 34 011 all‐cause deaths were confirmed, of which 8138 were CVD deaths and 12 173 were cancer deaths. For the participants with a history of gallstone disease compared with those without, the hazard ratio of total mortality was 1.16 (95% confidence interval 1.13, 1.20), of CVD mortality 1.11 (1.05, 1.17), of cancer mortality 1.15 (1.09, 1.20), and of other mortality 1.19 (1.14, 1.25) from a pooled‐analysis of women and men (all P < 0.001). The multi‐adjusted associations between gallstone disease and total mortality persisted among women and men, and among participants with various risk profiles including the different status of body mass index, hormone therapy use, diabetes, hypertension, and hypercholesterolemia (all P for interaction ≥ 0.09). Conclusion: These data suggest that gallstone disease is associated with a higher risk of total mortality and disease‐specific mortality, including CVD and cancer mortality, independent of various traditional risk factors. [ABSTRACT FROM AUTHOR]