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Antihypertensive treatments have been shown to reduce the risk of Alzheimer's disease (AD). The renin-angiotensin system (RAS) has been implicated in AD, and thus RAS-acting AHTs (angiotensin converting enzyme inhibitors (ACEIs), and angiotensin-II receptor blockers (ARBs)) may offer differential and additional protective benefits against AD compared with other AHTs, in addition to hypertension management. In a retrospective cohort design, we examined the medical and pharmacy claims of a 20% sample of Medicare beneficiaries from 2007 to 2013, and compared rates of AD diagnosis for 1,343,334 users of six different AHT drug treatments, 65 years of age or older (4,215,338 person-years). We compared AD risk between RAS and non-RAS AHT drug users, and between ACEI users and ARB users, by sex and race/ethnicity. Models adjusted for age, socioeconomic status, underlying health, and comorbidities. RAS-acting AHTs were slightly more protective against onset of AD than non-RAS-acting AHTs for males, (male OR = 0.931 (CI: 0.895-0.969)), but not so for females (female OR = 0.985 (CI: 0.963-1.007)). Relative to other AHTs, ARBs were superior to ACEIs for both men (male ARB OR = 0.834 (CI: 0.788-0.884); male ACEI OR = 0.978 (CI: 0.939-1.019)) and women (female ARB OR = 0.941 (CI: 0.913-0.969); female ACEI OR = 1.022 (CI: 0.997-1.048)), but only in white men and white and black women. No association was shown for Hispanic men and women. Hypertension management treatments that include RAS-acting ARBs may, in addition to lowering blood pressure, reduce AD risk, particularly for white and black women and white men. Additional studies and clinical trials that include men and women from different racial and ethnic groups are needed to confirm these findings. Understanding the potentially beneficial effects of certain RAS-acting AHTs in high-risk populations is of great importance.

Hyperlipidemia and hypertension are modifiable risk factors for Alzheimer's disease and related dementias (ADRD). Approximately 25% of adults over age 65 use both antihypertensives (AHTs) and statins for these conditions. While a growing body of evidence found statins and AHTs are independently associated with lower ADRD risk, no evidence exists on simultaneous use for different drug class combinations and ADRD risk. Our primary objective was to compare ADRD risk associated with concurrent use of different combinations of statins and antihypertensives. In a retrospective cohort study (2007-2014), we analyzed 694,672 Medicare beneficiaries in the United States (2,017,786 person-years) who concurrently used both statins and AHTs. Using logistic regression adjusting for age, socioeconomic status and comorbidities, we quantified incident ADRD diagnosis associated with concurrent use of different statin molecules (atorvastatin, pravastatin, rosuvastatin, and simvastatin) and AHT drug classes (two renin-angiotensin system (RAS)-acting AHTs, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin-II receptor blockers (ARBs), vs non-RAS-acting AHTs). Pravastatin or rosuvastatin combined with RAS-acting AHTs reduce risk of ADRD relative to any statin combined with non-RAS-acting AHTs: ACEI+pravastatin odds ratio (OR) = 0.942 (CI: 0.899-0.986, p = 0.011), ACEI+rosuvastatin OR = 0.841 (CI: 0.794-0.892, p<0.001), ARB+pravastatin OR = 0.794 (CI: 0.748-0.843, p<0.001), ARB+rosuvastatin OR = 0.818 (CI: 0.765-0.874, p<0.001). ARBs combined with atorvastatin and simvastatin are associated with smaller reductions in risk, and ACEI with no risk reduction, compared to when combined with pravastatin or rosuvastatin. Among Hispanics, no combination of statins and RAS-acting AHTs reduces risk relative to combinations of statins and non-RAS-acting AHTs. Among blacks using ACEI+rosuvastatin, ADRD odds were 33% lower compared to blacks using other statins combined with non-RAS-acting AHTs (OR = 0.672 (CI: 0.548-0.825, p<0.001)). Among older Americans, use of pravastatin and rosuvastatin to treat hyperlipidemia is less common than use of simvastatin and atorvastatin, however, in combination with RAS-acting AHTs, particularly ARBs, they may be more effective at reducing risk of ADRD. The number of Americans with ADRD may be reduced with drug treatments for vascular health that also confer effects on ADRD.

Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women. KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was -5.36 × 10(-2) (95% CI, -8.27 × 10(-2) to -2.44 × 10(-2); ES = 0.49, p < 0.001) and for the anxiety subscale was -3.01 × 10(-2) (95% CI, -5.09 × 10(-2) to -9.34 × 10(-3); ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y. The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles. ClinicalTrials.gov NCT00154180 and NCT00623311.

Black transgender women endure pervasive polyvictimization (experiencing multiple forms of violence throughout the lifespan). Polyvictimization is associated with poor mental health. Black transgender women also face barriers in access to healthcare, but the extent that such barriers modify the association between polyvictimization and poor mental health has not been described using convergent mixed-methods analysis. This convergent mixed-methods secondary analysis employs an intersectional lens and integrates two inter-related datasets to describe barriers to healthcare and the extent that such barriers modify the association between polyvictimization and mental health among Black transgender women. Investigators used survey data (n = 151 participants) and qualitative interview data (n = 19 participants) collected from Black transgender women (age 18 years and older) in Baltimore, MD and Washington, DC between 2016 and 2018. Analyses include thematic content analysis, bivariate analysis, joint display, and multivariate linear regression analysis examining mediation and moderation. Joint display illuminated three domains to describe how barriers to healthcare present among Black transgender women-Affordability, Accessibility, and Rapport and Continuity. Independent t-tests revealed significantly higher polyvictimization, Post Traumatic Stress Disorder (PTSD), and depression scores among participants who reported at least one barrier to healthcare (BHI) compared to those who reported no barriers. BHI significantly moderated and partially mediated the association between polyvictimization and PTSD symptom severity and BHI fully mediated the association between polyvictimization and depressive symptom severity-when accounting for age and location. Findings highlight the importance of access to healthcare in modifying the association between polyvictimization and PTSD and depression symptom severity among Black transgender women. Findings call for immediate interventions aimed at reducing barriers to healthcare and improved training for clinical providers serving Black transgender women.

Among patients with coronavirus disease (COVID-19), IgM levels increased early after symptom onset for those with mild and severe disease, but IgG levels increased early only in those with severe disease. A similar pattern was observed in a separate serosurveillance cohort. Mild COVID-19 should be investigated separately from severe COVID-19.

Introduction Subjective cognitive decline (SCD) represents self‐reported problems with memory, a possible early sign of dementia. Little is known about SCD among sexual and gender minority (SGM) adults who identify as lesbian, gay, bisexual, and/or transgender or gender non‐binary. Methods Data were weighted to represent population estimates from 25 states’ 2015–2018 Behavioral Risk Factor Surveillance System to describe SCD in adults ≥45 years by SGM status. Logistic regression tested associations between demographic and health conditions. Results SCD prevalence was higher in SGM (15.7%; 95% confidence interval [CI]:13.1–18.2) than in non‐SGM adults (10.5%; 95% CI:10.1–10.9; P < .0001). SGM adults with SCD were also more likely to report functional limitations due to SCD than non‐SGM adults with SCD, 60.8% versus 47.8%, P = .0048. Differences in SCD by SGM status were attenuated after accounting for depression. Discussion Higher prevalence of SCD in SGM adults highlights the importance of ensuring inclusive screenings, interventions, care services, and resources for SGM adults.

Neuroprotective properties of estrogen have poorly translated to reduced neurodegeneration in clinical trials of systemic estrogen replacement therapy. To more directly assess biological processes associated with brain estrogen (estrone, estradiol) levels, we recruited 81 women (42 non-white) and 28 men (13 non-white) for cerebrospinal fluid (CSF) hormone, targeted proteomic, and volumetric brain analysis. In the mostly post-menopausal women, we found CSF estrogen levels to only modestly correlate with their corresponding plasma levels, and were additionally influenced by body mass index or age. CSF estrone was also correlated with a marker of Alzheimer’s disease (AD) neuropathologic change (CSF Aβ42/Aβ40), but this was not the case for the more biologically active CSF estradiol. Aptamer-based proteomic analysis of 1,075 CSF markers for inflammation, proteolysis, signaling, and DNA/RNA regulation revealed CSF estrogen levels to associate with alternative complement pathway proteins, and shifts observed in AD (apoE, RAGE). Parallel MRI analysis correlated higher CSF estrogen with smaller volumes of the brain somatosensory and posterior-medial networks without influence from cognition or neurodegeneration. Analysis using plasma estrogens only partially reproduced CSF estrogens’ biochemical correlates but provided inconclusive relationships with brain volume correlates. These findings highlight the association between CSF levels of the more biologically active estradiol and CSF inflammatory pathways involving AD risk genes as potential mechanisms linking hormone status to AD risks, and suggest caution in using CSF estrone or plasma estrogens when interpreting treatment or preventive studies.

Introduction African Americans (AA)s have worse inflammation, worse sleep, and a greater incidence of Alzheimer's disease (AD) compared to whites; however, no studies have examined associations between biomarkers, sleep, and cognition, and differences by race. Methods Seventy‐six cognitively normal, middle aged (45–65 years) adults with a parental history of AD were included in this study. Associations between biomarkers (tumor necrosis factor‐α [TNF‐α], interleukin‐10 [IL‐10], intercellular adhesion molecule‐1 [ICAM‐1],, and C‐reactive protein [CRP]) and self‐reported sleep or cognition measures, were assessed. Results Average sleep duration was significantly lower for AA versus whites (average[SD]) in hours: 6.02(1.18) versus 7.23(0.91), P = .000004). We found a statistically significant association between plasma IL‐10 and sleep duration (Spearman's ρ = 0.26, P = .04) and CSF ICAM‐1 and sleep quality (Spearman's ρ = 0.30, P = .03). Discussion Longer sleep duration is positively associated with plasma IL‐10 levels irrespective of race. Sleep quality was positively associated with CSF ICAM‐1 only in African Americans.

INTRODUCTION Past Alzheimer's disease and related dementias (ADRD) research has not considered ways to ensure the representation of diverse sexual and gender minorities. This study used concept mapping (CM) to identify strategies for engaging and recruiting LGBTQIA+ older adults living with memory loss and their caregivers into ADRD research. METHODS CM, involving brainstorming, thematic analysis, and rating of strategies, was conducted with 46 members from one national and three local community advisory boards. Data was analyzed using The Concept Systems Global MAX™ web platform. RESULTS One hundred twenty‐two solutions were identified from June through December 2022, and represented five key themes: aging focused, LGBTQIA+ specific, memory loss and caregiving support focused, physical advertisements, and other media. Promising strategies included partnering with LGBTQIA+ health centers, attending social groups for older adults, and increasing community representation in marketing. DISCUSSION Tailored strategies, building trust, and community involvement are essential for engaging LGBTQIA+ individuals living with memory loss or ADRD and their caregivers in ADRD‐focused research. Highlights Innovative ways to ensure the inclusion of LGBTQIA+ older adults in Alzheimer's disease and related dementias (ADRD) research can be bolstered through collaboration with key community stakeholders. Promising strategies for recruitment and engagement include partnering with LGBTQIA+ centers, attending social groups for older adults, and ensuring diverse representation in marketing. Tailored recruitment and engagement strategies are crucial for building trust with LGBTQIA+ populations to increase participation in ADRD research.

INTRODUCTION Equol, a gut microbiome‐derived metabolite of soy isoflavone daidzein, functions as a selective estrogen receptor beta (ERβ) agonist. In preclinical studies, it has demonstrated vascular protective and antioxidant effects, with emerging evidence suggesting potential neuroprotective properties. However, its role in preventing vascular aging and cognitive decline in humans remains unexplored. The Arterial Stiffness, Cognition, and Equol (ACE) trial investigates whether daily equol supplementation can slow the progression of arterial stiffness, brain white matter lesions, and cognitive decline in older adults without dementia. METHODS ACE is a multicenter, randomized, double‐blind, placebo‐controlled clinical trial conducted at the University of Pittsburgh, Wake Forest University, and Emory University. Community‐dwelling adults aged 65 to 85 years without dementia were enrolled and randomized 1:1 to receive either 10 mg/day of equol or placebo for 24 months. The primary outcome is arterial stiffness assessed by carotid‐femoral pulse wave velocity. Secondary outcomes include white matter lesions detected on the brain magnetic resonance imaging and cognitive function as assessed by the Preclinical Alzheimer Cognitive Composite. Power calculations were based on a planned sample size of 400 participants, accounting for an anticipated 20% attrition rate. RESULTS A total of 1783 individuals were pre‐screened, and 764 underwent in‐person eligibility assessment. Of these, 369 participants were randomized into two groups: Arm A (n = 185) and Arm B (n = 184). The randomized sample self‐reported as 52% women and 22% Black/African American participants. Baseline demographic and clinical characteristics were well balanced between the two arms, indicating successful randomization. DISCUSSION ACE successfully enrolled a racially diverse population of older adults and achieved near‐target recruitment. ACE is the first large‐scale trial to evaluate whether equol, a selective ERβ agonist, can impact vascular and cognitive aging, paving the way for precision nutrition strategies in dementia prevention. Highlights We detail the first randomized controlled trial of equol, an estrogen receptor beta (ERβ) agonist, for vascular and cognitive aging. The study tested equol's effects on arterial stiffness, white matter lesions, and cognition. The multisite trial enrolled 369 self‐reported White and Black older adults aged 65 to 85 years. The trial investigated a novel dietary metabolite targeting ERβ pathways.