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Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P

According to the Household Pulse Survey conducted by the US Centers for Disease Control and Prevention in January 2023, up to 15% of all US adults had experienced >1 symptoms [...]

Background and objectivesPrevious studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.MethodsWe included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (

Background and objectivesThere are disparities in the prevalence of obesity by race, and the relationship between obesity and cognitive decline is unclear. The objective of this study was to determine whether obesity is independently associated with cognitive decline and whether the association between obesity and cognitive decline differs in Black and White adults. We hypothesized that obesity is associated with greater cognitive decline compared with normal weight and that the effect of obesity on cognitive decline is more pronounced in Black adults compared with their White counterparts.MethodsWe pooled data from 28,867 participants free of stroke and dementia (mean, SD: age 61 [10.7] years at the first cognitive assessment, 55% female, 24% Black, and 29% obese) from 6 cohorts. The primary outcome was the annual change in global cognition. We performed linear mixed-effects models with and without time-varying cumulative mean systolic blood pressure (SBP) and fasting plasma glucose (FPG). Global cognition was set to a t-score metric (mean 50, SD 10) at a participant's first cognitive assessment; a 1-point difference represents a 0.1 SD difference in global cognition across the 6 cohorts. The median follow-up was 6.5 years (25th percentile, 75th percentile: 5.03, 20.15).ResultsObese participants had lower baseline global cognition than normal-weight participants (difference in intercepts, -0.36 [95% CI, -0.46 to -0.17]; p < 0.001). This difference in baseline global cognition was attenuated but was borderline significant after accounting for SBP and FPG (adjusted differences in intercepts, -0.19 [95% CI, -0.39 to 0.002]; p = 0.05). There was no difference in the rate of decline in global cognition between obese and normal-weight participants (difference in slope, 0.009 points/year [95% CI, -0.009 to 0.03]; p = 0.32). After accounting for SBP and FPG, obese participants had a slower decline in global cognition (adjusted difference in slope, 0.03 points/year slower [95% CI, 0.01 to 0.05]; p < 0.001). There was no evidence that race modified the association between body mass index and global cognitive decline (p = 0.34).DiscussionThese results suggest that obesity is associated with lower initial cognitive scores and may potentially attenuate declines in cognition after accounting for BP and FPG.

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals and cis-gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM2.5) and oxides of nitrogen (NOX) were estimated at participants' homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals and cis-gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or near SDHAP3, ZFP57, HOXA5, and PRM1, respectively) were associated with PM2.5. The DMRs on chromosomes 5 and 6 also associated with NOX. The DMR on chromosome 5 had the smallest p-value for both PM2.5 (p = 1.4×10-6) and NOX (p = 7.7×10-6). Three differentially methylated CpGs were identified for PM2.5, and cg05926640 (near TOMM20) had the smallest p-value (p = 5.6×10-8). NOX significantly associated with cg11756214 within ZNF347 (p = 5.6×10-8). Several differentially methylated signals were also associated with cis-gene expression. The DMR located on chromosome 7 was associated with the expression of HOXA5, HOXA9, and HOXA10. The DMRs located on chromosomes 5 and 16 were associated with expression of MRPL36 and DEXI, respectively. The CpG cg05926640 was associated with expression of ARID4B, IRF2BP2, and TOMM20. We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.

IntroductionTo examine the independent association of body mass index (BMI) in early adulthood with dementia incidence among men and women.MethodsWe studied 5104 older adults from the Cardiovascular Health Study (CHS) and the Health, Aging, and Body Composition (Health ABC) study. We imputed early adulthood and midlife BMI using a pooled parent cohort with complete adult lifespan coverage and previously established methods. Dementia was ascertained using criteria such as neuropsychological test battery, medical records, and dementia-related drug use. Pooled logistic regression (PLR) models were used.ResultsCompared to women with normal BMI in early adulthood, the odds of dementia were higher among both overweight (odds ratio [OR] = 1.8; 95% confidence interval [CI] = 1.31 to 2.54) and obese (OR = 2.45; 95% CI = 1.47 to 4.06) women, independent of mid- and late-life BMI. Similar relationship was observed in men.ConclusionsWith the growing obesity epidemic among US adults, efforts aimed at reducing dementia may need to begin obesity prevention and treatment early in the life course.

Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (

BackgroundLimited data suggest air pollution exposures may contribute to pediatric high blood pressure (HBP), a known predictor of adult cardiovascular diseases.MethodsWe investigated this association in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study, a sociodemographically diverse pregnancy cohort in the southern United States with participants enrolled from 2006 to 2011. We included 822 mother-child dyads with available address histories and a valid child blood pressure measurement at 4-6 y. Systolic (SBP) and diastolic blood pressures (DBP) were converted to age-, sex-, and height-specific percentiles for normal-weight U.S. children. HBP was classified based on SBP or DBP ≥90th percentile. Nitrogen dioxide (NO2) and particulate matter ≤2.5μm in aerodynamic diameter (PM2.5) estimates in both pre- and postnatal windows were obtained from annual national models and spatiotemporal models, respectively. We fit multivariate Linear and Poisson regressions and explored multiplicative joint effects with maternal nutrition, child sex, and maternal race using interaction terms.ResultsMean PM2.5 and NO2 in the prenatal period were 10.8 [standard deviation (SD): 0.9] μg/m3 and 10.0 (SD: 2.4) ppb, respectively, and 9.9 (SD: 0.6) μg/m3 and 8.8 (SD: 1.9) ppb from birth to the 4-y-old birthday. On average, SBP percentile increased by 14.6 (95% CI: 4.6, 24.6), and DBP percentile increased by 8.7 (95% CI: 1.4, 15.9) with each 2-μg/m3 increase in second-trimester PM2.5. PM2.5 averaged over the prenatal period was only significantly associated with higher DBP percentiles [β= 11.6 (95% CI: 2.9, 20.2)]. Positive associations of second-trimester PM2.5 with SBP and DBP percentiles were stronger in children with maternal folate concentrations in the lowest quartile (pinteraction= 0.05 and 0.07, respectively) and associations with DBP percentiles were stronger in female children (pinteraction= 0.05). We did not detect significant association of NO2, road proximity, and postnatal PM2.5 with any outcomes.ConclusionsThe findings suggest that higher prenatal PM2.5 exposure, particularly in the second trimester, is associated with elevated early childhood blood pressure. This adverse association could be modified by pregnancy folate concentrations. https://doi.org/10.1289/EHP7486.

BackgroundThe intrauterine environment may influence offspring blood pressure, with effects possibly extending into adulthood. The associations between prenatal nutrition and offspring blood pressure, alone or in combination with other sociodemographic or behavioral factors, are unclear.ObjectivesTo investigate the associations of maternal dietary patterns and plasma folate concentrations with blood pressure in children aged 4-6 years, and assess the potential effect modifications by child sex, maternal race, pre-pregnancy overweight or obesity, maternal smoking, and breastfeeding.MethodsParticipants were 846 mother-child dyads from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study. Maternal nutrition was characterized by the Healthy Eating Index 2010 (HEI) scores and plasma folate concentrations in pregnancy. We calculated the systolic blood pressure (SBP) and diastolic blood pressure percentiles, incorporating sex, age, and height, and categorized children as either having high blood pressure (HBP; ≥90th percentile) or normal blood pressure. Linear regressions were performed to quantify the associations between maternal nutrition and continuous blood pressure percentiles, and Poisson regressions were used to estimate the incidence rate ratio (IRR) of binary HBP. We examined the effect modifications using interaction models.ResultsMean HEI scores and folate concentrations were 60.0 (SD, 11.3) and 23.1 ng/mL (SD, 11.1), respectively. Based on measurements at 1 visit, 29.6% of the children were defined as having HBP. Maternal HEI scores and plasma folate concentrations were not associated with child blood pressure percentiles or HBP in the full cohort. Among mothers self-identified as white, there was an inverse relationship between maternal HEI score and child SBP percentile (β, -0.40; 95%CI: -0.75 to -0.06). A maternal HEI score above 59 was associated with a reduced risk of HBP in girls (IRR, 0.53; 95% CI: 0.32-0.88). No modified associations by pre-pregnancy overweight or obesity, maternal smoking, or breastfeeding were indicated.ConclusionsWe found little evidence for effects of maternal nutrition during pregnancy on childhood blood pressure, but detected sex- and race-specific associations. The study contributes to the evolving scientific inquiry regarding developmental origins of disease.

BackgroundDepressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited.ObjectiveTo impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline.MethodsUsing a pooled study of 4 prospective cohorts (ages 20-89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20-49), mid-life (ages 50-69), and late-life (ages 70-89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score.ResultsIn separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment = 1.59 (95%CI: 1.35,1.87); mid-life OR = 1.94 (95%CI:1.16, 3.26); and late-life OR = 1.77 (95%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR = 1.73; 95%CI: 1.42,2.11) and late-life (OR = 1.43; 95%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p

The prevalence of atopic dermatitis (AD) in children has steadily increased over time, yet it remains largely unknown how maternal factors during pregnancy are associated with child AD. Few studies have specifically assessed the relationship between prenatal stress and child AD, with inconsistent findings. In this prospective cohort study following 426 mother-child dyads from pregnancy to middle childhood, women reported stressful life events (SLEs) experienced during the 12 months before delivery and AD outcomes in children aged approximately 4-6 years, including current, location-specific, and ever AD. We used Poisson regression to estimate risk ratios (RRs) and corresponding 95% confidence intervals (CIs) associated with a 1-unit increase in prenatal SLEs, adjusting for potential confounders. We also assessed whether the association between prenatal SLEs and child AD was modified by child sex, history of maternal atopy, or prenatal maternal resilient coping. The mean (standard deviation) of prenatal SLEs reported in the overall sample was 1.4 (1.6), with 37.1% of women reporting none. A 1-unit increase in prenatal SLEs was not significantly associated with current AD (RR: 1.08, 95% CI: 0.89, 1.31), location-specific AD (RR: 1.09, 95% CI: 0.78, 1.52), or ever AD (RR: 0.97, 95% CI: 0.87, 1.09). We did not find evidence of effect modification. Findings from this study suggest no association between prenatal SLEs and AD in middle childhood, although larger longitudinal studies with enhanced case definition and higher variability of SLE experience may more fully inform this question.

We sought to determine which facets of sleep neurophysiology were most strongly linked to cognitive performance in 3,819 older adults from two independent cohorts, using whole-night electroencephalography. From over 150 objective sleep metrics, we identified 23 that predicted cognitive performance, and processing speed in particular, with effects that were broadly independent of gross changes in sleep quality and quantity. These metrics included rapid eye movement duration, features of the electroencephalography power spectra derived from multivariate analysis, and spindle and slow oscillation morphology and coupling. These metrics were further embedded within broader associative networks linking sleep with aging and cardiometabolic disease: individuals who, compared with similarly aged peers, had better cognitive performance tended to have profiles of sleep metrics more often seen in younger, healthier individuals. Taken together, our results point to multiple facets of sleep neurophysiology that track coherently with underlying, age-dependent determinants of cognitive and physical health trajectories in older adults.

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10-6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

The relationship between alcohol consumption and mortality generally exhibits a U-shaped curve. The longevity observed with moderate alcohol consumption may be explained by other confounding factors, and, if such a relationship is present, the mechanism is not well understood. Indeed, the optimal amount of alcohol consumption for health has yet to be determined. Leukocyte telomere length is an emerging quantifiable marker of biological age and health, and a shorter telomere length is a predictor of increased mortality. Because leukocyte telomere length is a quantifiable and objectively measurable biomarker of aging, we sought to identify the amount of alcohol consumption associated with the longest telomere length and least telomere length attrition. Among over 2,000 participants from two distinct cohort studies, we found no pattern of alcohol consumption that was associated with longer telomere length or less telomere length attrition over time. Binge drinking may reduce telomere length. Using telomere length as a marker of age and health, these data fail to demonstrate any benefits of alcohol consumption, even when consumed in moderation.

Inflammaging, the chronic, progressive proinflammatory state associated with aging, has been associated with multiple negative health outcomes in humans. The pathophysiology of inflammaging is complex; however, it is often characterized by high serum concentrations of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and C-reactive protein (CRP). Few studies have evaluated the effects of age on inflammatory cytokines in companion dogs, and most of these studies included dogs of a single breed. In this cross-sectional study, we measured multiple circulating inflammatory markers and hematological parameters in banked serum samples from 47 healthy companion dogs of various breeds enrolled in the Dog Aging Project. Using univariate linear models, we investigated the association of each of these markers with age, sex, body weight, and body condition score (BCS), a measure of obesity in the dog. Serum IL-6, IL-8, and TNF-α concentrations were all positively associated with age. Lymphocyte count was negatively associated with age. Platelet count had a negative association with body weight. IL-2, albumin, cholesterol, triglyceride, bilirubin, S100A12, and NMH concentrations were not associated with age, weight, BCS, or sex after adjustment for multiple comparisons. Our findings replicate previous findings in humans, including increases in IL-6 and TNF-α with age, giving more evidence to the strength of the companion dog as a model for human aging. [ABSTRACT FROM AUTHOR]

Studies on the relationship of cholesterol concentrations and lipid-lowering medications with dementia risk have yielded inconsistent findings. Therefore, we investigated the association of lipid concentrations and lipid-lowering medications with cognitive function in the Multi-Ethnic Study of Atherosclerosis across 3 different cognitive domains assessed by means of the Cognitive Abilities Screening Instrument (CASI; version 2), the Digit Symbol Coding (DSC) Test, and the Digit Span (DS) Test in 2010-2012. After adjustment for sociodemographic and confounding factors, including concentrations of other lipids and use of lipid-lowering medication, higher total cholesterol, low-density lipoprotein cholesterol, and non-high-density-lipoprotein cholesterol concentrations were modestly associated with higher DS Test scores. None of the lipid parameters were associated with CASI or DSC Test scores. Similarly, changes in lipid concentrations were not associated with any cognitive function test score. Using treatment effects model analysis and after adjusting for confounding factors, including lipid concentrations, the use of any lipid-lowering medication, especially statins, was associated with higher scores on the CASI and backward DS tests but not on the DSC and forward DS tests. Our study does not support a robust association between lipid concentrations and cognitive function or between the use of lipid-lowering medication, especially statins, and worse cognitive function.

Preliminary studies suggest that neighborhood social and built environment (BE) characteristics may affect cognition in older adults. Older adults are particularly vulnerable to the neighborhood environment due to a decreasing range of routine travel with increasing age. We examined if multiple neighborhood BE characteristics are cross-sectionally associated with cognition in a diverse sample of older adults, and if the BE-cognition associations vary by individual-level demographics. The sample included 4539 participants from the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to examine the associations between five BE measures and four cognitive measures, and effect modification by individual-level education and race/ethnicity. In the overall sample, increasing social destination density, walking destination density, and intersection density were associated with worse overall cognition, whereas increasing proportion of land dedicated to retail was associated with better processing speed. Effect modification results suggest that the association between urban density and worse cognition may be limited to or strongest in those of non-white race/ethnicity. Although an increase in neighborhood retail destinations was associated with better cognition in the overall sample, these results suggest that certain BE characteristics in dense urban environments may have a disproportionately negative association with cognition in vulnerable populations. However, our findings must be replicated in longitudinal studies and other regional samples.

Background and purposeDepression is associated with stroke, but the effects of changes in depressive symptoms on stroke risk are not well understood. This study examined whether depressive symptom changes across 2 successive annual assessments were associated with incident stroke the following year.MethodsWe used visit data from 4319 participants of the Cardiovascular Health Study who were stroke free at baseline to examine whether changes in depressive symptoms classified across 2 consecutive annual assessments predicted incident first stroke during the subsequent year. Depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression scale (high versus low at ≥10). Survival models were inverse probability weighted to adjust for demographics, health behaviors, medical conditions, past depressive symptoms, censoring, and survival.ResultsDuring follow-up, 334 strokes occurred. Relative to stable low scores of depressive symptoms, improved depression symptoms were associated with almost no excess risk of stroke (adjusted hazards ratio, 1.02; 95% confidence interval, 0.66-1.58). New-onset symptoms were nonsignificantly associated with elevated stroke risk (adjusted hazards ratio, 1.44; 95% confidence interval, 0.97-2.14), whereas persistently high depressive symptoms were associated with elevated adjusted hazard of all-cause stroke (adjusted hazards ratio, 1.65; 95% confidence interval, 1.06-2.56). No evidence for effect modification by race, age, or sex was found.ConclusionsPersistently high symptoms of depression predicted elevated hazard of stroke. Participants with improved depressive symptoms had no elevation in stroke risk. Such findings suggest that strategies to reduce depressive symptoms may ameliorate stroke risk.

Background: Observational studies link high midlife systolic blood pressure to increased dementia risk. However, the synthesis of evidence from randomized controlled trials has not definitively demonstrated that antihypertensive medication use reduces dementia risk. Here, we emulate target trials of antihypertensive medication initiation on incident dementia using three cohort studies, with attention to potential violations of necessary assumptions. Methods: We emulated trials of antihypertensive medication initiation on incident dementia using data from the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, and Health and Retirement Study. We used data-driven methods to restrict participants to initiators and noninitiators with overlap in propensity scores and positive control outcomes to look for violations of positivity and exchangeability assumptions. Results: Analyses were limited by the small number of cohort participants who met eligibility criteria. Associations between antihypertensive medication initiation and incident dementia were inconsistent and imprecise (Atherosclerosis Risk in Communities: HR = 0.30 [0.05, 1.93]; Cardiovascular Health Study: HR = 0.66 [0.27, 1.64]; Health and Retirement Study: HR = 1.09 [0.75, 1.59]). More stringent propensity score restrictions had little effect on findings. Sensitivity analyses using a positive control outcome unexpectedly suggested antihypertensive medication initiation increased the risk of coronary heart disease in all three samples. Conclusions: Positive control outcome analyses suggested substantial residual confounding in effect estimates from our target trials, precluding conclusions about the impact of antihypertensive medication initiation on dementia risk through target trial emulation. Formalized processes for identifying violations of necessary assumptions will strengthen confidence in target trial emulation and avoid inappropriate confidence in emulated trial results. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Whether circulating levels of sphingolipids are prospectively associated with cognitive decline and dementia risk is uncertain. METHODS: We measured 14 sphingolipid species in plasma samples from 4488 participants (mean age 76.2 years; 40% male; and 25% apolipoprotein E (APOE) ε4 allele carriers). Cognitive decline was assessed annually across 6 years using modified Mini–Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST). Additionally, a subset of 3050 participants were followed for clinically adjudicated dementia. RESULTS: Higher plasma levels of sphingomyelin‐d18:1/16:0 (SM‐16) were associated with a faster cognitive decline measured with 3MSE, in contrast, higher levels of sphingomyelin‐d18:1/22:0 (SM‐22) were associated with slower decline in cognition measured with DSST. In Cox regression, higher levels of SM‐16 (hazard ration [HR] = 1.24 [95% confidence interval [CI]: 1.08–1.44]) and ceramide‐d18:1/16:0 (Cer‐16) (HR = 1.26 [95% CI: 1.10–1.45]) were associated with higher risk of incident dementia. DISCUSSION: Several sphingolipid species appear to be involved in cognitive decline and dementia risk. Highlights: Plasma levels of sphingolipids were associated with cognitive decline and dementia risk.Ceramides and sphingomyelins with palmitic acid were associated with faster annual cognitive decline and increased risk of dementia.The direction of association depended on the covalently bound saturated fatty acid chain length in analysis of cognitive decline. [ABSTRACT FROM AUTHOR]

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus