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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]

Dementia research lacks appropriate representation of diverse groups who often face substantial adversity and greater risk of dementia. Current research participants are primarily well‐resourced, non‐Hispanic White, cisgender adults who live close to academic medical centers where much of the research is based. Consequently, the field faces a knowledge gap about Alzheimer's‐related risk factors in those other groups. The Alzheimer's Association hosted a virtual conference on June 14–16, 2021, supported in part by the National Institute on Aging (R13 AG072859‐01), focused on health disparities. The conference was held entirely online and consisted of 2 days of core programming and a day of focused meetings centered on American Indian and Alaska Natives and on LGBTQIA+ populations. Over 1300 registrants attended discussions focused on the structural and systemic inequities experienced across diverse groups, as well as ways to investigate and address these inequities. [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: White matter hyperintensities (WMHs) are common in normally functioning older adults. While greater WMH volume may be associated with an increased risk of cognitive dysfunction and dementia, the impact of the location of WMHs is less well understood. We investigated whether WMH burden in specific white matter (WM) tracts is associated with clinical classification and global cognitive scores in at‐risk groups for Alzheimer's disease (AD). Method: Participants from Dementia Prevention Research Clinics, New Zealand, were classified as control, subjective cognitive decline, single‐domain amnestic mild cognitive impairment (MCI), multiple‐domain amnestic MCI, or early AD by a multidisciplinary team (Table 1). Several tract‐WMH "overlap scores" (the percentage of total tract voxels containing WMHs) were calculated for each participant's binarised WMH map (Lesion Segmentation Toolbox, SPM) using seven tract probability templates from a 140‐subject tract atlas (www.megatrackatlas.org). Tract templates were of the superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), inferior fronto‐occipital fasciculus (IFOF), uncinate fasciculus (UF), cingulum (CB), fornix, and corpus callosum (CC). Between‐group differences in overlap scores were tested with ANOVAs. Pearson's correlations examined associations between tract‐WMH overlap and global cognitive scores. Result: Figure 1 shows WMH overlap with one tract, the IFOF, in a representative participant. Considering the whole sample, the highest tract‐WMH overlap scores can be seen in the IFOF and CC. Significant between‐group differences were found for the SLF, ILF, IFOF, UF, and CC (p <.05), but not the CB or fornix (Fig. 2), with significant linear trends describing the relationship between overlap scores and clinical classification. Post‐hoc tests confirmed significant pairwise comparisons for overlap scores in all aforementioned tracts except the SLF (Fig. 2). We found Addenbrooke's Cognitive Examination‐III scores negatively correlated with overlap scores in the ILF (r = ‐0.19), IFOF(r = ‐0.22), UF(r = ‐0.22), and CC(r = ‐0.19) (all p <.01), but not the SLF, CB, or fornix (p >.05). Conclusion: Our findings highlight that WMH burden within specific WM tracts is associated with degree of clinical impairment in groups at‐risk of AD. Future research will investigate relationships between overlap scores in specific WM tracts and executive functioning, episodic memory, and processing speed performance. [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]

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]

Introduction: Distinguishing Alzheimer's disease (AD) patient subgroups may optimize positive clinical outcomes. Cortical atrophy is correlated with memory deficits, but these associations are understudied in American Indians. Methods: We collected imaging and cognition data in the Strong Heart Study (SHS), a cohort of 11 tribes across three regions. We processed 1.5T MRI using FreeSurfer and iterative principal component analysis. Linear mixed models estimated volumetric associations with diabetes. Results: Over mean 7 years follow‐up (N = 818 age 65–89 years), overall volume loss was 0.5% per year. Significant losses associated with diabetes were especially strong in the right hemisphere. Annualized hippocampal, parahippocampal, entorhinal atrophy were worse for men, older age, diabetes, hypertension, stroke; and associated with both encoding and retrieval memory losses. Discussion: Our findings suggest that diabetes is an important risk factor in American Indians for cortical atrophy and memory loss. Future research should examine opportunities for primary prevention in this underserved population. [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]

Introduction: Little is known about treatment costs for American Indian and Alaska Native (AI/AN) adults with dementia who access services through the Indian Health Service (IHS) and Tribal health programs. Methods: We analyzed fiscal year 2013 IHS/Tribal treatment costs for AI/ANs aged 65+ years with dementia and a matched sample without dementia (n = 1842) to report actual and adjusted total treatment costs and costs by service type. Adjusted costs were estimated using multivariable regressions. Results: Mean total treatment cost for adults with dementia were $13,027, $5400 higher than for adults without dementia ($7627). The difference in adjusted total treatment costs was $2943 (95% confidence interval [CI]: $1505, $4381), the majority of which was due to the difference in hospital inpatient costs ($2902; 95% CI: $1512, $4293). Discussion: Knowing treatment costs for AI/ANs with dementia can guide enhancements to policies and services for treating dementia and effectively using health resources. [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]

Background: Longitudinal electronic health record (EHR) data provides an opportunity to evaluate associations between certain risk factors and dementia incidence. In practice, researchers using EHR usually extract data for multiple years and use the first 2‐4 years as a washout period to exclude baseline prevalent cases. However, identifying dementia via clinical diagnostic codes during a washout period likely under‐detect some cases, with time to dementia diagnosis for these cases left censored and estimates for the associations of interest potentially biased. This study aims to assess the amount of left censoring when analyzing time to dementia using EHR data from the Indian Health Service (IHS). Methods: We extracted data from the IHS National Data Warehouse and related EHR databases between fiscal year (FY) 2007‐2013. Adults aged 45+ years were identified as having dementia if they had at least one qualifying ICD‐9 diagnostic code for all‐cause dementia. A total of 1,117 AI/AN adults were identified as dementia patients in FY2007. Among these, we calculated the proportions of patients with 1+ ICD‐9 code for dementia within 1‐5 years after FY2007. We used diabetes, identified in a similar manner, as a comparison condition. Results: Among the FY2007 dementia patients who used IHS services in FY2008, only 63.7% had 1+ qualifying ICD‐9 code for dementia in FY2008. In contrast, 93.7% of FY2007 diabetes patients had an ICD‐9 code for diabetes in FY2008 (Fig1). If FY2007 data are not included in the analytical dataset and only one year of data (FY2008) is used as the washout period, the remaining 36.3% prevalent dementia cases are classified as incidence after FY2008 with their time to dementia left censored. Even using a 5‐year washout period, 25.0% prevalent dementia patients in FY2007 are classified as incident cases after FY2012 (Fig2a) while 4.6% prevalent diabetes patients in FY2007 are classified as incidence (Fig2b). Conclusions: Longitudinal analysis of dementia risk using EHR data might be subject to relatively high amount of left censoring. It is important to recognize the potential biases associated with relatively high proportion of left censored observations when estimating longitudinal associations of risk factors with dementia incidence. [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]

Introduction: Recent studies suggest that both sex‐specific genetic risk factors and those shared between dementia and stroke are involved in dementia pathogenesis. Methods: We performed both single‐variant and gene‐based genome‐wide association studies of >11,000 whole genome sequences from the Women's Health Initiative cohort to discover loci associated with dementia, with adjustment for age, ethnicity, stroke, and venous thromboembolism status. Evidence for prior evidence of association and differential gene expression in dementia‐related tissues and samples was gathered for each locus. Results: Our multiethnic studies identified significant associations between variants within APOE, MYH11, FZD3, SORCS3, and GOLGA8B and risk of dementia. Ten genes implicated by these loci, including MYH11, FZD3, SORCS3, and GOLGA8B, were differentially expressed in the context of Alzheimer's disease. Discussion: Our association of MYH11, FZD3, SORCS3, and GOLGA8B with dementia is supported by independent functional studies in human subjects, model systems, and associations with shared risk factors for stroke and dementia. [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: 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]

Background: American Indian and Alaska Native (AI/AN) adults have one of the highest prevalence of diabetes (14.7%) in the United States, nearly double that of the White population. As AI/ANs age, they are at high risk for chronic diseases that have diabetes as a well‐established risk factor, such as cardiovascular complications and dementia. Approximately half of AI adults with dementia have diabetes, but little is known about their treatment costs. Our aims were to profile treatment costs of AI adults with diabetes, with and without dementia, and to understand how dementia influences costs by type of service. Method: We analyzed fiscal year 2013 treatment cost data from the Indian Health Service and Tribal health programs for American Indian (AI) adults aged ≥65 years with diabetes. Using data for 921 adults with dementia and a matched sample without dementia (n = 921), matched by age, sex, and location, we report actual and adjusted total treatment costs and costs by service type. Adjusted costs were estimated using a generalized linear model with a log link function and gamma distribution. Results: The morbidity burden of AI adults with both diabetes and dementia was high. Over seventy percent (71.4%) had cardiovascular disease (CVD) and 39.4% had renal disease. The prevalence of these conditions was lower (57.8% and 30.6%, respectively) among adults with diabetes without dementia. Mean total treatment cost was higher for adults with dementia ($15,978) than for adults without dementia ($8,857), a difference of $7,121. The difference in adjusted total treatment costs between adults with and without dementia was $3,891 (95% confidence interval [CI]: $2,122‐$5,659), most of which was due to the difference in hospital inpatient costs ($3,754; 95% CI: $2,221‐$5,286). Furthermore, among adults with both dementia and CVD, adjusted hospital inpatient costs were $8,114 (95% CI: $6,018‐$10,211), significantly higher than that among adults with dementia only ($2,075; 95% CI: $992‐$3,158) and among adults with CVD only ($3,050; 95% CI: $2,399‐$3,701) (Figure 1). Conclusion: Knowing CVD is strongly associated with high inpatient costs among AI adults with both diabetes and dementia may inform enhancements to outpatient and home‐based services that address their CVD health risks. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence, mortality, and healthcare impact of Alaska Native and American Indian (ANAI) people with Alzheimer's disease and related dementias (ADRD) are unknown. Methods: We conducted a cohort study of electronic health record data that compared healthcare service utilization in patients with and without an ADRD diagnosis. Zero‐inflated negative binomial regression with robust standard errors was used to estimate utilization rates. Results: Compared with patients without ADRD, utilization rates were similar before but higher after ADRD diagnosis. For those with diagnosed ADRD, utilization increased gradually over time with sharp upward change during the year of diagnosis. Discussion: This is the only study quantifying changes in healthcare service utilization before and after ADRD diagnosis among ANAI people, which is crucial for tailoring geriatric care for ANAI populations. [ABSTRACT FROM AUTHOR]

Background: Episodic memory (EM) declines vary by age and underlying neuropathology. Whether exposure to ambient air pollutants contributes to the observed heterogeneity of EM decline in older people is unclear. Method: We examined the associations between exposures and EM trajectories in the US‐based Women's Health Initiative Memory Study‐Epidemiology of Cognitive Health Outcomes (WHIMS‐ECHO) cohort (N=2042, aged 74‐92 in 2008). EM was assessed annually (2008‐18) using the immediate recall total correct (3 trials) in the telephone‐based California Verbal Learning Test. Recent 3‐year average exposures to regional PM2.5 (particulate matter with aerodynamic diameter < 2.5μm) and NO2 (a proxy of traffic‐related air pollutants) and the corresponding remote 3‐year averages approximately at 10 years prior to inception were derived from yearly exposures estimated by regionalized national universal kriging. Latent‐class mixed models were used to classify EM trajectories and examine the exposure effect in each identified latent class. All models adjusted for social‐demographic factors, lifestyle, cardiovascular risk and other clinical covariates. Result: There were two latent EM trajectories that differed by WHIMS‐ECHO baseline age (≤80 vs. oldest‐old 80+; Figure 1) and exposure characteristics (Table 1). In women aged ≤80 (N=836), greater EM decline was associated with higher PM2.5 in the subgroup with slow‐decline (76%; −0.18/year), but not in those with fast‐decline (24%; −1.75/year). The observed association, equivalent to 1‐2 years of aging, was stronger for recent 3‐year exposure (−0.151/year, per inter‐quartile‐range [IQR]=2.86µg/m3, p=0.02), as compared with remote exposure (−0.096/year, per IQR=3.28µg/m3, p=0.09). In the oldest‐old (aged>80; N=1206), EM decline (70% steady decline by −1.37/year; 30% no apparent decline) was not associated with recent or remote PM2.5 exposures. In both age groups, no appreciable NO2 effects on EM decline were observed, and neither PM2.5 nor NO2 exposures during recent or remote years affected the levels of EM trajectories. Adjusted models further accounting for propensity scores of exposures revealed very similar results. Conclusion: The accelerated EM declines associated with late‐life exposures to ambient air pollutants vary by age‐related cognitive trajectories, exposure time‐windows and pollution sources. The observed association was most consistent with PM2.5 exposure during recent years in older women aged ≤80 with slow EM decline. [ABSTRACT FROM AUTHOR]

Background: Air pollution has been identified as an important risk factor for dementia in previous studies. As a unique population with a history of colonization, American Indians have long been disproportionately affected by air pollution. However, few studies have investigated the effects of air pollution on the risk of developing dementia in American Indians. This study aims to address this important knowledge gap. Method: County‐level average air pollution data in 2003‐2007 were downloaded from the land‐use regression models developed by the Center for Air, Climate, & Energy Solutions (CACES) and merged with data from the Indian Health Service (IHS) National Data Warehouse and related electronic health record databases between fiscal year (FY) 2007‐2013. We assigned air pollution exposure to IHS users based on their county of residence and calculated 5‐year averages of PM2.5, O3, CO, and NO2 in each county. A total of 14,910 American Indians who were 65+ years old in FY2007, used IHS services at least once each year, and were dementia free between FY2007‐2009 were included in the main analysis. Cox proportional hazard models with age as the time scale were employed to examine the association of air pollution with dementia incidence, adjusting for potential confounders. Result: The PM2.5 levels in the IHS counties were lower than those in all US counties during 2003‐2013, while the levels of other air pollutants were similar to the US (Figure 1). More dementia incident cases were found in IHS counties with higher O3 levels (Figure 2). In multivariable Cox regression models (Table1), we found a significant positive association between dementia and O3 with a hazard ratio (HR) of 1.26 (95% CI: 1.02‐1.55) per 1 ppb standardized O3, while the associations between dementia and PM2.5, and CO were not statistically significant. We found similar results in sensitivity analyses using longer lags between air pollution and dementia or replacing CO by NO2 in the regression model. Conclusion: Our study suggests that exposure to O3 is associated with the higher risk of dementia in American Indians. Future efforts to reduce exposure to air pollution might help lower dementia risk in American Indian communities. [ABSTRACT FROM AUTHOR]

Background: American Indian and Alaska Native people (AI/ANs) bear a disproportionate burden of diabetes. Growing evidence has shown significant associations between several acute diabetes complications and dementia among diabetes patients in the general population. However, little is known about these relationships among AI/ANs. Methods: This cross‐sectional study extracted patient registration and health service utilization data from the Indian Health Service's National Data Warehouse and related administrative databases. A total of 29,337 AI/AN adults with diabetes who were 45+ years old and used IHS or tribal health services during fiscal year 2013 were included. All‐cause dementia and acute diabetes complications were identified using ICD‐9 diagnostic codes in the utilization data. Negative binomial regression models were used to evaluate the associations of interest after adjusting for potential confounders. Results: Nearly 3% (n = 843) of AI/AN diabetes patients had a dementia diagnosis. Among AI/ANs with diabetes, similar proportions of patients had a history of hospitalization or ED visits for hypoglycemia only (3.6%) or hyperglycemia only (4.1%). About 0.8% had both types of acute diabetes complications. As shown in Fig1, after controlling for demographics, health care coverage, and comorbidities, dementia diagnosis was associated with 94% higher rate of severe hypoglycemia (Incidence Rate Ratio [IRR = 1.94, 95% CI:1.50‐2.51), 52% higher rate of severe hyperglycemia (IRR = 1.52, 95% CI, 1.11‐2.08), and 92% higher rate of any acute complication (IRR = 1.92, 95% CI:1.53‐2.41). Dementia was not significantly associated with diabetic ketoacidosis (DKA) in the adjusted model (IRR = 1.82, 95% CI:0.83‐4.01). Further adjustments on clinical measurements and medications did not substantially change the estimated IRRs for hypoglycemia and hyperglycemia. Conclusions: AI/AN diabetes patients with dementia suffered from considerably higher rates of severe hypoglycemia and hyperglycemia than their counterparts without dementia. Clinical management of patients with comorbid diabetes and dementia is particularly challenging and requires individualized treatment approaches. [ABSTRACT FROM AUTHOR]

Introduction The Mediterranean and Dietary Approaches to Stop Hypertension diets have been associated with lower dementia risk. We evaluated dietary inflammatory potential in relation to mild cognitive impairment (MCI)/dementia risk. Methods Baseline food frequency questionnaires from n = 7085 women (aged 65–79 years) were used to calculate Dietary Inflammatory Index (DII) scores that were categorized into four groups. Cognitive function was evaluated annually, and MCI and all-cause dementia cases were adjudicated centrally. Mixed effect models evaluated cognitive decline on over time; Cox models evaluated the risk of MCI or dementia across DII groups. Results Over an average of 9.7 years, there were 1081 incident cases of cognitive impairment. Higher DII scores were associated with greater cognitive decline and earlier onset of cognitive impairment. Adjusted hazard ratios (HRs) comparing lower (anti-inflammatory; group 1 referent) DII scores to the higher scores were group 2-HR: 1.01 (0.86–1.20); group 3-HR: 0.99 (0.82–1.18); and group 4-HR: 1.27 (1.06–1.52). Conclusions Diets with the highest pro-inflammatory potential were associated with higher risk of MCI or dementia. [ABSTRACT FROM AUTHOR]

Background: Late‐life ambient air pollution is a novel risk factor for brain aging. Air quality improvement has been associated with improved cardiopulmonary health and reduced mortality; however, whether it is associated with reduced dementia risk is unknown. Method: We studied a geographically‐diverse cohort from the Women's Health Initiative Memory Study‐Epidemiology of Cognitive Health Outcomes (WHIMS‐ECHO). Participants included 2239 older women (aged 74‐92) without dementia at WHIMS‐ECHO enrollment in 2008‐12. Incident dementia cases, based on DSM‐IV criteria, were centrally‐adjudicated annually (2008‐18). Yearly mean concentrations of ambient PM2.5 (fine particulate matter) and NO2 at residential locations were estimated using validated regionalized universal kriging models. These annual estimates were then averaged over 3‐year periods at both immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS‐ECHO enrollment. Individual‐level improved air quality was defined as reduction from remote to recent exposures. We used Cox proportional hazard models to estimate the hazard ratios (HR) for dementia risk associated with air quality measures, adjusting for sociodemographic, lifestyle, and clinical characteristics. We incorporated inverse‐probability weighting to account for differential attrition during the follow up. Models were replicated using multiple imputation to include those with missing air pollution and covariate data as sensitivity analyses. Results: We identified 398 incident dementia cases during median 6.1 years of follow up (interquartile range [IQR]=5.2 years). PM2.5 and NO2 reduced significantly over the 10 years before WHIMS‐ECHO enrollment. Greater improvement in air quality was significantly associated with reduced dementia risks (HRPM2.5=0.80 per IQR=1.78µg/m3, 95% confidence interval [CI]=[0.71, 0.91]; HRNO2=0.80 per IQR=3.91ppb, 95%CI=[0.71, 0.90]), equivalent to the lower risk observed in women 2.4 years younger at baseline. There was some evidence that recent PM2.5 exposure was associated with higher dementia risk (HRPM2.5=1.16 per IQR=2.90µg/m3, 95%CI=[0.98, 1.38]), but the lower dementia risk associated with improved air quality remained after further adjusting for the recent exposure effects. The observed associations did not substantially differ by age, education, geographic region, APOE e4 genotypes, or cardiovascular risk factors. Similar results were found in the sensitivity analyses using multiple imputation. Conclusions: Long‐term air quality improvement in late‐life was associated with lower dementia risk in older women. [ABSTRACT FROM AUTHOR]

Background: Late‐life exposure to ambient air pollution is a modifiable risk factor for dementia, but epidemiological studies have shown inconsistent evidence for cognitive decline. Improved air quality (AQ) is associated with decreased mortality and improved respiratory health, but no studies have examined the association with cognitive function. Methods: Participants included 2,232 U.S. community‐dwelling older women (aged 74‐92) from the Women's Health Initiative Memory Study‐Epidemiology of Cognitive Health Outcomes (WHIMS‐ECHO) without dementia at enrollment. Measures of annual (2008‐18) cognitive function included general cognitive status (assessed by the Telephone Interview for Cognitive Status‐modified, TICSm) and episodic memory (assessed by the telephone‐based California Verbal Learning Test, CVLT). Regionalized universal kriging models were used to estimate annual exposures (1996‐2012) to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) at residential locations, which were averaged over the 3‐year periods immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS‐ECHO enrollment. Individual‐level improvements in AQ were calculated as the reduction from remote to recent exposures. We used linear mixed effect models to examine the associations between improved AQ and the rates of cognitive decline in TICSm and CVLT trajectories, adjusting for sociodemographic, lifestyle, and clinical characteristics. Results: AQ improved significantly for both PM2.5 and NO2 over the 10 years before enrollment. During a median of 6.2 (inter‐quartile‐range [IQR]=5.0) years of follow‐up, general cognitive status (βTICSm=‐0.42/year, 95% CI: ‐0.44, ‐0.40) and episodic memory (βCVLT=‐0.59/year, 95% CI: ‐0.64, ‐0.54) significantly declined. Greater AQ improvement was associated with slower decline in TICSm (βPM2.5=0.026/year per IQR=1.79 µg/m3, 95% CI: 0.001, 0.05; βNO2=0.034/year per IQR=3.92 ppb, 95% CI: 0.01, 0.06) and CVLT (βPM2.5=0.070/year per IQR=1.79 µg/m3, 95% CI: 0.02, 0.12; βNO2=0.060/year per IQR=3.97 ppb, 95% CI: 0.005, 0.12). The respective associations with TICSm and CVLT were equivalent to the slower declines found in women 0.9‐1.2 and 1.4‐1.6 years younger, and did not significantly differ by age, region, education, ApoE e4 genotypes, or cardiovascular risk factors. The benefits were attenuated after excluding incident dementia cases but remained after excluding prevalent or incident stroke cases. Conclusions: Long‐term improvement in AQ in late‐life was associated with slower cognitive declines in older women. [ABSTRACT FROM AUTHOR]

Background: Elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) are risk factors for white matter (WM) injury associated with cognitive decline and dementia. White matter hyperintensities (WMH) on MRI, markers of WM injury, increase with aging and are more common in women than in men after the age of 60. We examined SBP and DBP in relation to WMH volume and diffusion MRI measures of WM integrity in postmenopausal women. Method: Women (n=144) with median age of 67 (range 58‐72) and of good cardiovascular health who were previously enrolled in the multi‐site randomized clinical trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP, DBP, and MRI data were collected approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions. WM integrity was assessed with WMH volume measurements (log transformed) on structural MRI and with measures of WM microstructure on diffusion MRI. Multiple linear regression analyses, adjusted for age, were used to test for associations of SBP and DBP with MRI measures. Result: The median SBP was 128 (range 86‐180) and DBP was 77 (range 47‐106). Higher SBP (r=0.332;p=0.015) and DBP (r=0.346;p=0.007) were associated with higher WMH volumes. Among the WM tracts, higher SBP was associated with lower fractional anisotropy (FA) in lateral orbitofrontal gyrus WM (r=0.198;p=0.039) and sagittal stratum (r=0.226;p=0.043), and higher DBP was associated with lower FA in the superior occipital gyrus WM (r=0.370;p=0.045). Higher SBP and DBP were associated with higher mean diffusivity (MD) in the external capsule [(r=0.311;p=0.007);(r=375;p<0.001)] and the fronto‐occipital fasciculus [(r=0.286;p=0.016); (r=0.303;p=0.008)]. Furthermore, higher DBP was associated with higher MD in the anterior corona radiata (r=0.233;p=0.039), internal capsule (r=0.303;p=0.042), and the middle (r=0.275; p=0.03) and superior frontal gyrus (r=0.269;p=0.03) WM. Conclusion: Elevated SBP and DBP measurements are associated with greater WM injury in postmenopausal women. In particular, the frontal lobe WM and its connecting tracts may be more vulnerable to elevation in SBP and DBP. Whether BP control reduces the risk for WM injury, a risk factor for dementia, in post‐menopausal women warrants study. [ABSTRACT FROM AUTHOR]

Background: Genome‐wide DNA methylation assay (DNAm) reflects epigenetic aging and differences in gene expression, and may help to elucidate the role of systemic aging in cognitive decline. Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment (MCI) and may increase the risk of progression to dementia. However, few investigations have addressed whether genome‐wide differences in DNA methylation underlie presentations of NPS in MCI. Method: We included 45 older participants (mean age=70 years) from a depression prevention ancillary study (VITAL‐DEP) to the VITamin D and OmegA‐3 TriaL. We defined 3 groups: cognitively normal (CN; n=20); amnestic MCI (aMCI; n=16); non‐amnestic MCI (naMCI; n=9). Genomic DNA was extracted from leukocytes; DNA methylation was assayed using Illumina MethylationEPIC (Methyl850K chip). DNAm age metrics were computed using Horvath methods; genome‐wide differential methylation was examined among the 866,836 CpG sites in MethylationEPIC. Annotations were performed using Gene Ontology (GO) databases and tools. Result: The sample was balanced by age and sex across cognitive groups (CN and MCI). Participants with MCI had higher DNAmAge compared to those with CN [median (interquartile range): 66.4 (63.5‐71.1) vs. 65.3 (63.4‐69.2)]. Comparing MCI vs. CN, there were 48 CpG sites at p<1x10‐4, but not genome‐wide‐significant, suggesting possible differential methylation in novel genes. For example, over‐representation analysis revealed genes associated with dysregulation of the tight junction (ACTR3, TUBA4A, JUN) and one‐carbon folate pathways (DPYD, GART), suggesting blood‐brain barrier dysfunction and metabolic dysregulation. Comparing MCI with vs. without NPS, there were 49 CpG sites at p<1x10‐4, but not genome‐wide significant. Top hits in GO suggested involvement of negative regulation of neuron projection development (KANK1, RAP1GAP2), activation of protein kinase C activity (PARD3, F2R), regulation of blood coagulation (STXBP5, F2R), and glycosaminoglycan degradation (HSPG2, HGSNAT). Functional annotations suggested involvement of important cellular pathways (e.g., serotonergic synapse, alpha‐linolenic metabolism, calcium signaling). Further, several identified genes had prior reports as summarized in the AlzGene database (e.g., PPP1R10, HSPG2). Conclusion: Genome‐wide differential methylation in DNAm analysis suggested potential genomic variations in MCI vs. CN and in NPS among patients with MCI. If confirmed, such genomic biomarkers could inform development of targets in prevention studies. [ABSTRACT FROM AUTHOR]

Background: DNA 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. Method: Participants 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. Result: Among 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. Conclusion: Blood‐based AgeAccel may be a marker of cognitive and brain health among women with underlying vascular pathologies. [ABSTRACT FROM AUTHOR]

Background: 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). Method: 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. Result: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Introduction Consistent evidence linking habitual sleep duration with risks of mild cognitive impairment (MCI) and dementia is lacking. Methods We conducted a prospective study on 7444 community-dwelling women (aged 65–80 y) with self-reported sleep duration, within the Women's Health Initiative Memory Study in 1995–2008. Incident MCI/dementia cases were ascertained by validated protocols. Cox models were used to adjust for multiple sociodemographic and lifestyle factors, depression, cardiovascular disease (CVD), and other clinical characteristics. Results We found a statistically significant ( P = .03) V-shaped association with a higher MCI/dementia risk in women with either short (≤6 hours/night) or long (≥8 hours/night) sleep duration (vs. 7 hours/night). The multicovariate-adjusted hazard for MCI/dementia was increased by 36% in short sleepers irrespective of CVD, and by 35% in long sleepers without CVD. A similar V-shaped association was found with cognitive decline. Discussion In older women, habitual sleep duration predicts the future risk for cognitive impairments including dementia, independent of vascular risk factors. [ABSTRACT FROM AUTHOR]

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Background: Ambient air pollution, especially fine particulate matter (aerodynamic diameter <2.5 μm; PM2.5), is a novel neurotoxin. Psychosocial stress has been linked to Alzheimer's disease (AD) and other dementias (ADRD). We test the hypothesis that PM2.5 and psychosocial stress may interact to accelerate brain aging, by investigating their potential joint effects on neuroanatomic risk for AD. Method: Community‐dwelling older women (aged 71‐89) from the Women's Health Initiative (WHI) Memory Study of MRI completed two structural brain MRI scans (MRI‐1: 2005‐6; MRI‐2: 2010‐11). To focus on the preclinical stage, we excluded women who developed MCI or dementia over follow‐up. The AD pattern similarity (AD‐PS) score, developed by supervised machine learning and validated with the AD Neuroimaging Initiative data, was used to determine the degree of high‐dimensional gray matter atrophy in brain areas vulnerable to AD. Residential three‐year average PM2.5 exposure preceding MRI‐1 were aggregated from daily estimates, based on nationwide spatiotemporal modeling. A structured questionnaire was administered to gather information on the frequency of stressful life events (SLEs) and self‐reported sleep duration. Sleep disturbance was measured using the WHI Insomnia Rating Scale, with higher numbers indicating greater insomnia. We examined whether the source (frequency of SLEs) or behavioral manifestation (sleep disturbance; sleep duration) of psychosocial stress modified the association between PM2.5 and AD‐PS scores (5‐year standardized difference) using generalized linear models. Result: Among 542 women, PM2.5 (per 2.87 µg/m3 increase) was significantly associated with increased AD‐PS scores (β=0.020; p=0.028), adjusting for geographic region, age, socioeconomic status, lifestyle, clinical characteristics, hormone therapy use, and intracranial volume. This negative association with PM2.5, equivalent to a 7% increase in the relative risk for ADRD, was greater among women reporting high (β=0.041; p=0.004) vs. low (β=0.008; p=0.460) frequencies of SLEs (pinteraction=0.06) and among women reporting high (β=0.040; p=0.003) vs. low (β=0.005; p=0.702) sleep disturbance (pinteraction=0.04). There was no evidence of effect modification by sleep duration. Conclusion: Our novel findings suggest psychosocial stress may increase susceptibility to PM2.5 neurotoxicity based on neuroanatomic AD risk at the preclinical stage. Psychosocial stress may lower the brain's threshold to neurotoxicity, further accelerating the PM2.5‐induced neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Late‐life exposure to ambient air pollutants may accelerate episodic memory (EM) declines in older women, but very little is known about the midlife exposure effects. Animal data suggests that hormone therapy (HT) may protect female brain from neurotoxic insult. We examined the EM trajectories associated with air pollutants and whether the associations varied by HT, exposure time‐window or pollution sources. Method: We studied 916 women from the Women's Health Initiative Memory Study in Younger (WHIMS‐Y) Women. At age of 50‐54, postmenopausal women were randomly assigned to an average of 5 years of conjugated equine estrogen alone (E‐alone) if they had hysterectomy, its combination with medroxyprogesterone acetate (E+P) if without hysterectomy or matching placebos. From the WHIMS‐Y inception age of 62‐71, EM was assessed annually (2008‐16) using the telephone‐based California Verbal Learning Test. Three‐year average exposures at midlife (aged 50‐59) and late‐life (at inception) were derived from yearly exposures estimated by regionalized universal kriging models for PM2.5 (particulate matter <2.5μm) and NO2 (a proxy of traffic‐related air pollutants). We used linear mixed‐effect models to estimate the associations, adjusting for social‐demographic variables, lifestyles, HT, hysterectomy, cardiovascular risk factors and other clinical covariates. Result: EM performance improved (0.60/year, p<0.001) over the study period. Higher PM2.5 exposures in midlife, but not in late‐life, were associated with lower EM levels (β=‐0.49, per inter‐quartile‐range [IQR]=3.44 µg/m3, p=0.045). NO2 exposures in midlife or late‐life were not associated with EM levels. Compared to the women assigned to placebo group, the observed association between midlife PM2.5 and EM level differed by HT (interaction p=0.005). The putative adverse PM2.5 effect was greater (β=‐1.29 per IQR; p=0.03) in the E‐alone group, with no statistically significant difference in the E+P group (p=0.16). A similar pattern of effect modification was found for NO2 exposure (interaction p=0.09) in midlife, but not in late‐life. The slope of EM trajectory was not associated with either exposure, HT, or their interactions. Conclusion: Higher midlife PM2.5 exposure decrease the EM levels of older women, with stronger associations in those randomly assigned to E‐alone treatment, which did not support the protection of HT against air pollution neurotoxicity. [ABSTRACT FROM AUTHOR]

Background: Identification of factors that help preserve cognitive function in late life could facilitate interventions that can improve the lives of millions of people as they age. However, the large number of potential factors associated with cognitive resiliency pose an analytical challenge. Machine learning can be used to discover complex functional relationships in high dimensional data. We used data from the Women's Health Initiative Memory Study (WHIMS) and Random Forests (RF) methods to investigate predictors of cognitive resiliency in 80+ year old women from a set of demographic, biological, behavioral, social, and psychological variables. Method: We included WHIMS women who were at least 80 years old as of 01/01/18, and had at least one cognitive assessment following their 80th birthday. We created two groups of participants: a cognitively resilient group and an impaired group of participants. The cognitively resilient group (N=205) included participants: (a) not previously adjudicated to have mild cognitive impairment (MCI) or probable dementia; (b) had a score >39 on the most recent administration of the TICSm and (c) the average of scores in previous visits>=39. The cognitively impaired group (N=176) included participants: (a) adjudicated with probable dementia within the first 14 years of follow‐up or; (b) who had at least two classifications of MCI within the first 14 years of follow‐up and (c) whose last TICS score was<31. RF classification was used to identify discriminative predictors of these two groups based on 67 baseline variables available in WHIMS. Analyses used the randomForestSRC R library. The minimal depth index (MDI) was used to determine predictors' relevance. Result: Discrimination between the resilient and impaired groups based on area under the curve was 0.80(95% CI‐0.76‐0.85). Figure 1 shows that according to the MDI values the most relevant predictors were age, self‐reported forgetfulness, physical function, optimism, hemoglobin, glucose, sleep disturbances, education, systolic pressure and depression. Conclusion: We investigated discrimination of cognitively resilient older women from women who develop cognitive impairment using machine learning applied to a large set of predictors. The potential contributors to cognitive resilience include demographic, psychological, physical, metabolic and vascular factors suggesting multiple influences contributing to cognitive resiliency. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes and mid‐life obesity increase the risk for cognitive decline and cognitive impairment in men and women. Studies disagree, however, on whether the associations diabetes and obesity have with cognitive function vary by sex. Method: We analyzed data from the COSMOS clinical trial and its COSMOS‐Mind ancillary study of cocoa extract (including 600 mg/d cocoa flavanols) and a multivitamin to reduce risks for major cardiovascular events and total invasive cancer (COSMOS), and cognitive decline (COSMOS‐Mind). In COSMOS‐Mind we administered a standardized telephone‐based cognitive battery to assess episodic memory, executive function and global cognition in 2,262 adults, age>65 (mean=73) years, 58% women, 33% obese (body mass index >30 kg/m2), and 10% diabetes. Individuals with histories of myocardial infarction, stroke, or cancer (excluding non‐melanoma skin cancer) were excluded. Sex, obesity, and diabetes were based on self‐report. Multiple regression analyses were used to compare cross‐sectional associations between cognitive function and age for women and men grouped by obesity and diabetes, with adjustments for education and race/ethnicity. Result: Women averaged better scores than men for memory (mean+standard error difference=0.42+0.04 SDs), executive function (0.26+0.04 SDs), and global cognitive function (0.30+0.4 SDs), all p<0.001. These differences were evident for individuals both with and without obesity or diabetes (all two‐way interactions p>0.20). Obesity, compared with no obesity, was associated with less steep slopes with greater age among women in all domains (all p<0.04), with no differences seen in men for any domain. This held without and with adjustment for diabetes. For composite cognitive function, the slope of the association with greater age was ‐0.064+0.005 SD/year among women without obesity compared with ‐0.030+0.009 SD/year among those with obesity (p=0.001), and the differences between women and men with obesity increased with age. After adjustment for obesity, diabetes was not associated with steeper slopes with age for any domain in either sex. Conclusion: In the COSMOS‐Mind cohort of clinical trial volunteers, the difference in cognitive function between women and men with obesity increased with age. However, in these cross‐sectional analyses we cannot rule out potential biases related to self‐report or differential survival. [ABSTRACT FROM AUTHOR]

Background: Clonal Hematopoiesis of Indeterminate Potential (CHIP) occurs when hematopoietic stem cells in bone marrow undergo somatic mutations and yield genetically distinct leukocyte subpopulations with increased expression of inflammatory genes in innate immune cells. Genes commonly mutated in CHIP are associated with DNA methylation, inflammation, generation of reactive oxygen species, and DNA damage response. Factors associated with CHIP, including inflammation, cardiovascular disease (CVD), metabolic disorders, and stroke are risks for Alzheimer's disease and other dementias, however the association between CHIP and dementia is unknown. We examined the association between CHIP and the incidence of MCI or probable dementia over 22 years of follow‐up in the Women's Health Initiative Memory Study (WHIMS). We also examined these associations by common driver mutations for CHIP. Method: Women without a baseline (1993‐1998) history of stroke, who participated in WHIMS and had baseline blood sample, were followed with annual cognitive assessments, adjudication of MCI or probable dementia, and provided self‐report of dementia diagnoses for up to 22 years. CHIP was defined by whole genome sequencing through TOPMed. Proportional hazards models were used to examine survival to onset of cognitive impairment (mild cognitive impairment (MCI), probable dementia, or self‐reported dementia). Result: We classified 934 women into two groups, CHIP (11%) and no CHIP (89%). A total of 300 women developed cognitive impairment by Year 22. Survival analyses for time to cognitive impairment was adjusted for baseline age, education, 3MS score, hypertension, diabetes, and BMI. There was no difference in risk of cognitive impairment between the women with and without CHIP (p = 0.63). When CHIP was categorized by gene‐specific driver mutations, survival free of impairment among women with DNMT3A mutations was not different from those without CHIP. Risk for impairment was higher among women with TET2 (HR 1.75, p=0.19). Overall results were not statistically significant, however power was limited by low numbers of women with CHIP (see Figure). Conclusion: CHIP was not associated with cognitive outcomes overall but when stratified by the primary CHIP mutations (DNMT3A or TET2), different trends emerged. Future work in WHIMS will explore the cognitive performance over time by different CHIP mutations. [ABSTRACT FROM AUTHOR]

We review and analyze the historical development and challenges facing ecology as a science in Mexico, a country with limited financial and human (one scientist per 5000 inhabitants) resources and numerous environmental problems. We outline a set of research, collaborative, and financial strategies that could help to strengthen the role of ecological science in decision-making processes, and increase cutting-edge research, thus helping to foster economic sustainability and human well-being in the country. Both curiosity driven and applied research will be important in this context. Interdisciplinary and inter-institutional approaches, as well as international collaborations, are also key elements in the continued development of ecology in Mexico. Ecological knowledge is predicted to play an increasingly important role in promoting the conservation and sustainable use of Mexico's natural resources and rich biodiversity. As the history and development of ecology in Mexico parallels other Latin American countries, some of our recommendations for the future of ecology in Mexico may apply elsewhere in Central and South America. [ABSTRACT FROM AUTHOR]

Background: Our knowledge regarding dementia epidemiology for American Indians and Alaska Natives (AI/ANs) is very limited. Longitudinal electronic health record (EHR) data available in the Indian Health Service (IHS) provides an opportunity to estimate dementia prevalence and incidence among AI/ANs at the national level. However, as with other EHR‐based studies, identifying dementia patients via clinical diagnostic codes likely underestimates the prevalence of dementia. Furthermore, longitudinal studies of dementia using EHR could be challenging if some prevalent cases of dementia cannot be identified at baseline, which might be mistakenly considered as incident cases in subsequent years. Methods: We extracted data from the IHS National Data Warehouse and related EHR databases between fiscal year (FY) 2007‐2013. Adults were identified as having dementia if they had at least one qualifying ICD‐9 diagnostic code for all‐cause dementia. A total of 1,117 AI/AN adults who were 45+ years old were identified as dementia patients in FY2007. Among these patients, we evaluated the number of years needed to correctly classify them as prevalent cases using data after FY2007. We also examined the impact of different dementia definitions on our ability to identify these prevalent cases using FY2008‐2013 data. Results: Among the FY2007 dementia patients who used IHS services in FY2008, only 63.7% of them were identified as having dementia in FY2008. The remaining 36.3% prevalent cases might be classified as incident cases if they have a qualifying diagnostic code after FY2008. Even when we used a 5‐year window (FY2008‐FY2012), only 78.9% of the FY2007 dementia patients were identified as prevalent cases. Among dementia patients who were 65+ years old in FY2007, a 5‐year window correctly identified 87.7% of the FY2007 dementia patients as prevalent cases. Altering the definition of dementia by adding dementia medications or diagnostic codes for other types of cognitive disorders did not substantially change our ability in distinguishing prevalent vs. incident cases of dementia. Conclusions: It is challenging to distinguish dementia prevalent and incident cases using EHR data from the IHS. The accuracy of estimating prevalence and incidence of dementia using this data source might be higher among older patients. [ABSTRACT FROM AUTHOR]

Background: High intake of marine omega‐3 (n‐3) fatty acids has been associated with lower risk of cognitive decline; however, few large‐scale, long‐term randomized trials have been conducted. We evaluated n‐3 supplementation (1 gram/day, including 840 mg of EPA + DHA) and change in cognitive function over 2‐3 years. Method: Community‐dwelling participants aged 60+ years (mean[SD]=70.9[5.8]y) in the Vitamin D and Omega‐3 Trial (VITAL) were included: 3424 had cognitive function assessment by phone (VITAL‐Cog; 8 neuropsychological tests; mean follow‐up=2.8 years) and 794 were evaluated in‐person at the Harvard Clinical and Translational Science Center (CTSC‐Cog; 9 neuropsychological tests; mean follow‐up=2.0 years). The primary, pre‐specified outcome was a global composite score (average z‐scores across all tests) of change over two assessments. We used multivariable‐adjusted linear mixed models and meta‐analyzed the results for the two settings. Result: We observed no significant effect of n‐3 supplementation on the global composite score: the mean difference in annual rate of change for the n‐3 versus placebo group was ‐0.01 standard units (95% CI:‐0.02,0.003) in VITAL‐Cog and ‐0.002 (95% CI:‐0.04,0.03) in CTSC‐Cog; the pooled mean difference was ‐0.01 (95%CI:‐0.02,0.003; p=0.15). For secondary outcomes of change in verbal memory, executive function/attention and general cognition, we observed null results to trends of adverse associations with n‐3 treatment versus placebo that were not statistically significant after multiple‐testing correction. In pre‐specified secondary analyses, we observed no significant interaction of the intervention with baseline plasma omega‐3 fatty acid levels for the global composite score (pooled p‐interaction=0.37). Conclusion: Marine n‐3 supplementation (1 gram/day) did not confer cognitive benefits over 2‐3 years in community‐dwelling older adults. [ABSTRACT FROM AUTHOR]

Chemical contaminants may play a role in the etiology of external skin lesions on walleyes Stizostedion vitreum in the Great Lakes. We examined the population of walleyes spawning in the Thames River, Ontario, for skin lesions, and compared contaminant levels in walleyes with conspicuous lesions to contaminant levels in visibly normal walleyes. In 1987, 9% of postspawning downstream migrants exhibited skin lesions. Twenty affected fish, many with multiple abnormalities, were autopsied and the external skin lesions were examined histologically. Eight walleyes were affected by only lymphocystis, seven by only dermal sarcoma, four by both conditions, and one by a calcareous nodule; 68% of the individual lesions affecting these walleyes were lymphocystis. Muscle tissue from the walleyes with lymphocystis or dermal sarcoma had lower concentrations of polychlorinated biphenyls, hexachlorobenzene, and the DDT metabolite p, p-DDE than did muscle from unaffected walleyes. Thus, it appears unlikely that contaminants, such as measured in this study, increase the susceptibility of these walleyes to skin diseases such as lymphocystis and dermal sarcoma. [ABSTRACT FROM AUTHOR]

The article presents a study on three cases of ichthyosis follicularis. He discusses the significance of these studies giving the uncommon occurence of the condition as the main reason. Next is the unusual distribution of these cases in the patients who were studied. The disease is described since the children were born.

Suggests the usefulness of a closer cooperation between those who employ, for professional or scientific reasons, some form of conversation. Types of worker that are professionally interested in conversation; Study of the features of conversation; Biosocial value of conversation.