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Background:Accurate assessment of fat intake is essential to examine relationships between diet and disease risk. However, estimating individual intakes of fat quantity by dietary assessment is difficult., Objective:We assessed the association of plasma phospholipid fatty acid levels with dietary intake of fatty acids in the INTERMAP/INTERLIPID study, conducted with a standardized protocol., Methods:The study participants were 1339 men and women ages 40-59 years from five Japanese populations one from Hawaii; four from Japan. Fatty acid intake was estimated from four standardized 24-hour dietary recalls. Plasma phospholipid fatty acid composition was analyzed by gas chromatography. We illustrated the relationship between intake and circulating fatty acid levels using Spearman's rank-correlation coefficients, mean, and median values., Results:Spearman's rank-correlation coefficients between intake (g/d) and circulating fatty acid levels (µg/ml) were -0.03 to 0.21 for saturated fatty acids and monounsaturated fatty acids and -0.04 to 0.32 for trans fatty acids. The coefficients for essential n-3 and n-6 fatty acids were moderate to high, especially for eicosapentaenoic acid (EPA), 0.60; docosahexaenoic acid (DHA), 0.41; and EPA+DHA, 0.51. The circulating levels and intake of marine-derived n-3 fatty acids showed a linear association, at least for the intake of EPA+DHA up to 2.1 g/d., Conclusion:We observed high correlation between intake and circulating levels of marine-derived n-3 fatty acids in participants from Japanese and Japanese-American populations with high and low fish intake. Plasma phospholipid marine-derived n-3 fatty acid measurements are a simple and reliable biomarker for assessing dietary intake.

Percentage of Participants Enrolled in the Women's Health Initiative Dietary Modification Trial Who Were Alive and Not Withdrawn on March 31, 2005 Who Consented to Extended Follow-up (n=45560 )

Medians and inter-decile ranges of estrogens and estrogen metabolites for controls and ovarian cancer cases by subtype, nested case-control study within the Women's Health Initiative-Observational Study.

Supplemental Table 1. Quintile-specific odds ratios and 95% confidence intervals for the risk of endometrial cancer for each estrogen metabolite. Supplemental Table 2. Spearman's rank correlation coefficients of estrogens and estrogen metabolites, measured in controls (n=476)1, nested case-control study, Women's Health Initiative Observational Study Supplementary Table 3. Risk of endometrial cancer comparing the 5th to the 1st quintile for 2-, 4-, and 16-hydroxylation pathway metabolites across categories of BMI, age, and years of oral contraceptive use.

Background: Although endometrial cancer is clearly influenced by hormonal factors, few epidemiologic studies have investigated the role of endogenous estrogens or especially estrogen metabolites.Methods: We conducted a nested case–control study within the Women's Health Initiative Observational Study (WHI-OS), a cohort of 93,676 postmenopausal women recruited between 1993 and 1998. Using baseline serum samples from women who were non-current hormone users with intact uteri, we measured 15 estrogens/estrogen metabolites via HPLC/MS-MS among 313 incident endometrial cancer cases (271 type I, 42 type II) and 354 matched controls, deriving adjusted ORs and 95% confidence intervals (CI) for overall and subtype-specific endometrial cancer risk.Results: Parent estrogens (estrone and estradiol) were positively related to endometrial cancer risk, with the highest risk observed for unconjugated estradiol (OR 5th vs. 1st quintile = 6.19; 95% CI, 2.95–13.03, Ptrend = 0.0001). Nearly all metabolites were significantly associated with elevated risks, with some attenuation after adjustment for unconjugated estradiol (residual risks of 2- to 3-fold). Body mass index (kg/m2, BMI) relations were somewhat reduced after adjustment for estrogen levels. The association with unconjugated estradiol was stronger for type I than type II tumors (Phet = 0.01).Conclusions: Parent estrogens as well as individual metabolites appeared to exert generalized uterotropic activity, particularly for type I tumors. The effects of obesity on risk were only partially explained by estrogens.Impact: These findings enhance our understanding of estrogen mechanisms involved in endometrial carcinogenesis but also highlight the need for studying additional markers that may underlie the effects on risk of certain risk factors, for example, obesity. Cancer Epidemiol Biomarkers Prev; 25(7); 1081–9. ©2016 AACR.

Supplementary Fig. 1. Longitudinal plots of mean (95% CI) percentage of energy as fat during follow-up and the extension period, stratified by quartiles of percentage energy as fat at baseline. Estimates of mean (95% CI) for percentage of energy from fat were based on 24-hour dietary recall.

Background: The Women's Health Initiative (WHI) low-fat (20% kcal) dietary modification (DM) trial (1993–2005) demonstrated a nonsignificant reduction in breast cancer, a nominally significant reduction in ovarian cancer, and no effect on other cancers (mean 8.3 years intervention). Consent to nonintervention follow-up was 83% (n = 37,858). This analysis was designed to assess postintervention cancer risk in women randomized to the low-fat diet (40%) versus usual diet comparison (60%).Methods: Randomized, controlled low-fat diet intervention for prevention of breast and colorectal cancers conducted in 48,835 postmenopausal U.S. women, ages 50 to 79 years at 40 U.S. sites. Outcomes included total invasive cancer, breast cancer, and colorectal cancer, and cancer-specific and overall mortality.Results: There were no intervention effects on invasive breast or colorectal cancer, other cancers, or cancer-specific or overall mortality during the postintervention period or the combined intervention and follow-up periods. For invasive breast cancer, the hazard ratios (HR) and 95% confidence interval (CI) were 0.92 (0.84–1.01) during intervention, 1.08 (0.94–1.24) during the postintervention period, and 0.97 (0.89–1.05) during cumulative follow-up. A reduced risk for estrogen receptor positive/progesterone receptor–negative tumors was demonstrated during follow-up. In women with higher baseline fat intake (quartile), point estimates of breast cancer risk were HR, 0.76 (95% CI, 0.62–0.92) during intervention versus HR, 1.11 (95% CI, 0.84–1.4) during postintervention follow-up (Pdiff = 0.03).Conclusions: Dietary fat intake increased postintervention in intervention women; no long-term reduction in cancer risk or mortality was shown in the WHI DM trial.Impact: Dietary advisement to reduce fat for cancer prevention after menopause generally was not supported by the WHI DM trial. Cancer Epidemiol Biomarkers Prev; 23(12); 2924–35. ©2014 AACR.

Supplementary Table 2. Effects of Randomization Assignment to Dietary Modification Intervention vs. Comparison on Clinical Outcomes Before and After Termination of the Intervention in the Women's Health Initiative Dietary Modification Trial

Odds ratios and 95% confidence intervals for the risk of epithelial ovarian cancer comparing the 5th quintile to the 1st quintile for individual estrogens and estrogen metabolites analyzed by time between blood draw and diagnosis among the cases, nested case-control study within the Women's Health Initiative-Observational Study.

Odds ratios and 95% confidence intervals for the risk of epithelial ovarian cancer comparing the 5th quintile to the 1st quintile for individual estrogens and estrogen metabolites stratified by age at blood draw, nested case-control study within the Women's Health Initiative-Observational Study.

PDF file - 64K, Breast cancer risk OR(95% CI) for 1 year change in estrogen metabolites (EM) among women randomized to active treatment in the WHI Hormone Trials, with cases stratified by median follow-up time

Background: Hormonal and reproductive factors contribute to the development of ovarian cancer, but few studies have examined associations between circulating estrogens and estrogen metabolites and ovarian cancer risk. We evaluated whether serum estrogens and estrogen metabolite levels are associated with ovarian cancer risk among postmenopausal women in a nested case–control study in the Women's Health Initiative (WHI) Observational Study (OS).Methods: We selected all 169 eligible epithelial ovarian cancer cases and 412 matched controls from women enrolled in WHI-OS who were not using menopausal hormones at baseline. Baseline levels of 15 estrogens and estrogen metabolites were measured via liquid chromatography/tandem mass spectrometry. Associations with ovarian cancer risk overall and stratified by histologic subtype (serous/nonserous) were analyzed using logistic regression. The mean time from serum collection to cancer diagnosis was 6.9 years.Results: Overall, we observed modest ovarian cancer risk associations among women with higher levels of estrone [OR (95% confidence interval) quintile (Q)5 vs. Q1: 1.54 (0.82–2.90), Ptrend = 0.05], as well as 2- and 4-methoxyestrone metabolites [2.03 (1.06–3.88), Ptrend = 0.02; 1.86 (0.98–3.56), Ptrend = 0.01, respectively]. Associations of estrogens and estrogen metabolites varied substantially by histologic subtype. Associations with serous tumors were universally null, while estrone [2.65 (1.09–6.45), Ptrend = 0.01, Pheterogeneity = 0.04], unconjugated estradiol [2.72 (1.04–7.14), Ptrend = 0.03, Pheterogeneity = 0.02] and many of the 2-, 4-, and 16-pathway metabolites were positively associated with nonserous tumors.Conclusions: Our study provides novel molecular data showing an association of the parent estrogens and several estrogen metabolites with nonserous ovarian cancers.Impact: These findings further support the heterogeneous etiology of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 25(4); 648–56. ©2016 AACR.

Background Recommended systolic blood pressure targets often do not consider the relationship of low diastolic blood pressure (DBP) levels with cardiovascular disease (CVD) and all-cause mortality risk, which is especially relevant for older people with concurrent comorbidities. We examined the relationship of DBP levels to CVD and all-cause mortality in older women in the Women’s Health Initiative Long Life Study (WHI-LLS). Methods The study sample included 7,875 women (mean age: 79 years) who underwent a blood pressure measurement at an in-person home visit conducted in 2012–2013. CVD and all-cause mortality were centrally adjudicated. Hazard ratios (HRs) were obtained from adjusted Cox proportional hazards models. Results After 5 years follow-up, all-cause mortality occurred in 18.4% of women. Compared with a DBP of 80 mm Hg, the fully adjusted HR for mortality was 1.33 (95% confidence interval [CI]: 1.04–1.71) for a DBP of 50 mm Hg and 1.67 (95% CI: 1.29–2.16) for a DBP of 100 mm Hg. The HRs for CVD were 1.14 (95% CI: 0.78–1.67) for a DBP of 50 mm Hg and HR 1.50 (95% CI: 1.03–2.17) for a DBP of 100 mm Hg. The nadir DBP associated with lowest mortality risk was 72 mm Hg overall. Conclusions In older women, consideration should be given to the potential adverse effects of low and high DBP. Low DBP may serve as a risk marker. DBP target levels between 68 and 75 mm Hg may avoid higher mortality risk.

Introduction: Sphingolipids are fundamental components of brain structure and function. They are located in the myelin sheath insulating neuronal axons and in the cell membranes of neurons, astrocytes, and microglia involved in signal transduction. Although circulating sphingolipid profiles reflect clinical neurodegeneration, few prospective studies have investigated their utility as pre-clinical risk markers in community-based cohorts. For heart disease and diabetes, themselves risk factors for dementia, associations with sphingolipids differed across species and the length of the saturated fatty acid carried. Hypothesis: We hypothesized that plasma levels of sphingolipid species containing palmitic acid (16:0) would be positively associated with incident dementia risk and cognitive decline, while those with arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) would be associated with lower risk. Methods: We measured 18 sphingolipid species in plasma samples from 4612 participants of the Cardiovascular Health Study (CHS) (mean age 76.2 years; 40% male; and 25% APOE ε4 allele carriers). Cognitive decline was assessed across 6 years using annual 100-point modified Mini-Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST) scores. A total of 3088 non-demented participants were enrolled in the CHS Cognition Study and followed with adjudication for dementia. To correct the analyses for multiple comparisons, we applied a false discovery rate (FDR) correction and used a significance threshold of 0.05. Results: Higher baseline levels of lactosylceramide-24:0 (LacCer-24) were associated with a faster 6-year cognitive decline (time x sphingolipid interaction p=0.04 for 3MSE and 0.03 for DSST). Conversely, higher baseline plasma levels of hexosylceramide -16:0 (HexCer-16) and sphingomyelin-22:0 (SM-22) were associated with slower cognitive decline measured with DSST (time x sphingolipid interaction p=0.02 for HexCer and p=0.05 for SM-22). During a median follow-up of 4.5 years, we identified 366 incident dementia cases. In proportional Cox regression analyses, higher plasma levels of ceramide-16:0 (Cer-16) were positively associated with incident dementia upon adjustment for demographics, lifestyle factors, medical history, C-reactive protein, and lipids [hazard ratio per SD: 1.18 (95% CI, 1.06; 1.31)]. Conclusions: In older adults without dementia, higher plasma levels of Cer-16, a species previously associated with cardiovascular disease and mortality, were associated with higher risk of clinical dementia as we hypothesized. LacCer-24 was associated with faster, and HexCer-16 and SM-22 with slower, cognitive decline, but these species were not statistically associated with dementia risk. These novel and inconsistent findings will need to be replicated in other longitudinal studies.

Background Phospholipids are biomarkers of dietary fat intake and metabolism, linked to several cardiometabolic disorders. Few prospective studies have assessed plasma phospholipids in relation to dementia risk and cognitive function. Objectives We aimed to evaluate the association between a decrease in linoleic acid accompanied with an increase in other fatty acids and cognitive function and dementia risk. Methods We conducted a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 1252 participants, 498 of whom who developed dementia during a mean of 5 y of follow-up. We measured 45 individual plasma phospholipids (as a percentage of total plasma phospholipid fatty acids) by GC and related these to Modified Mini-Mental State Examination (3MSE) scores at baseline and neurologist-adjudicated incidence of all-cause dementia and Alzheimer disease (AD), adjusting for sociodemographic and clinical characteristics. Results Substitution of 1% of SFAs for 1% of linoleic acid, the predominant polyunsaturated n-6 (ɷ-6) fatty acid, was associated with higher risk of dementia (HR per 1% of SFAs instead of linoleic acid = 1.03; 95% CI: 1.00, 1.07) and a 0.08 point lower 3MSE score at baseline (95% CI: -0.12, -0.03), signifying worse cognitive function. When compared with linoleic acid, we found no associations of total monounsaturated, n-3 polyunsaturated, or trans fatty acids with risk of dementia or AD. However, the substitution of 1% of the marine n-3 PUFA DHA for linoleic acid was associated with lower risk of dementia (HR = 0.86 per 1% of DHA instead of linoleic acid; 95% CI: 0.76, 0.96). These associations were not modified by apolipoprotein E genotype, mild cognitive impairment at baseline, age, or sex. Conclusions Specific elements of diet may be associated with late-life dementia, a hypothesis that requires formal testing in randomized controlled trials and that represents a possible preventive intervention.

BackgroundThe potential cardiovascular impact of dietary cholesterol intake has been actively debated for decades.ObjectivesWe aimed to evaluate associations of dietary cholesterol and egg intakes with incident cardiovascular disease (CVD) and all-cause and cause-specific mortality.MethodsWe included 96,831 US postmenopausal women aged 50-79 y without known CVD or cancer during baseline enrollment (1993-1998) of the Women's Health Initiative. Dietary information was collected using a validated FFQ. Incident CVD [i.e., ischemic heart disease (IHD) and stroke] and all-cause and cause-specific mortality were ascertained and adjudicated through February 2018.ResultsA total of 9808 incident CVD cases and 19,508 all-cause deaths occurred during a median follow-up of 17.8 y and 18.9 y, respectively. After multivariable adjustment for traditional risk factors and key dietary nutrients including dietary saturated fat, there were modest associations of dietary cholesterol intake with incident CVD (HRQ5versusQ1: 1.12; 95% CI: 1.03, 1.21; P-trend0.05). Higher egg consumption was also associated with modestly higher risk of incident CVD (P-trend=0.004) and all-cause mortality (P-trend&nbsp

The potential benefit of the anti‐amyloid drug aducanumab based on results of recent EMERGE and ENGAGE clinical trials has generated great controversy and has very important implications for the future of anti‐amyloid drug therapies. The two trials of 18‐month duration were done in patients with mild cognitive impairment (MCI) and early dementia. The ENGAGE trial showed no benefit while the high‐dose EMERGE trial initially also showed no benefit but with longer follow‐up there was a significant positive benefit. A recent review form the U.S. Food and Drug Administration (FDA) Advisory Committee was negative while the FDA Office of Neurological Drugs was positive and the statisticians negative. This has generated debate about whether the drug should be approved, disapproved, require a new clinical trial, or approved for a subsample only. The implications for treating both MCI and Alzheimer's disease (AD) patients with anti‐amyloid drugs is very substantial as well as the brain amyloid‐AD‐dementia hypothesis.

Hearing and vision problems are individually associated with increased dementia risk, but the impact of having concurrent hearing and vision deficits, ie, dual sensory impairment (DSI), on risk of dementia, including its major subtypes Alzheimer disease (AD) and vascular dementia (VaD), is not well known.To evaluate whether DSI is associated with incident dementia in older adults.This prospective cohort study from the Cardiovascular Health Study (CHS) was conducted between 1992 and 1999, with as many as 8 years of follow-up. The multicenter, population-based sample was recruited from Medicare eligibility files in 4 US communities with academic medical centers. Of 5888 participants aged 65 years and older in CHS, 3602 underwent cranial magnetic resonance imaging and completed the modified Mini-Mental State Examination in 1992 to 1994 as part of the CHS Cognition Study. A total of 227 participants were excluded due to prevalent dementia, leaving a total of 3375 participants without dementia at study baseline. The study hypothesis was that DSI would be associated with increased risk of dementia compared with no sensory impairment. The association between the duration of DSI with risk of dementia was also evaluated. Data analysis was conducted from November 2019 to February 2020.Hearing and vision impairments were collected via self-report at baseline and as many as 5 follow-up visits.All-cause dementia, AD, and VaD, classified by a multidisciplinary committee using standardized criteria.A total of 2927 participants with information on hearing and vision at all available study visits were included in the analysis (mean [SD] age, 74.6 [4.8] years; 1704 [58.2%] women; 455 [15.5%] African American or Black; 2472 [85.5%] White). Compared with no sensory impairment, DSI was associated with increased risk of all-cause dementia (hazard ratio [HR], 2.60; 95% CI, 1.66-2.06; P .001), AD (HR, 3.67; 95% CI, 2.04-6.60; P .001) but not VaD (HR, 2.03; 95% CI, 1.00-4.09; P = .05).In this cohort study, DSI was associated with increased risk of dementia, particularly AD. Evaluation of hearing and vision in older adults may help to identify those at high risk of developing dementia.

Introduction: Elevated high-sensitive cardiac troponin T (hs-cTnT>14 ng/L) and low ankle-brachial index (ABI < 0.9) are known to be associated with cardiovascular diseases (CVD) but their joint effect on the risk of CVD events is unknown. Methods: We used data from the MESA and CHS among 10,900 participants free of CVD events at baseline (mean age 66.3 years, 44.7% males). Incident coronary heart disease (CHD) was defined as fatal or non-fatal myocardial infarction or revascularization and incident CVD was defined as CHD, transient ischemic attack, stroke, or atrial fibrillation. Hazard ratio (HR) and 95% CI was calculated from a Cox regression model. Interaction on the additive scale was assessed using relative excess risk due to interaction (RERI) and interaction on the multiplicative scale was assessed by Likelihood ratio (LR) test. Results: At baseline (2000-2002 for MESA and 1989-1990 for CHS), 10.2% of participants had elevated hs-cTnT and 7.5% had low ABI. During 26.1 years of total follow-up (median follow-up 18.4 years), there were 3,911 incident CVD events. The risk of CHD and CVD was higher in participants with both elevated hs-cTnT and low ABI [CHD HR: 2.1 (1.5, 2.9), CVD HR: 2.1 (1.7, 2.5)], only elevated hs-cTnT [CHD HR: 1.7 (1.4, 2.0), CVD HR: 1.6 (1.5, 1.8)], and only low ABI [CHD HR: 1.8 (1.5, 2.2), CVD HR: 1.5 (1.3, 1.7)] than those with unelevated hs-cTnT and normal ABI. Interaction on the multiplicative scale was observe in both adjusted and unadjusted models for CHD (unadjusted LR test p-value=0.002, adjusted LR test p-value=0.042) and only in unadjusted model for CVD (LR test p-value=0.001). No significant additive interaction was detected for both CHD and CVD (RERI p-value≥0.25 for unadjusted and adjusted models). Conclusion: Having both elevated cTnT and low ABI was associated more strongly with CVD events than only elevated cTnT or low ABI. Antagonistic multiplicative interaction was found indicating the observed joint effect of elevated cTnT and low ABI was smaller than the expected combined individual effects.

Background and ObjectivesNeurofilament light chain (NfL) in blood is a sensitive but nonspecific marker of brain injury. This study sought to evaluate associations between NfL concentration and MRI findings of vascular brain injury in older adults.MethodsA longitudinal cohort study included 2 cranial MRI scans performed about 5 years apart and assessed for white matter hyperintensities (WMH) and infarcts. About 1 year before their second MRI, 1,362 participants (median age 77 years, 61.4% women) without a history of TIA or stroke had measurement of 4 biomarkers: NfL, total tau, glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L1. Most (n = 1,279) also had the first MRI scan, and some (n = 633) had quantitative measurements of hippocampal and WMH. In primary analyses, we assessed associations of NfL with a 10-point white matter grade (WMG) and prevalent infarcts on second MRI and with worsening WMG and incident infarct comparing the 2 scans. A p value ResultsIn fully adjusted models, log2(NfL) concentration was associated with WMG (β = 0.27; p = 2.3 × 10−4) and worsening WMG (relative risk [RR] 1.24; p = 0.0022), but less strongly with prevalent brain infarcts (RR 1.18; p = 0.013) and not with incident brain infarcts (RR 1.18; p = 0.18). Associations were also present with WMH volume (β = 2,242.9, p = 0.0036). For the other 3 biomarkers, the associations for log2 (GFAP) concentration with WMG and worsening WMG were significant.DiscussionAmong older adults without a history of stroke, higher serum NfL concentration was associated with covert MRI findings of vascular brain injury, especially the burden of WMH and its worsening. Whether these results offer opportunities for the use of NfL as a noninvasive biomarker of WMH or to control vascular risk factors remains to be determined.

Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia—yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self‐reported HT use on brain volume in 562 elderly women (71–94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate‐adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design., Declining estrogen levels for women in all stages of menopause can affect memory and risk of Alzheimer's Disease (AD), emphasizing a role for hormone therapy (HT). Effects may differ due to several factors including lifestyle and cardiovascular risk, genetic makeup, and timing and duration of HT. We addressed this hypothesis using self‐reported HT in 562 elderly women with mixed cognitive status, covarying for aforementioned factors. Voxelwise regression showed HT use as correlated with higher brain volume regardless of cognitive status

ObjectiveTo test the hypothesis that orthostatic hypotension (OH) might cause cerebral hypoperfusion and injury, we examined the longitudinal relationship between OH or orthostatic symptoms and incident neurologic outcomes in a community population of older adults.MethodsCardiovascular Health Study participants (≥65 years) without dementia or stroke had blood pressure (BP) measured after lying down for 20 minutes and after standing 3 for minutes. Participants reported dizziness immediately upon standing and any dizziness in the past 2 weeks. OH was defined as a drop in standing systolic/diastolic BP ≥20/≥10 mm Hg. We determined the association between OH or dizziness with (1) MRI brain findings (ventricular size, white matter hyperintensities, brain infarcts) using linear or logistic regression, (2) cognitive function (baseline and over time) using generalized estimating equations, and (3) prospective adjudicated events (dementia, stroke, death) using Cox models. Models were adjusted for demographic characteristics and OH risk factors. We used multiple imputation to account for missing OH or dizziness (n = 534).ResultsPrior to imputation, there were 5,007 participants (mean age 72.7 ± 5.5 years, 57.6% women, 10.9% Black, 16% with OH). OH was modestly associated with death (hazard ratio [HR] 1.11; 95% confidence interval 1.02–1.20), but not MRI findings, cognition, dementia, or stroke. In contrast, dizziness upon standing was associated with lower baseline cognition (β = −1.20; −1.94 to −0.47), incident dementia (HR 1.32; 1.04–1.62), incident stroke (HR 1.22; 1.06–1.41), and death (HR 1.13; 1.06–1.21). Similarly, dizziness over the past 2 weeks was associated with higher white matter grade (β = 0.16; 0.03–0.30), brain infarcts (OR 1.31; 1.06–1.63), lower baseline cognition (β = −1.18; −2.01 to −0.34), and death (HR 1.13; 1.04–1.22).ConclusionsDizziness was more consistently associated with neurologic outcomes than OH 3 minutes after standing. Delayed OH assessments may miss pathologic information related to cerebral injury.

Background: In postmenopausal women, use of hormone therapy is associated with a lower incidence of diabetes (DM). The association of adjuvant endocrine therapy (AET) with DM has not been well studied among women treated for early stage breast cancer. The objective of this study was to examine the association of AET with risk of developing DM among postmenopausal women who developed breast cancer. Methods: 5,013 postmenopausal women from the Women’s Health Initiative diagnosed with non-metastatic breast cancer who were diabetes-free at cancer diagnosis and who had information on use of AET were included. AET use was gathered using 2 methods: 1) review of medication inventories for use of tamoxifen or aromatase inhibitors (AI) and 2) review of the Life and Longevity after Cancer (LILAC), a supplemental questionnaire used from 2009-2010 to gather treatment information from women who developed cancer. Results from these 2 collection methods were analyzed separately due to the timing of the surveys as well as data granularity (i.e. LILAC queried use of AET, not type). The primary outcome of interest for this study was diabetes-free survival, which was calculated from the date of breast cancer diagnosis to first diagnosis of DM. Participants who did not develop DM after breast cancer were censored at their last follow-up visit or date of death. Cox proportional hazards models were used to compute hazard ratios (HR) and 95% confidence intervals (CI). Results: After 10.4 median year’s follow-up post breast cancer diagnosis, 13% (632/5,013) of participants developed DM. Of the 2,646 who had medication inventory data, 1,352 (51%) reported AI use and 1,449 (55%) reported tamoxifen use. Participants who reported use of AIs were 13% more likely to develop DM than participants who did not use AIs (HR=1.13, CI=0.91-1.39). Participants who reported use of tamoxifen were 11% less likely to develop DM than those who did not use tamoxifen (HR=0.89, CI=0.72-1.11). Of the 3,769 participants with LILAC data from the supplemental questionnaire, 2,543 (67%) reported use of AET; these participants were 25% more likely to develop DM than those who did not use AET (HR=1.25, CI=1.02-1.53). When plotted over time, the risk of diabetes in AET users versus non-users was identical at 5 years (5% v 5%, respectively), was 35% higher at 10 years (12% v 9%, respectively), and 30% higher at 15 years (18% v 14%, respectively) (log-rank p=0.029). Conclusion: DM has not been reported as an adverse event in women on AET. Our data suggest an association of AET with DM among postmenopausal women with early stage breast cancer. When looking at specific types of AETs, the risk was marginally increased for AIs but marginally decreased for tamoxifen, with risk more apparent in subsequent years. These data have significance for survivorship care. Citation Format: Joanne E Mortimer, Rebecca A Nelson, Laura Kruper, Kathy Pan, Christina M Dieli Conwright, Aladdin H Shadyab, Lewis Kuller, Barbara Howard, Rowan T Chlebowski. Association of adjuvant endocrine therapy with diabetes among women with postmenopausal breast cancer in the Women’s Health Initiative (WHI) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-04.

ObjectiveTo determine changes in the incidence of dementia between 1988 and 2015.MethodsThis analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex.ResultsOf 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65–69 years to 65 per 1,000 person-years for those aged 85–89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%–19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%–32%] vs 8% [0%–15%]).ConclusionThe incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.

The increasing longevity of the population has resulted in dementia becoming a leading cause of both death and disability. Dementia is not a single disease. Studies of rare Mendelian disorders have documented that Alzheimer's disease, the most common cause of dementia, is associated with a long incubation period from amyloid deposition to neurodegeneration to mild cognitive impairment and dementia. There are three broad hypotheses related to the causes of Alzheimer's dementia: (1) an aging process; (2) brain vascular disease; and (3) metabolic abnormalities associated with either increased production of amyloid-β or decreased clearance from the brain. Therefore, research on the early stages of the dementia process are of high priority. This paper reports that higher energy intake in both the Nurses' Health Study and Health Professionals Follow-up Study is associated with very early symptoms that lead to mild cognitive impairment and dementia. The results are very interesting but hard to interpret because they also show that higher energy intake is not related to body mass index, a very unusual observation. A likely hypothesis is that there is an association between reporting of dietary intake and subjective symptoms, i.e. reporting bias, accounting for their results.

This individual participant data analysis assesses the cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia., Key Points Question Is thyroid dysfunction associated with cognitive decline? Findings In this individual participant data analysis of 23 cohorts including 74 565 participants with cognitive function and/or dementia measurements, subclinical thyroid dysfunction was not associated with global cognitive function at baseline (standardized mean difference, −0.02 for subclinical hyperthyroidism and 0.05 for subclinical hypothyroidism) or annual decline (standardized mean difference, −0.02 for subclinical hyperthyroidism and −0.00 for subclinical hypothyroidism). Meaning These findings do not support the need for screening for subclinical thyroid dysfunction for prevention of cognitive decline or dementia., Importance In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism—cross-sectionally (−0.06 standardized mean difference in score; 95% CI, –0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, –0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.