Women's Health Initiative Memory Study Research Articles

Proteomic analysis of APOEε4 carriers implicates lipid metabolism, complement and lymphocyte signaling in cognitive resilience

BackgroundApolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood.MethodsAPOEε4 carriers and APOEε3 homozygotes enrolled in the Women’s Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß42/40) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank.ResultsA total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß42/40/tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P < 0.05. While one of the candidate proteins, a marker of neuronal injury (NfL), also distinguished resilient from non-resilient APOEε3 homozygotes, the other three proteins, known to be involved in lipid metabolism (ANGPTL4) and immune signaling (PTX3, NCR1), only predicted resilient vs. non-resilient status among APOEε4 carriers (protein*genotype interaction-P < 0.05). Three of these four proteins also predicted 14-year dementia risk among APOEε4 carriers in the UK Biobank validation sample (N = 9420). While the candidate proteins showed little to no association with targeted biomarkers of AD pathology, protein network and enrichment analyses suggested that natural killer (NK) cell and T lymphocyte signaling (via PKC-θ) distinguished resilient from non-resilient APOEε4 carriers.ConclusionsWe identified and replicated a plasma proteomic signature associated with cognitive resilience among APOEε4 carriers. These proteins implicate specific immune processes in the preservation of cognitive status despite elevated genetic risk for AD. Future studies in diverse cohorts will be needed to assess the generalizability of these results.

Comparison of Air Pollution Exposures and Health Effects Associations Using 11 Different Modeling Approaches in the Women's Health Initiative Memory Study (WHIMS).

Many approaches to quantifying air pollution exposures have been developed. However, the impact of choice of approach on air pollution estimates and health-effects associations remains unclear. Our objective is to compare particulate matter with aerodynamic diameter () concentrations and resulting health effects associations using multiple estimation approaches previously used in epidemiologic analyses. We assigned annual exposure estimates from 1999 to 2004 derived from 11 different approaches to Women's Health Initiative Memory Study (WHIMS) participant addresses within the contiguous US. Approaches included geostatistical interpolation approaches, land-use regression or spatiotemporal models, satellite-derived approaches, air dispersion and chemical transport models, and hybrid models. We used descriptive statistics and plots to assess relative and absolute agreement among exposure estimates and examined the impact of approach on associations between and death due to natural causes, cardiovascular disease (CVD) mortality, and incident CVD events, adjusting for individual-level covariates and climate-based region. With a few exceptions, relative agreement of approach-specific exposure estimates was high for concentrations across the contiguous US. Agreement among approach-specific exposure estimates was stronger near monitors, in certain regions of the country, and in 2004 vs. 1999. Collectively, our results suggest but do not quantify lower agreement at local spatial scales for . There was no evidence of large differences in health effects associations with among estimation approaches in analyses adjusted for climate region. Different estimation approaches produced similar spatial patterns of concentrations across the contiguous US and in areas with dense monitoring data, and effects associations were similar among estimation approaches. estimates and effects associations may differ more in samples drawn from smaller areas or areas without substantial monitoring data, or in analyses with finer adjustment for participant location. Our results can inform decisions about estimation approach in epidemiologic studies, as investigators balance concerns about bias, efficiency, and resource allocation. Future work is needed to understand whether these conclusions also apply in the context of other air pollutants of interest. https://doi.org/10.1289/EHP12995.

Plasma proteins related to inflammatory diet predict future cognitive impairment

Dysregulation of the immune system and dietary patterns that increase inflammation can increase the risk for cognitive decline, but the mechanisms by which inflammatory nutritional habits may affect the development of cognitive impairment in aging are not well understood. To determine whether plasma proteins linked to inflammatory diet predict future cognitive impairment, we applied high-throughput proteomic assays to plasma samples from a subset (n = 1528) of Women’s Health Initiative Memory Study (WHIMS) participants (mean [SD] baseline age, 71.3 [SD 3.8] years). Results provide insights into how inflammatory nutritional patterns are associated with an immune-related proteome and identify a group of proteins (CXCL10, CCL3, HGF, OPG, CDCP1, NFATC3, ITGA11) related to future cognitive impairment over a 14-year follow-up period. Several of these inflammatory diet proteins were also associated with dementia risk across two external cohorts (ARIC, ESTHER), correlated with plasma biomarkers of Alzheimer’s disease (AD) pathology (Aβ42/40) and/or neurodegeneration (NfL), and related to an MRI-defined index of neurodegenerative brain atrophy in a separate cohort (BLSA). In addition to evaluating their biological relevance, assessing their potential role in AD, and characterizing their immune-tissue/cell-specific expression, we leveraged published RNA-seq results to examine how the in vitro regulation of genes encoding these candidate proteins might be altered in response to an immune challenge. Our findings indicate how dietary patterns with higher inflammatory potential relate to plasma levels of immunologically relevant proteins and highlight the molecular mediators which predict subsequent risk for age-related cognitive impairment.

An Association Between Large Optic Cupping and Total and Regional Brain Volume: The Women's Health Initiative

To investigate the relationships between optic nerve cupping and total and regional brain volumes. Secondary analysis of randomized clinical trial data. Women 65 to 79 years of age without glaucoma with cup-to-disc ratio (CDR) measurements from the Women's Health Initiative (WHI) Sight Examination study and magnetic resonance imaging (MRI)-based total and regional brain volumes from the WHI Memory Study MRI-1 were included. Large CDR was defined as 0.6 or greater in either eye. Generalized estimating equation models were used to account for intra-brain correlations between the right and left sides. The final analysis was adjusted for demographic and clinical characteristics and for total brain volume (for regional analyses). Final analyses included 471 women, with the mean age ± SD was 69.2 ± 3.6 years; 92.8% of the subjects were white. Of 471 women, 34 (7.2%) had large CDR. Controlling for total brain volume and for demographic and clinical characteristics, lateral ventricle volume was 3.01 cc larger for subjects with large CDR compared to those without large CDR (95% CI=0.02 to 5.99; P=.048). Furthermore, frontal lobe volume was 4.78 cc lower for subjects with large CDR compared to those without (95% CI=-8.71, -0.84; P=0.02), and occipital lobe volume was 1.86 cc lower for those with large CDR compared to those without (95% CI=-3.39, -0.3; P =.02). Our analysis suggests that in women aged 65 years or more, large CDR is associated with lower relative total brain volume and absolute regional volume in the frontal and occipital lobes. Enlarged CDR in individuals without glaucoma may represent a sign of optic nerve and brain aging, although more longitudinal data are needed.

Natural premature menopause relates to higher risk of mild cognitive impairment and Alzheimer’s disease and related dementias in APOE‐ε4 carriers only

AbstractBackgroundOverall risk of Alzheimer’s disease (AD) and APOE‐ε4‐related risk for AD is higher among women than men, but the sex‐specific biological underpinnings of these sex differences are unknown. Earlier age at menopause has been associated with higher risk of AD and related dementias (ADRD); however, it is unclear whether this relationship holds among naturally menopausal (versus surgically menopausal) women only or whether it is impacted by APOE‐ε4 genetic risk. We examined the association of natural premature (occurring ≤40 years of age) menopause with MCI and ADRD risk among older women and whether this relationship was moderated by APOE‐ε4 genotype.MethodThis study included 3,557 older women (age range: 65‐79 years at baseline; all White; 5.3% premature menopause; 25.5% APOE‐ε4 carriers) from the Women’s Health Initiative Memory Study (WHIMS) who experienced menopause spontaneously and not as a result of hysterectomy or bilateral oophorectomy. All participants had data on reproductive history, APOE genotype and longitudinal cognitive evaluations, and were cognitively unimpaired at baseline (follow‐up time: range = 0.92‐24.19, mean = 9.92 years). Incident MCI and ADRD were determined with a comprehensive neuropsychological battery and centrally adjudicated by a panel of specialists with expertise in dementia diagnosis. A set of Cox regression models was applied to determine whether premature menopause and its interaction with APOE‐ε4 carrier status was associated with risk of MCI or ADRD, adjusting for age, education, cardiovascular risk factors, parity, age at menarche, past contraceptive use and current or past hormone therapy use and the timing of initiation relative to menopause.ResultThe APOE‐ε4 X premature menopause interaction was significant (p = .04). Among APOE‐ε4 allele carriers, premature (vs. non‐premature) menopause was associated with an approximate two‐fold increased risk of MCI/ADRD (HR = 2.05, 95%CI: 1.22‐3.44). No such association was present among women without an APOE‐ε4 allele (HR = 1.16, 95%CI: 0.72‐1.86).ConclusionNatural premature vs non‐premature menopause was associated with two‐fold higher risk of MCI/ADRD but only among APOE‐ε4 carriers. Results suggest interactive effects of premature menopause and the APOE‐ε4 genotype. Future studies are needed to determine whether the menopause and APOE‐ε4 pathophysiological mechanisms of dyslipidemia, inflammation and brain metabolism deficiencies may explain this association.

Association of social support with mild cognitive impairment and dementia among older women: the Women’s Health Initiative Memory Study

AbstractBackgroundWomen comprise approximately two‐thirds of older adults with Alzheimer’s disease in the United States. Social support may be a modifiable risk factor for cognitive impairment. However, few long‐term, large prospective studies have examined associations of various forms of social support with cognitive impairment. Therefore, we examined the association of perceived social support with incident mild cognitive impairment (MCI) and dementia among older women.MethodThis prospective cohort study included 6,670 older women from the Women’s Health Initiative (WHI) Memory Study (WHIMS), a sub‐cohort of the WHI hormone therapy (HT) trials, who were free of dementia upon enrollment. Perceived social support was assessed at baseline using nine items from the Medical Outcomes Study Social Support Survey. All item ratings were summed to generate a summary score (range = 9‐45), with higher scores indicating greater perceived social support. Incident MCI and dementia were ascertained using a comprehensive neuropsychological battery and central adjudication by a panel of specialists with expertise in dementia diagnosis during up to 25 years of follow‐up. Cox proportional hazards models were used to assess associations of perceived social support with incident MCI, dementia, and overall cognitive impairment (MCI or dementia). We also examined associations of four types of social support (emotional/informational, affection, tangible, and positive social interaction) with MCI/dementia.ResultOverall, (mean age at baseline = 70.0 [SD 3.8] years; 97.0% non‐Hispanic/Latina; 89.8% White) 753 women had incident MCI, 697 had incident dementia, and 1,197 had incident overall cognitive impairment. There were no significant associations of social support with MCI (HR = 0.99; 95%CI = 0.98‐1.00), dementia (HR = 0.99; 95% CI = 0.98‐1.01), or overall cognitive impairment (HR = 0.99; 95% CI = 0.98‐1.00) after adjusting for age, education, income, race, ethnicity, marital status, smoking, alcohol intake, body mass index, history of diabetes, hormone therapy trial assignment, history of hormone therapy use, history of hypertension, and depressive symptom severity. There were no significant associations between the four types of social support and MCI/dementia.ConclusionPerceived social support was not significantly associated with incident cognitive impairment among older women. Future studies should explore other social factors, such as social isolation and loneliness, particularly in larger and racially/ethnically diverse populations.

The relationship between depressive symptoms and subtypes of mild cognitive impairment in post-menopausal women: Results from the Women's Health Initiative Memory Study.

Depressive symptoms are associated with age-related cognitive impairment, but the relative risk of specific subtypes of mild cognitive impairment (MCI) conferred by depressive symptoms is unclear. The purpose of this exploratory study was to determine the longitudinal association between baseline depressive symptoms and incident cases of MCI subtypes (amnestic vs. non-amnestic) and probable dementia (PD) (Alzheimer's disease, vascular, mixed) among postmenopausal women. Depressive symptoms were assessed at study baseline using an 8-item Burnam algorithm in 7043 postmenopausal women who participated in the Women's Health Initiative Memory Study (WHIMS) and the WHIMS-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) extension study. During the median 9.4-year follow-up interval, the presence of MCI and PD was classified by a central adjudication committee. Classification of participants by MCI subtype (amnestic single and multi-domain, non-amnestic single and multi-domain) was done algorithmically based on established criteria using data from annual cognitive testing. At baseline, 557 women (7.9%) had clinically significant depressive symptoms based on Burnam algorithm cut-point of 0.06. Depressive symptoms at baseline were associated with an increased risk of incident amnestic MCI (hazard ratio [HR]=1.91, 95% confidence interval [CI] 1.32-2.78, p<0.0001), but not non-amnestic MCI (HR=1.39, 95% CI 0.91-2.14, p=0.13) after controlling for demographic factors. This relationship between depressive symptoms and amnestic MCI remained consistent after controlling for lifestyle variables, cardiovascular risk factors, antidepressant use, and history of hormone therapy. There were no significant associations between depressive symptoms and incidence ofPD. Depressive symptoms at baseline among postmenopausal older women are associated with higher incidence of amnestic MCI, suggesting that they may be an independent risk factor or part of the early prodrome of dementia.

Comparison of PM2.5 air pollution exposure estimates at WHIMS participant locations based on different modelling approaches and impact on health effects estimation

Background and Aim: Many approaches to quantifying air pollution exposures for use in epidemiologic analyses have been developed. However, whether exposure estimates from different approaches are comparable and whether choice of approach affects reported associations with health-related outcomes remains unclear. We compare PM2.5 concentrations at addresses from participants of the Women’s Health Initiative Memory Study (WHIMS) derived using multiple estimation approaches and assess differences in associated health effects estimates. Methods: We linked annual PM2.5 exposure estimates from 1999 to 2004 from 12 different approaches to WHIMS participant addresses from across the continental United States and restricted analyses to data from participants with stable addresses within each calendar year. Approaches included geo-statistical interpolation approaches, geographic information system (GIS)-based statistical models, air dispersion and chemical transport models, and hybrid models. We used descriptive statistics and visualizations to assess relative and absolute agreement of exposure estimates from different approaches across space and time and examined the impact of estimation approach on associations between PM2.5 and non-accidental mortality, CVD-related mortality, and incident CVD events. Results: Annual PM2.5 exposure estimates were reasonably similar across approaches, although the specific shapes and ranges of the distributions varied. Interquartile ranges tended to be similar, though ranges were more variable. Relative agreement was consistently higher than absolute agreement. After controlling for putative confounders, associations of PM2.5 with mortality and CVD were similar regardless of estimation approach. Conclusions: Agreement across different air pollution estimation approaches for PM2.5 was generally high when considering participants drawn from a broad geographic area, suggesting that all models predicted similar between-area differences. The implications of fine-scale variability between exposure estimation approaches warrants further investigation. Keywords: Air pollution, exposure assessment

The relationship between optimism, MCI, and dementia among postmenopausal women

Objectives The relationship between optimism and cognitive functioning is not fully understood. We examined the association of optimism with risk of mild cognitive impairment (MCI) and dementia in the Women’s Health Initiative Memory Study (WHIMS). Methods Optimism was measured by the Life Orientation Test-Revised (LOT-R) total score, and optimism and pessimism subscales. A panel of experts adjudicated cognitive endpoints based on annual cognitive assessments. We used cox proportional hazard regression models to examine the association of LOT-R total score and optimism and pessimism sub-scores with MCI/dementia. We also examined the relationship between vascular disease, LOT-R total score, optimism and pessimism, and cognition. Results Mean age was 70.5 (SD = 3.9) years. The sample (N = 7249) was 87% white, and 29.8% of participants had < 12 years of education. Total LOT-R score (HR = 0.96, 95% CI: 0.94, 0.98, p < 0.001) was associated with lower risk of combined MCI or dementia. More pessimism (HR = 1.08, 95% CI: 1.05, 1.11, p < 0.0001) was associated with higher risk of MCI or dementia after adjustment for ethnicity, education, vascular disease, and depression. No significant relationships emerged from the optimism subscale. Conclusion These data suggest that less pessimism, but not more optimism, was associated with a lower risk of MCI and dementia.

Air quality improvement and cognitive decline in community-dwelling older women in the United States: A longitudinal cohort study.

Late-life exposure to ambient air pollution is a modifiable risk factor for dementia, but epidemiological studies have shown inconsistent evidence for cognitive decline. Air quality (AQ) improvement has been associated with improved cardiopulmonary health and decreased mortality, but to the best of our knowledge, no studies have examined the association with cognitive function. We examined whether AQ improvement was associated with slower rate of cognitive decline in older women aged 74 to 92 years. We studied a cohort of 2,232 women residing in the 48 contiguous US states that were recruited from more than 40 study sites located in 24 states and Washington, DC from the Women's Health Initiative (WHI) Memory Study (WHIMS)-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) study. They were predominantly non-Hispanic White women and were dementia free at baseline in 2008 to 2012. Measures of annual (2008 to 2018) cognitive function included the modified Telephone Interview for Cognitive Status (TICSm) and the telephone-based California Verbal Learning Test (CVLT). We used regionalized universal kriging models to estimate annual concentrations (1996 to 2012) of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) at residential locations. Estimates were aggregated to the 3-year average immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS-ECHO enrollment. Individual-level improved AQ was calculated as the reduction from remote to recent exposures. Linear mixed effect models were used to examine the associations between improved AQ and the rates of cognitive declines in TICSm and CVLT trajectories, adjusting for sociodemographic (age; geographic region; race/ethnicity; education; income; and employment), lifestyle (physical activity; smoking; and alcohol), and clinical characteristics (prior hormone use; hormone therapy assignment; depression; cardiovascular disease (CVD); hypercholesterolemia; hypertension; diabetes; and body mass index [BMI]). For both PM2.5 and NO2, AQ improved significantly over the 10 years before WHIMS-ECHO enrollment. During a median of 6.2 (interquartile range [IQR] = 5.0) years of follow-up, declines in both general cognitive status (β = -0.42/year, 95% CI: -0.44, -0.40) and episodic memory (β = -0.59/year, 95% CI: -0.64, -0.54) were observed. Greater AQ improvement was associated with slower decline in TICSm (βPM2.5improvement = 0.026 per year for improved PM2.5 by each IQR = 1.79 μg/m3 reduction, 95% CI: 0.001, 0.05; βNO2improvement = 0.034 per year for improved NO2 by each IQR = 3.92 parts per billion [ppb] reduction, 95% CI: 0.01, 0.06) and CVLT (βPM2.5 improvement = 0.070 per year for improved PM2.5 by each IQR = 1.79 μg/m3 reduction, 95% CI: 0.02, 0.12; βNO2improvement = 0.060 per year for improved NO2 by each IQR = 3.97 ppb reduction, 95% CI: 0.005, 0.12) after adjusting for covariates. The respective associations with TICSm and CVLT were equivalent to the slower decline rate found with 0.9 to 1.2 and1.4 to 1.6 years of younger age and did not significantly differ by age, region, education, Apolipoprotein E (ApoE) e4 genotypes, or cardiovascular risk factors. The main limitations of this study include measurement error in exposure estimates, potential unmeasured confounding, and limited generalizability. In this study, we found that greater improvement in long-term AQ in late life was associated with slower cognitive declines in older women. This novel observation strengthens the epidemiologic evidence of an association between air pollution and cognitive aging.

Ambient air pollution exposure and increasing depressive symptoms in older women: The mediating role of the prefrontal cortex and insula

Exposures to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) have been associated with the emergence of depressive symptoms in older adulthood, although most studies used cross-sectional outcome measures. Elucidating the brain structures mediating the adverse effects can strengthen the causal role between air pollution and increasing depressive symptoms. We evaluated whether smaller volumes of brain structures implicated in late-life depression mediate associations between ambient air pollution exposure and changes in depressive symptoms. This prospective study included 764 community-dwelling older women (aged 81.6 ± 3.6 in 2008–2010) from the Women's Health Initiative Memory Study (WHIMS) Magnetic Resonance Imaging study (WHIMS-MRI; 2005–06) and WHIMS-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO; 2008–16). Three-year average annual mean concentrations (scaled by interquartile range [IQR]) of ambient PM2.5 (in μg/m3; IQR = 3.14 μg/m3) and NO2 (in ppb; IQR = 7.80 ppb) before WHIMS-MRI were estimated at participants' addresses via spatiotemporal models. Mediators included structural brain MRI-derived grey matter volumes of the prefrontal cortex and structures of the limbic-cortical-striatal-pallidal-thalamic circuit. Depressive symptoms were assessed annually by the 15-item Geriatric Depression Scale. Structural equation models were constructed to estimate associations between exposure, structural brain volumes, and depressive symptoms. Increased exposures (by each IQR) were associated with greater annual increases in depressive symptoms (βPM2.5 = 0.022; 95% Confidence Interval (CI) = 0.003, 0.042; βNO2 = 0.019; 95% CI = 0.001, 0.037). The smaller volume of prefrontal cortex associated with exposures partially mediated the associations of increased depressive symptoms with NO2 (8%) and PM2.5 (13%), and smaller insula volume associated with NO2 contributed modestly (13%) to the subsequent increase in depressive symptoms. We demonstrate the first evidence that the smaller volumes of the prefrontal cortex and insula may mediate the subsequent increases in depressive symptoms associated with late-life exposures to NO2 and PM2.5.

Association between blood pressure levels and cognitive impairment in older women: a prospective analysis of the Women's Health Initiative Memory Study

SummaryBackgroundWhether blood pressure (BP), and at what level of controlled BP, reduces risk of cognitive impairment remains uncertain. We investigated the association of BP and hypertension treatment status with mild cognitive impairment and dementia in older women.MethodsWe prospectively analysed a sample of 7207 community-dwelling women aged 65–79 years participating in the Women’s Health Initiative Memory Study (WHIMS). Participants were recruited between May 28, 1996, and Dec 13, 1999, at 39 US clinical centres, and they were followed up until Dec 31, 2019. Cognitive function was assessed annually. Mild cognitive impairment and probable dementia were defined through a centralised adjudication process. BP was measured by trained and certified staff at baseline. Pulse pressure (PP) was calculated as systolic BP (SBP) minus diastolic BP. Hypertension was defined using the American Heart Association 2017 Guideline for High BP in Adults. Outcomes were (1) mild cognitive impairment, (2) probable dementia, and (3) cognitive loss (the combined endpoint of either mild cognitive impairment or probable dementia, or both). We estimated hazard ratios (HRs) to assess the association between hypertension, SBP, and PP with the risk of study outcomes using Cox proportional hazards regression models, with adjustment for key covariates.FindingsDuring a median follow-up of 9 years (IQR 6–15), 1132 (15·7%) participants were classified as mild cognitive impairment, 739 (10·3%) as probable dementia, and 1533 (21·3%) as cognitive loss. The incidence rates per 1000 person-years were 15·3 cases (95% CI 14·4–16·2) for mild cognitive impairment, 9·7 cases (9·0–10·4) for probable dementia, and 20·3 (19·3–21·3) for cognitive loss. Elevated SBP and PP were significantly associated with increased risk of mild cognitive impairment and cognitive loss (test for trends across SBP and PP strata, p<0·01). Individuals with hypertension, but with controlled SBP of less than 120 mm Hg did not have a significantly increased risk of mild cognitive impairment (HR 1·33, 95% CI 0·98–1·82, p=0·071), and of cognitive loss (1·09, 0·82–1·44, p=0·57) compared with normotension. Individuals on anti-hypertensive treatment with PP of less than 50 mm Hg did not have a significantly higher risk of mild cognitive impairment (1·26, 0·98–1·62, p=0·07) and of cognitive loss (1·17, 0·94–1·46, p=0·16). There were no significant associations between hypertension, SBP, or PP and probable dementia.InterpretationResults of our study show significant associations of hypertension and elevated SBP and PP levels with risk of mild cognitive impairment and the combined endpoint of either mild cognitive impairment or probable dementia, suggesting that intensive control of hypertension, SBP, and PP can preserve cognitive health in older women.FundingNational Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services.

Analysis of pleiotropic genetic effects on cognitive decline and systemic inflammation in the Women’s Health Initiative Memory Study

SNPs associated with C-reactive protein (CRP) and plasma lipids have been investigated for polygenic overlap with Alzheimer's disease (AD) risk SNPs. Previously, we reported pleiotropic effects between SNPs associated with cognitive impairment (CI) and SNPs associated with systemic inflammation as measured by CRP and plasma lipids in the Health and Retirement Study (HRS). We sought to replicate our results in the Women's Health Initiative Memory Study (WHIMS). Analysis of SNP pleiotropic effects was completed using data from 6,078 non-Hispanic White women (aged 71.4 [SD 7.4] at baseline) for whom genetic, cognitive, and/or biomarker data were available. We identified CI using WHIMS adjudicated case status (normal vs. mild cognitive impairment or probable dementia). Secondary phenotypes included baseline CRP and plasma lipid levels (HDL, LDL, and total cholesterol [TC]). Genome-wide association analyses were conducted for all phenotypes. A conditional false discovery rate framework defined genetic pleiotropy. Genetic pleiotropy was identified if SNPs were associated with CI conditional on association with secondary phenotypes (CRP, HDL, LDL, TC) at an FDR < 0.05. Functional genomic bioinformatics analysis and comparison with prior findings were conducted. Genetic pleiotropy was observed for CI conditional on association with the secondary phenotypes of plasma CRP, HDL, LDL, and TC. These results replicate associations for SNPs in the APOE, APOC1, PVRL2/NECTIN2 loci reported in the prior HRS study for CRP, LDL, TC. The odds ratios for the association of these SNPs with CI ranged from 0.5 to 4.0, consistent with moderate effect sizes for the APOE ε2 or ε4 alleles. For WHIMS, FDR significant results were observed in both directions for several of the traits (CRP, lipids), further supporting evidence of genetic pleiotropy. Moreover, we observed associations for SNPs in the APOE, APOC1, PVRL2/NECTIN2 loci for CI conditional on HDL. We identified polygenic overlap between CI and CRP, LDL, HDL, and TC phenotypes in WHIMS, largely replicating prior results in the HRS. The variants and associated genes identified are involved in pathological processes including metabolic, cardiovascular, and immune response and are potentially important for AD risk prediction and development of therapeutic approaches based on anti-inflammatory mechanisms.

Association of blood‐based epigenetic age acceleration with cognitive impairment and brain outcomes by cardiovascular disease among women

AbstractBackgroundDNA methylation‐based epigenetic age acceleration (AgeAccel), an aging biomarker indicating faster biological aging relative to chronological age, is associated with many age‐related phenotypes. Blood‐based AgeAccel has been associated with lower cognitive function in several studies. However, there are limited data on associations of AgeAccel with mild cognitive impairment (MCI), dementia, and brain structure. Further, no prior study investigated whether associations of AgeAccel with cognitive and brain outcomes vary by cardiovascular disease (CVD), despite evidence linking vascular pathologies to both AgeAccel and dementia.MethodParticipants were 615 older women from a case‐cohort study of CVD in the Women’s Health Initiative (WHI) Clinical Trials and Observational Study who also enrolled in the WHI Memory Study (n=327 with incident CVD during follow‐up and n=288 without incident CVD). AgeAccel was measured in blood collected at baseline when women had no CVD or cognitive impairment. Women were followed for up to 25 years to determine centrally adjudicated diagnoses of MCI and dementia according to DSM‐IV criteria. A subset (n=90) had structural brain MRI scans performed ∼8 years after baseline. Associations between four measures of AgeAccel (intrinsic AgeAccel [IEAA], extrinsic AgeAccel [EEAA], AgeAccelPheno, and AgeAccelGrim) and risks for MCI/dementia incidence were estimated using Cox proportional hazards regression models. Associations of AgeAccel with brain volumes were examined using multiple linear regression models. Models were stratified by incident CVD status and adjusted for chronological age and other sociodemographic characteristics, lifestyle behaviors, and clinical factors.ResultAmong women who developed CVD, a 1‐year increase in IEAA was associated with higher risk of MCI (HR=1.10; 95% CI=1.03‐1.18), higher risk of combined MCI/dementia (HR=1.07; 95% CI=1.01‐1.13), and higher ventricular volume (in cm3; β=1.04; 95% CI=0.15‐1.94). A 1‐year increase in AgeAccelPheno was associated with higher risk of combined MCI/dementia (HR=1.05; 95% CI=1.00‐1.10) in women with incident CVD. The other two measures of AgeAccel were not associated with any outcome among women with incident CVD. No associations of AgeAccel with cognitive impairment or brain volumes were observed among women who did not develop CVD.ConclusionBlood‐based AgeAccel may be a marker of cognitive and brain health among women with underlying vascular pathologies.

Waist‐hip ratio as a moderator of the effects of hormone therapy on cognitive function in recently menopausal women

AbstractBackgroundResearch 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 &gt;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.MethodsKEEPS‐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.ResultsWHR 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.ConclusionsWHR 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.

Investigating Predictors of Preserved Cognitive Function in Older Women Using Machine Learning: Women's Health Initiative Memory Study.

Identification of factors that may help to preserve cognitive function in late life could elucidate mechanisms and facilitate interventions to improve the lives of millions of people. However, the large number of potential factors associated with cognitive function poses an analytical challenge. We used data from the longitudinal Women's Health Initiative Memory Study (WHIMS) and machine learning to investigate 50 demographic, biomedical, behavioral, social, and psychological predictors of preserved cognitive function in later life. Participants in WHIMS and two consecutive follow up studies who were at least 80 years old and had at least one cognitive assessment following their 80th birthday were classified as cognitively preserved. Preserved cognitive function was defined as having a score ≥39 on the most recent administration of the modified Telephone Interview for Cognitive Status (TICSm) and a mean score across all assessments ≥39. Cognitively impaired participants were those adjudicated by experts to have probable dementia or at least two adjudications of mild cognitive impairment within the 14 years of follow-up and a last TICSm score < 31. Random Forests was used to rank the predictors of preserved cognitive function. Discrimination between groups based on area under the curve was 0.80 (95%-CI-0.76-0.85). Women with preserved cognitive function were younger, better educated, and less forgetful, less depressed, and more optimistic at study enrollment. They also reported better physical function and less sleep disturbance, and had lower systolic blood pressure, hemoglobin, and blood glucose levels. The predictors of preserved cognitive function include demographic, psychological, physical, metabolic, and vascular factors suggesting a complex mix of potential contributors.

Effects of menopausal hormone therapy on erythrocyte n–3 and n–6 PUFA concentrations in the Women’s Health Initiative randomized trial

The factors other than dietary intake that determine tissue concentrations of EPA and DHA remain obscure. Prior studies suggested that, in women, endogenous estrogen may accelerate synthesis of DHA from ɑ-linolenic acid (ALA), but the effects of exogenous estrogen on RBC n-3 (ɷ-3) PUFA concentrations are unknown. We tested the hypothesis that menopausal hormone therapy (HT) would increase RBC n-3 PUFA concentrations. Postmenopausal women (ages 50-79 y) were assigned to HT or placebo in the Women's Health Initiative (WHI) randomized trial. The present analyses included a subset of 1170 women (ages 65-79 y) who had RBC PUFA concentrations measured at baseline and at 1 y as participants in the WHI Memory Study. HT included conjugated equine estrogens (E) alone for women without a uterus (n=560) and E plus medroxyprogesterone acetate (P) for those with an intact uterus (n=610). RBC n-3 and n-6 (ɷ-6) PUFAs were quantified. Effects of E alone and E+P on PUFA profiles were similar and were thus combined in the analyses. Relative to the changes in the placebo group after 1 y of HT, docosapentaenoic acid (DPA; n-3) concentrations decreased by 10% (95% CI: 7.3%, 12.5%), whereas DHA increased by 11% (95% CI: 7.4%, 13.9%) in the HT group. Like DHA, DPA n-6 increased by 13% from baseline (95% CI: 10.0%, 20.3%), whereas linoleic acid decreased by 2.0% (95% CI: 1.0%, 4.1%; P values at least <0.01 for all). EPA and arachidonic acid concentrations were unchanged. HT increased RBC concentrations of the terminal n-3 and n-6 PUFAs (DHA and DPA n-6). These findings are consistent with an estrogen-induced increase in DHA and DPA n-6 synthesis, which is consistent with an upregulation of fatty acid elongases and/or desaturases in the PUFA synthetic pathway. The clinical implications of these changes require further study. The Women's Health Initiative Memory Study is registered at clinicaltrials.gov as NCT00685009. Note that the data presented here were not planned as part of the original trial, and therefore are to be considered exploratory.

The association between low social support and risk of cognitive impairment is partially mediated by neuroanatomic biomarkers of Alzheimer’s disease

AbstractBackgroundSocial relationships with less support are linked to greater risk of developing Alzheimer’s disease (AD) and other dementias. Despite growing evidence of this link, to our knowledge, no studies have examined neuropathological processes through which low social support may affect risk of cognitive impairment. We used data from the Women’s Health Initiative Memory Study (WHIMS)‐MRI Study to examine whether neuroanatomical characteristics indicative of AD risk and cerebrovascular diseases underlie the greater risk of cognitive impairment or dementia over time in those with less supportive social relationships.MethodParticipants included 989 women (aged 73‐87 years) from the WHIMS‐MRI study who completed the Medical Outcomes Study Social Support Scale, assessing perceived emotional, tangible, and affectionate support, in 2004‐05. Structural brain scans were performed in 2005‐06 to assess small‐vessel ischemic disease (SVID) volume and determine AD pattern similarity scores (AD‐PS), a brain‐MRI measured neuroanatomical biomarker reflecting diffuse gray matter atrophy in brain regions vulnerable to AD neuropathologies, developed by supervised machine learning and validated with AD Neuroimaging Initiative data. Annual WHIMS follow‐ups included extensive neuropsychological assessments to ascertain centrally‐adjudicated incident cases of mild cognitive impairment (MCI) or all‐cause dementia. Structural equation models were used to assess the association between social support and risk of MCI/dementia (diagnosis data available through June 2018), and whether the association was mediated by global SVID volumes or AD‐PS scores. Models were adjusted for depressive symptoms, demographic, lifestyle, and clinical covariates.ResultLow social support was associated with higher MCI/dementia risk (hazard ratio= 1.23 per 1‐SD; 95% CI: 1.07, 1.44) and also with higher AD‐PS scores (β=.067; 95% CI: .01, .12), but not SVID volume. Higher AD‐PS score accounted for 18.6% (95% CI: 4%, 43%) of the total effect of low social support on risk of MCI/dementia (Figure 1). Higher SVID only accounted for 1.9% (95% CI: ‐1.5%, 8.8%) of the total effect.ConclusionOur study illustrates an association between low social support and higher MCI/dementia risk among older women, which was partly mediated by gray matter atrophy indicative of higher AD risk. Findings also suggest less of a role of cerebrovascular disease in mediating these associations.

Association of Visual Impairment With Risk of Incident Dementia in a Women’s Health Initiative Population

Dementia affects a large and growing population of older adults. Although past studies suggest an association between vision and cognitive impairment, there are limited data regarding longitudinal associations of vision with dementia. To evaluate associations between visual impairment and risk of cognitive impairment. A secondary analysis of a prospective longitudinal cohort study compared the likelihood of incident dementia or mild cognitive impairment (MCI) among women with and without baseline visual impairment using multivariable Cox proportional hazards regression models adjusting for characteristics of participants enrolled in Women's Health Initiative (WHI) ancillary studies. The participants comprised community-dwelling older women (age, 66-84 years) concurrently enrolled in WHI Sight Examination (enrollment 2000-2002) and WHI Memory Study (enrollment 1996-1998, ongoing). The study was conducted from 2000 to the present. Objectively measured visual impairment at 3 thresholds (visual acuity worse than 20/40, 20/80, or 20/100) and self-reported visual impairment (determined using composite survey responses). Hazard ratios (HRs) and 95% CIs for incident cognitive impairment after baseline eye examination were determined. Cognitive impairment (probable dementia or MCI) was based on cognitive testing, clinical assessment, and centralized review and adjudication. Models for (1) probable dementia, (2) MCI, and (3) probable dementia or MCI were evaluated. A total of 1061 women (mean [SD] age, 73.8 [3.7] years) were identified; 206 of these women (19.4%) had self-reported visual impairment and 183 women (17.2%) had objective visual impairment. Forty-two women (4.0%) were ultimately classified with probable dementia and 28 women (2.6%) with MCI that did not progress to dementia. Mean post-eye examination follow-up was 3.8 (1.8) years (range, 0-7 years). Women with vs without baseline objective visual impairment were more likely to develop dementia. Greatest risk for dementia was among women with visual acuity of 20/100 or worse at baseline (HR, 5.66; 95% CI, 1.75-18.37), followed by 20/80 or worse (HR, 5.20; 95% CI, 1.94-13.95), and 20/40 or worse (HR, 2.14; 95% CI, 1.08-4.21). Findings were similar for risk of MCI, with the greatest risk among women with baseline visual acuity of 20/100 or worse (HR, 6.43; 95% CI, 1.66-24.85). In secondary analysis of a prospective longitudinal cohort study of older women with formal vision and cognitive function testing, objective visual impairment appears to be associated with an increased risk of incident dementia. However, incident cases of dementia and the proportion of those with visual impairment were low. Research is needed to evaluate the effect of specific ophthalmic interventions on dementia.

Low-fat dietary pattern and global cognitive function: Exploratory analyses of the Women's Health Initiative (WHI) randomized Dietary Modification trial

BackgroundMeta-analyses of observational studies associate adherence to several dietary patterns with cognitive health. However, limited evidence from full scale, randomized controlled trials precludes causal inference regarding dietary effects on cognitive function. MethodsThe Women's Health Initiative (WHI) Dietary Modification (DM) randomized trial, in 48,835 postmenopausal women, included a subset of 1,606 WHI Memory Study (WHIMS) participants >= 65 years old, to assess low-fat dietary pattern influence on global cognitive function, evaluated with annual screening (Modified Mini–Mental State Examinations [3MSE]). Participants were randomized by a computerized, permuted block algorithm, stratified by age group and center, to a dietary intervention (40%) to reduce fat intake to 20% of energy and increase fruit, vegetable and grain intake or usual diet comparison groups (60%). The study outcome was possible cognition impairment (failed cognitive function screening) through the 8.5 year (median) dietary intervention. Those failing screening received a comprehensive, multi-phase cognitive function assessment to classify as: no cognitive impairment, mild cognitive impairment, or probable dementia. Exploratory analyses examined the composite endpoint of death after possible cognitive impairment through 18.7 years (median) follow-up. The WHI trials are registered at ClinicalTrials.gov:NCT00000611. FindingsAmong the 1,606 WHIMS participants, the dietary intervention statistically significantly reduced the incidence of possible cognitive impairment (n = 126; hazard ratio [HR] 0.59 95% confidence interval [CI] 0.38–0. 91, P = 0.01) with HR for dietary influence on subsequent mild cognitive impairment of 0.65 (95% CI 0.35–1.19) and HR of 0.63 (95% CI 0.19–2.10) for probable dementia (PD). Through 18.7 years, deaths from all-causes after possible cognitive impairment were non-significantly lower in the dietary intervention group (0.56% vs 0.77%, HR 0.83 95% CI 0.35 to 2.00, P = 0.16). InterpretationAdoption of a low-fat eating pattern, representing dietary moderation, significantly reduced risk of possible cognitive impairment in postmenopausal women. FundingSeveral Institutes of the US National Institutes of Health.