Search

A large interventional trial, the Systolic Blood Pressure Intervention Trial sub-study termed Memory and Cognition in Decreased Hypertension (SPRINT-MIND), found reduced risk of cognitive impairment in older adults with intensive, relative to standard, blood-pressure-lowering targets (systolic BP  80 years), will maximize external validity and global implementation of trial findings. New biomarkers will improve phenotyping to stratify patients to optimal treatments. Currently no antihypertensive drug class stands out for dementia risk reduction. Multi-domain interventions, incorporating lifestyle change (exercise, diet) alongside medications, may maximize global impact. Given the low cost and wide availability of antihypertensive drugs, intensive BP reduction may be a cost-effective means to reduce dementia risk in diverse, aging populations worldwide.

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 (

IntroductionWe investigated associations between neighborhood racial/ethnic segregation and cognitive change.MethodsWe used data (n = 1712) from the Multi-Ethnic Study of Atherosclerosis. Racial/ethnic segregation was assessed using Getis-Ord (Gi*) z-scores based on American Community Survey Census tract data (higher Gi* = greater spatial clustering of participant's race/ethnicity). Global cognition and processing speed were assessed twice, 6 years apart. Adjusted multilevel linear regression tested associations between Gi* z-scores and cognition. Effect modification by race/ethnicity, income, education, neighborhood socioeconomic status, and neighborhood social support was tested.ResultsParticipants were on average 67 years old; 43% were White, 11% Chinese, 29% African American/Black, 17% Hispanic; 40% had high neighborhood segregation (Gi* > 1.96). African American/Black participants with greater neighborhood segregation had greater processing speed decline in stratified analyses, but no interactions were significant.DiscussionSegregation was associated with greater processing speed declines among African American/Black participants. Additional follow-ups and comprehensive cognitive batteries may further elucidate these findings.HighlightsA study of neighborhood racial/ethnic segregation and change in cognition. Study was based on a racially and geographically diverse, population-based cohort of older adults. Racial/ethnic segregation (clustering) was measured by the Getis-ord (Gi*) statistic. We saw faster processing speed decline among Black individuals in segregated neighborhoods.

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

Despite the prognostic value of arterial stiffness (AS) and pulsatile hemodynamics (PH) for cardiovascular morbidity and mortality, epigenetic modifications that contribute to AS/PH remain unknown. To gain a better understanding of the link between epigenetics (DNA methylation) and AS/PH, we examined the relationship of eight measures of AS/PH with CpG sites and co-methylated regions using multi-ancestry participants from Trans-Omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA) with sample sizes ranging from 438 to 874. Epigenome-wide association analysis identified one genome-wide significant CpG (cg20711926-CYP1B1) associated with aortic augmentation index (AIx). Follow-up analyses, including gene set enrichment analysis, expression quantitative trait methylation analysis, and functional enrichment analysis on differentially methylated positions and regions, further prioritized three CpGs and their annotated genes (cg23800023-ETS1, cg08426368-TGFB3, and cg17350632-HLA-DPB1) for AIx. Among these, ETS1 and TGFB3 have been previously prioritized as candidate genes. Furthermore, both ETS1 and HLA-DPB1 have significant tissue correlations between Whole Blood and Aorta in GTEx, which suggests ETS1 and HLA-DPB1 could be potential biomarkers in understanding pathophysiology of AS/PH. Overall, our findings support the possible role of epigenetic regulation via DNA methylation of specific genes associated with AIx as well as identifying potential targets for regulation of AS/PH.

IntroductionThe burden of Alzheimer's disease (AD) and AD-related dementias (ADRD) is increasing nationally and globally, with disproportionate impacts on lower-income, lower education and systematically marginalised older adults. Presence of inequalities in neighbourhood factors (eg, social context, physical and built environments) may affect risk of cognitive decline and be key for intervening on AD/ADRD disparities at the population level. However, existing studies are limited by a dearth of longitudinal, detailed neighbourhood measures linked to rich, prospective cohort data. Our main objective is to identify patterns of neighbourhood change related to prevalence of-and disparities in-cognitive decline and dementia.Methods and analysesWe describe the process of collecting, processing and linking extensive neighbourhood data to the Multi-Ethnic Study of Atherosclerosis (MESA), creating a 25+ years dataset. Within the MESA parent study, the MESA Neighborhoods and Aging cohort study will characterise dynamic, longitudinal neighbourhood social and built environment variables relevant to cognition for residential addresses of MESA participants. This includes administering new surveys, expanding residential address histories, calculating new measures derived from spatial data and implementing novel deep learning algorithms on street-level imagery. Applying novel statistical techniques, we will examine associations of neighbourhood environmental characteristics with cognition and clinically relevant AD/ADRD outcomes. We will investigate determinants of disparities in outcomes by socioeconomic position and race/ethnicity and assess the contribution of neighbourhood environments to these disparities. This project will provide new evidence about pathways between neighbourhood environments and cognitive outcomes, with implications for policies to support healthy ageing.Ethics and disseminationThis project was approved by the University of Washington and Drexel University Institutional Review Boards (protocols #00009029 and #00014523, and #180900605). Data will be distributed through the MESA Coordinating Center. Findings will be disseminated in peer-reviewed scientific journals, briefs, presentations and on the participant website.

Both education and cardiovascular risk factors are strongly associated with dementia risk. However, it is not clear whether these associations persist or vary among individuals with high genetic risk for Alzheimer's disease. We examined the interactive relationship between lifestyle and genetic dementia risk factors in a prospective cohort study. Our data came from the Atherosclerosis Risk in Communities study participants (n = 13 715; baseline age 45-64; 25% Black; 55% female), who were followed for incident dementia from 1987 through 2017. We used Cox proportional hazard models to estimate the risk of dementia (ascertained through in-person examination, telephone cognitive screeners, and/or hospital and death records) associated with baseline education and cardiovascular risk factors (measured using the American Heart Association's "Life Simple 7") among ε4 carriers and non-carriers separately. We also examined differences by race and sex. Two thousand two hundred and twenty-six incident dementia cases occurred over a median 25 years of follow-up. Lower educational attainment and poorer cardiovascular health were associated with greater risk of incident dementia. There was an education by apolipoprotein E (APOE) status interaction (p = .005) whereby the association of education and dementia was weaker for ε4 carriers (HR college graduates vs less than high school: 0.71 [0.59-0.84] than non-carriers (0.54 [0.47-0.63]). There was no interaction between APOE status and cardiovascular health on dementia risk. These relationships did not vary significantly by race or sex. Education and cardiovascular health were associated with lower dementia risk regardless of APOE genotype, though the protective effects of education were somewhat diminished among ε4 carriers.

IntroductionLittle is known about how antecedent vascular risk factor (VRF) profiles impact late-life brain health.MethodsWe examined baseline VRFs, and cognitive testing and neuroimaging measures (β-amyloid [Aβ] PET, MRI) in a diverse longitudinal cohort (N = 159; 50% African-American, 50% White) from Wake Forest's Multi-Ethnic Study of Atherosclerosis Core.ResultsAfrican-Americans exhibited greater baseline Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham stroke risk profile (FSRP), and atherosclerotic cardiovascular disease risk estimate (ASCVD) scores than Whites. We observed no significant racial differences in Aβ positivity, cortical thickness, or white matter hyperintensity (WMH) volume. Higher baseline VRF scores were associated with lower cortical thickness and greater WMH volume, and FSRP and CAIDE were associated with Aβ. Aβ was cross-sectionally associated with cognition, and all imaging biomarkers were associated with greater 6-year cognitive decline.DiscussionResults suggest the convergence of multiple vascular and Alzheimer's processes underlying neurodegeneration and cognitive decline.

IntroductionCoronavirus disease 2019 (COVID-19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term.MethodsThis article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions.ResultsSuccessful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe.DiscussionThe Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection.Key pointsThe following review describes what is known so far in terms of molecular and epidemiological links among COVID-19, the brain, neurological symptoms, and AD and related dementias (ADRD)The primary objective of this large-scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long-term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS-CoV-2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS-CoV-2 triggers ADRD-like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility.The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under-represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long-term consequences, and trends in cognitive aging, ADRD, and vascular disease.We provide a framework for current and future studies to be carried out within the Consortium. and offers a "green paper" to the research community with a very broad, global base of support, on tools suitable for low- and middle-income countries aimed to compare and combine future longitudinal data on the topic.The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID-19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high-quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations.

BackgroundEthnic differences in cognitive decline have been reported. Whether they can be explained by differences in systolic blood pressure (SBP) is uncertain.ObjectiveDetermine whether cumulative mean SBP levels explain differences in cognitive decline between Hispanic and White individuals.MethodsPooled cohort study of individual participant data from six cohorts (1971-2017). The present study reports results on SBP and cognition among Hispanic and White individuals. Outcomes were changes in global cognition (GC) (primary), executive function (EF) (secondary), and memory standardized as t-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1 SD difference in cognition. Median follow-up was 7.7 (Q1-Q3, 5.2-20.1) years.ResultsWe included 24,570 participants free of stroke and dementia: 2,475 Hispanic individuals (median age, cumulative mean SBP at first cognitive assessment, 67 years, 132.5 mmHg; 40.8% men) and 22,095 White individuals (60 years,134 mmHg; 47.3% men). Hispanic individuals had slower declines in GC, EF, and memory than White individuals when all six cohorts were examined. Two cohorts recruited Hispanic individuals by design. In a sensitivity analysis, Hispanic individuals in these cohorts had faster decline in GC, similar decline in EF, and slower decline in memory than White individuals. Higher time-varying cumulative mean SBP was associated with faster declines in GC, EF, and memory in all analyses. After adjusting for time-varying cumulative mean SBP, differences in cognitive slopes between Hispanic and White individuals did not change.ConclusionWe found no evidence that cumulative mean SBP differences explained differences in cognitive decline between Hispanic and White individuals.

IntroductionFederally funded Alzheimer's Disease Centers in the United States have been using a standardized neuropsychological test battery as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) since 2005. Version 3 (V3) of the UDS replaced the previous version (V2) in 2015. We compared V2 and V3 neuropsychological tests with respect to their ability to distinguish among the Clinical Dementia Rating (CDR) global scores of 0, 0.5, and 1.MethodsFirst, we matched participants receiving V2 tests (V2 cohort) and V3 tests (V3 cohort) in their cognitive functions using tests common to both versions. Then, we compared receiver-operating characteristic (ROC) area under the curve in differentiating CDRs for the remaining tests.ResultsSome V3 tests performed better than V2 tests in differentiating between CDR 0.5 and 0, but the improvement was limited to Caucasian participants.DiscussionFurther efforts to improve the ability for early identification of cognitive decline among diverse racial groups are required.

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

Blood-based bioenergetic profiling has promising applications as a minimally invasive biomarker of systemic bioenergetic capacity. In the present study, we examined peripheral blood mononuclear cell (PBMC) mitochondrial function and brain morphology in a cohort of African Americans with long-standing Type 2 diabetes. Key parameters of PBMC respiration were correlated with white matter, gray matter, and total intracranial volumes. Our analyses indicate that these relationships are primarily driven by the relationship of systemic bioenergetic capacity with total intracranial volume, suggesting that systemic differences in mitochondrial function may play a role in overall brain morphology.

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.

Introduction: Growing interest centers on the association between circulating ketone bodies (KB) and cognitive function, notably in aging and neurodegenerative diseases. Methods: Associations of plasma KB with incident dementia and cognitive performances were examined among Multi‐Ethnic Study of Atherosclerosis (MESA) participants. KB were measured using plasma samples collected following an overnight fasting at Exam 1 (2000–02) and detailed cognitive testing at Exam 5 (2010–2012, N = 4392), Exam 6 (2016–2018, N = 1838), and in MESA‐MIND (2019–2021, N = 2060). Results: Over 16.7 years, a doubling of total KB was associated with a greater risk of incident dementia (hazard ratio [HR]: 1.14 [1.04–1.29]). Higher total KB was associated with worse cognitive performance in the Digit Span test at exam 5 [β: −0.30 (−0.47, −0.14)]. We also found that a higher KB was associated with greater functional impairment and a higher Quick Dementia Rating Scale (QDRS) score. Discussion: In a diverse, cardiovascular disease‐free population, elevated KB levels were associated with incident dementia and impaired cognitive performance in specific domains. Highlights: A study of ketone bodies (KB) and cognitive performance and incident dementia.Nuclear magnetic resonance (NMR) spectroscopy was used to measure plasma KB at baseline.Doubling of baseline total KB was associated with higher incident dementia.Higher KB was also associated with worse performance on a test of working memory. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Neighborhood disadvantage may be an important determinant of cardiometabolic health and cognitive aging. However, less is known about relationships among individuals with mild cognitive impairment (MCI). METHODS: The objective of this study is to investigate the relationship between neighborhood disadvantage measured by national Area Deprivation Index (ADI) rank with measures of cardiometabolic health and cognition among Wake Forest (WF) Alzheimer's Disease Research Center (ADRC) participants, with and without MCI. RESULTS: ADI was positively associated with blood pressure and cardiometabolic index (CMI), and negatively associated with global and Preclinical Alzheimer's Cognitive Composite (PACC5) scores, in cognitively unimpaired (CU) individuals. ADI was only positively associated with hemoglobin A1c (HbA1c) in MCI. DISCUSSION: Neighborhood disadvantage is associated more strongly with measures of cardiometabolic health and cognition among CU individuals rather than MCI. These findings demonstrate a need for structural solutions to address social determinants of health in an attempt to reduce cardiometabolic and cognitive risks. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Adverse psychosocial exposure is associated with increased pro‐inflammatory gene expression and reduced type‐1 interferon gene expression known as the conserved transcriptional response to adversity (CTRA). CTRA is not well‐studied in cognitive impairment but may contribute to late‐life cognitive decline. METHODS: We examined perceived stress, loneliness, well‐being, and the impact of coronavirus disease 2019 (COVID‐19) and the relationship to the expression of genes associated with the CTRA. Mixed‐effect linear models were used to quantify associations between psychosocial variables and CTRA gene expression. RESULTS: Eudaimonic well‐being (EWB) was inversely associated with CTRA gene expression in participants with both normal cognition (NC) and mild cognitive impairment (MCI). Self‐reported coping strategies differed by cognitive status and variably impacted CTRA gene expression. DISCUSSION: EWB is an important correlate of stress, even in people with MCI. The prodromal cognitive decline appears to moderate the significance of coping strategies as a correlate of CTRA gene expression. Highlights: Conserved transcriptional response to adversity (CTRA) gene expression is higher with lower eudaimonic well‐being.Eudaimonic well‐being was important in both participants with normal cognition and those with mild cognitive impairment.Coping strategies and impact on CTRA gene expression differed by cognitive status.Loneliness in a population with relatively low loneliness scores did not impact CTRA gene expression. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The impact of age of diabetes diagnosis on dementia risk across the life course is poorly characterized. We estimated the lifetime risk of dementia by age of diabetes diagnosis. RESEARCH DESIGN AND METHODS: We included 13,087 participants from the Atherosclerosis Risk in Communities Study who were free from dementia at age 60 years. We categorized participants as having middle age–onset diabetes (diagnosis <60 years), older-onset diabetes (diagnosis 60–69 years), or no diabetes. Incident dementia was ascertained via adjudication and active surveillance. We used the cumulative incidence function estimator to characterize the lifetime risk of dementia by age of diabetes diagnosis while accounting for the competing risk of mortality. We used restricted mean survival time to calculate years lived without and with dementia. RESULTS: Among 13,087 participants, there were 2,982 individuals with dementia and 4,662 deaths without dementia during a median follow-up of 24.1 (percentile 25–percentile 75, 17.4–28.3) years. Individuals with middle age–onset diabetes had a significantly higher lifetime risk of dementia than those with older-onset diabetes (36.0% vs. 31.0%). Compared with those with no diabetes, participants with middle age–onset diabetes also had a higher cumulative incidence of dementia by age 80 years (16.1% vs. 9.4%) but a lower lifetime risk (36.0% vs. 45.6%) due to shorter survival. Individuals with middle age–onset diabetes developed dementia 4 and 1 years earlier than those without diabetes and those with older-onset diabetes, respectively. CONCLUSIONS: Preventing or delaying diabetes may be an important approach for reducing dementia risk throughout the life course. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Substantial racial and ethnic disparities in hypertension and dementia exist in the United States. We evaluated the effect of maintaining systolic blood pressure (SBP) below clinical thresholds on dementia incidence. METHODS: We included 6806 Multi‐Ethnic Study of Atherosclerosis participants (44 to 84 years old). We implemented the parametric g‐formula to simulate the hypothetical interventions to reduce SBP below 120 and 140 mmHg over time, accounting for time‐varying confounding. We estimated risk ratios (RRs) and risk differences for dementia incidence at 19 years. RESULTS: The RRs (95% confidence intervals [CIs]) comparing an intervention reducing SBP below 120 mmHg to no intervention were 0.93 (0.87 to 0.99) for total sample, 0.95 (0.88 to 1.02) for White, 0.90 (0.79 to 1.02) for Black, 0.90 (0.78 to 1.05) for Latino, and 1.16 (0.83 to 1.55) for Chinese American participants. Results for lowering SBP below 140 mmHg and with death as competing event were attenuated. DISCUSSION: The reduction of SBP below 120 mmHg over time has modest effects on reducing dementia incidence. More work is needed to understand the heterogeneity across racial and ethnic groups. Highlights: There is a potential beneficial effect in lowering SBP to reduce the risk of dementia, which may vary by race and ethnicity.The percentage of participants who would need intervention on blood pressure to meet clinical thresholds is greater for Black and Latino communities.Results are sensitive to the way that death is specified in the research question and analysis. [ABSTRACT FROM AUTHOR]

The association between cardiometabolic risk factors and cognitive function has been well documented, but the underlying mechanisms are not fully understood. This longitudinal study aimed to investigate the potential mediating role of DNA methylation in this association. We conducted the analyses in 3 708 participants (mean [standard deviation { SD }] age: 67.3 [9.5], women: 57.9%) from the Health and Retirement Study who were assessed in the 2014–2020 waves, had Infinium Methylation EPIC BeadChip methylation assays from the 2016 Venous Blood Study, and had cognitive assessment between 2016 and 2020. Causal mediation analyses were used to test the mediation role of DNA methylation in the associations between cardiometabolic risk factors and cognition, adjusting for demographic, socioeconomic, and lifestyle factors. Hypertension (−0.061 in composite cognitive z -score; 95% confidence interval [CI: −0.119, −0.004]) and diabetes (−0.134; 95% CI: [−0.198, −0.071]) were significantly associated with worse cognitive function while abnormal body weight and hypercholesterolemia were not. An increased number of cardiometabolic risk factors was associated with worse cognitive function (p  = .002). DNA methylation significantly mediated the association of hypertension (mediated effect on composite cognitive z -score: −0.023; 95% CI: −0.033, −0.014), diabetes (−0.022; 95% CI: −0.032, −0.014), and obesity (−0.021; 95% CI: −0.033, −0.011) with cognitive function, whereas the mediation effect was not observed for having hypercholesterolemia. The estimated proportions mediated were 37.4% for hypertension and 16.7% for diabetes. DNA methylation may be an important mediator linking cardiometabolic risk factors to worse cognition and might even provide a potential target for dementia prevention. [ABSTRACT FROM AUTHOR]

Background: Vascular‐based dementia risk scores (VDRS) which reliably predict risk of Alzheimer's disease and related dementias (ADRDs), may be useful to identify at‐risk individuals for secondary prevention trials. Dementia risk scores have typically focused on predicting ADRD‐associated symptoms, with fewer studies assessing capacity for detecting individuals with underlying brain pathologies. We compare the predictive value of two vascular‐based risk scores (CAIDE and Reitz VDRSs) for discriminating AD‐related histopathological and structural abnormalities, further considering race and gender differences. Method: We included non‐demented (self‐identified) White and Black participants at the Wake Forest ADRC Clinical Core with baseline UDSv3 cognitive testing (used to calculate the Preclinical Alzheimer's Cognitive Composite ‐ PACC5), clinical adjudication, amyloid (PiB) PET, APOE genotype, and metabolic characterization for diabetes including prediabetes. WHICAP/Reitz scores were calculated using components of sex, education, age, race, ethnicity, hypertension, diabetes, WHR, HDL, smoking and APOE‐ε4 status. CAIDE scores included age, education, sex, systolic BP, BMI, physical activity, total cholesterol, and APOE‐ε4. We assessed differences in VDRS among cognitive, amyloid PET and racial groups. Result: 616 participants (Table 1) had baseline data available for analysis. Of 287 with amyloid PET, 33% were amyloid positive (CL>20). Median Reitz scores differed by cognitive status (Figure 1A), with higher mean scores noted for those with amnestic (aMCI) and non‐amnestic MCI (naMCI) compared to those with normal cognition (naMCI/aMCI: median 17, p<.001). Reitz scores were also significantly higher in amyloid positive vs negative participants (Figure 1C) as well as in Black vs White participants (Figure 2A) (median (IQR): 16 (2,34) vs 12 (0,28), 17 (0,33) vs 14 (0,40) respectively; p<.001), however no sex differences were noted. In contrast, we found no significant differences in CAIDE scores among cognitive and amyloid pathology groups (p>0.05, Figures 1B and 1D), except ethno‐racial groups (p<.001, Figure 2B). Conclusion: Significant differences in distinct VDRSs were found in relation to brain amyloid pathology levels and clinico‐cognitive status, with ethno‐racial influences potentially contributing to noted differences. Risk composites accounting for these factors will be useful for greater precision around pre‐selection of at‐risk populations towards targeted trials for disease modifying therapies and optimal management of clinical care. [ABSTRACT FROM AUTHOR]

Strategies to prevent or delay Alzheimer's disease and related dementias (AD/ADRD) are urgently needed, and blood pressure (BP) management is a promising strategy. Yet the effects of different BP control strategies across the life course on AD/ADRD are unknown. Randomized trials may be infeasible due to prolonged follow-up and large sample sizes. Simulation analysis is a practical approach to estimating these effects using the best available existing data. However, existing simulation frameworks cannot estimate the effects of BP control on both dementia and cardiovascular disease. This manuscript describes the design principles, implementation details, and population-level validation of a novel population-health microsimulation framework, the MIchigan ChROnic Disease SIMulation (MICROSIM), for The Effect of Lower Blood Pressure over the Life Course on Late-life Cognition in Blacks, Hispanics, and Whites (BP-COG) study of the effect of BP levels over the life course on dementia and cardiovascular disease. MICROSIM is an agent-based Monte Carlo simulation designed using computer programming best practices. MICROSIM estimates annual vascular risk factor levels and transition probabilities in all-cause dementia, stroke, myocardial infarction, and mortality in a nationally representative sample of US adults 18+ using the National Health and Nutrition Examination Survey (NHANES). MICROSIM models changes in risk factors over time, cognition and dementia using changes from a pooled dataset of individual participant data from 6 US prospective cardiovascular cohort studies. Cardiovascular risks were estimated using a widely used risk model and BP treatment effects were derived from meta-analyses of randomized trials. MICROSIM is an extensible, open-source framework designed to estimate the population-level impact of different BP management strategies and reproduces US population-level estimates of BP and other vascular risk factors levels, their change over time, and incident all-cause dementia, stroke, myocardial infarction, and mortality. [ABSTRACT FROM AUTHOR]