University of Mississippi Medical Center

Viral variant and host vaccination status impact infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), yet how these factors shift cellular responses in the human nasal mucosa remains uncharacterized. We performed single-cell RNA sequencing (scRNA-seq) on nasopharyngeal swabs from vaccinated and unvaccinated adults with acute Delta and Omicron SARS-CoV-2 infections and integrated with data from acute infections with ancestral SARS-CoV-2. Patients with Delta and Omicron exhibited greater similarity in nasal cell composition driven by myeloid, T cell and SARS-CoV-2hi cell subsets, which was distinct from that of ancestral cases. Delta-infected samples had a marked increase in viral RNA, and a subset of PER2⁺EGR1⁺GDF15⁺ epithelial cells was enriched in SARS-CoV-2 RNA⁺ cells in all variants. Prior vaccination was associated with increased frequency and activation of nasal macrophages. Expression of interferon-stimulated genes negatively correlated with coronavirus disease 2019 (COVID-19) severity in patients with ancestral and Delta but not Omicron variants. Our study defines nasal cell responses and signatures of disease severity across SARS-CoV-2 variants and vaccination.

Background Racial disparities in mortality rates have been well-documented in the last century. Intersectionality theory has helped to identify the root causes of these health disparities. Few studies have examined disparities using the latest data for the state of Mississippi. Methods Mortality data for the state of Mississippi (MS) were obtained from the vital statistics program of the Centers for Disease Control & Prevention for years 1999–2020. The age-adjusted mortality rate (AAMR) for ages 35–84 years was calculated by county, gender—male (M) vs female (F), and race—black (B) vs white (W), among non-Hispanics (NH) for all causes of death. Results In 2020, MS had the highest AAMR per 100,000 among states in the US: 1624.76 (1605.61–1643.91) for age group 35–84. In 1999–2020 combined, AAMR varied among counties for each gender-race group. High AAMR was concentrated in the delta region for NH black males (NHBM) and females (NHBF). This was less so for NH white males (NHWM) and not so for females (NHWF). The Black/White AAMR ratio among males and females was highest (1.42, 1.36) in the small metropolitan areas and lowest (1.18, 1.05) in the large fringe metropolitan areas. In 1999–2020 for NH males, the ratio of AAMR in NHB to NHW varied from 0.9 to 1.8. In NH females, the ratio varied from 0.9 to 2.2. In both genders, the ratio was significantly correlated with the percent of the population that was NH black. Conclusions The AAMR in MS varied greatly among counties as did the Black/White ratio of AAMR. Further research is needed to explain this geographic variation in racial disparity.

Osteonecrosis (ON) is a disease that is characterized by lesions of dead bone, most frequently detected in the subchondral bone of the convex side of the major diarthrodial joints (hips, knees, shoulders, and talus). High-dose corticosteroid therapy is one major risk factor for ON. The pathological appearance of ON of the femoral head, however, is fairly consistent regardless of the etiology. Depending on the stage of the disease, this includes evidence of bone marrow edema, lipocyte and bone cell necrosis, fibrosis, creeping substitution (new bone lying on dead bone), and the presence of osteoporosis (Chernetsky SG et al., Clin Orthop Relat Res. 368:149–61, 1999). Hemorrhage within the bone marrow compartment has also been observed in patient specimens from corticosteroid-associated ON (Saito S et al., Clin Orthop Relat Res. 277:98–110, 1992). Previous investigators have suggested that corticosteroid-associated ON has more rapid progression than other etiologies (Chernetsky SG et al., Clin Orthop Relat Res. 368:149–61, 1999; Hastings and Macnab, Can J Surg. 8:68–83, 1965). The mechanisms involved in the development of ON are difficult to explore from clinical samples as they provide a single snapshot at one timepoint subsequent to the onset of the disease, usually months after the onset of the disease when the symptoms first appear. While some investigators have used corticosteroid-associated animal models to evaluate different potential treatments (Li X et al., Bone. 33(4):652–9, 2003; Zhang KJ et al., Rheumatol Int. 32(11):3405–11, 2012; Erken HY et al., Int Orthop. 36(7):1523–8, 2012), it is not clear whether the results can be extrapolated to the human condition. A better understanding of the pathophysiological mechanisms is needed.

Purpose of Review Traditionally viewed as a passive player in circulation, the right ventricle (RV) has become a pivotal force in hemodynamics. RV failure (RVF) is a recognized complication of primary cardiac and pulmonary vascular disorders and is associated with a poor prognosis. Unlike treatments for left ventricular failure (LVF), strategies such as adrenoceptor signaling inhibition and renin-angiotensin system modulation have shown limited success in RVF. This review aims to reassure about the progress in RVF treatment by exploring the potential of contemporary therapies for heart failure, including angiotensin receptor and neprilysin inhibitors, sodium-glucose co-transporter 2 inhibitors, and soluble guanylate cyclase stimulators, which may be beneficial for treating RV failure, particularly when associated with left heart failure. Additionally, it examines novel therapies currently in the pipeline. Recent Findings Over the past decade, a new wave of RVF therapies has emerged, both pharmacological and device-centered. Novel pharmacological interventions targeting metabolism, calcium homeostasis, oxidative stress, extracellular matrix remodeling, endothelial function, and inflammation have shown significant promise in preclinical studies. There is also a burgeoning interest in the potential of epigenetic modifications as therapeutic targets for RVF. Summary Undoubtedly, a deeper understanding of the mechanisms underlying RV failure, both with and without pulmonary hypertension, is urgently needed. This knowledge is not just a theoretical pursuit, but a crucial step that could lead to the development of pharmacological and cell-based therapeutic options that directly target the RV and pulmonary vasculature, aligning with the principles of precision medicine.

Background and objectives: Chronic kidney disease (CKD) is known to be associated with increased plasma phosphorylated tau217 (p-tau217) concentrations, potentially confounding the utility of plasma p-tau217 measurements as a marker of amyloid pathology in individuals with suspected Alzheimer disease (AD). In this study, we quantitatively investigate the relationship of plasma p-tau217 concentrations vs estimated glomerular filtration rate (eGFR) in individuals with CKD with and without amyloid pathology. Methods: This was a retrospective examination of data from 2 observational cohorts from either the Mayo Clinic Study of Aging or the Alzheimer's Disease Research Center cohorts. p-Tau217 was determined using the ALZpath Simoa p-tau217 immunoassay and an immunoprecipitation mass spectrometry assay that simultaneously measures p-tau217 and nonphosphorylated-tau217 (np-tau217) to determine %p-tau217 ([p-tau217/nonphosphorylated-tau217]) × 100%) (C2N Diagnostics). Amyloid positivity was defined by amyloid-PET and a centiloid of ≥25. Log-log linear regression fits were used to quantitatively predict increases in plasma p-tau217 associated with decreasing eGFR. Results: Participants (n = 202, mean age of 78 years, 38% female) with diagnoses of cognitive unimpairment (n = 109), mild cognitive impairment (n = 71), and dementia (n = 22) were included. In all, 114 (56%) of all participants were amyloid-PET positive (A+). In addition, 86 (43%) of all participants were classified as having CKD (CKD stages 3-4). p-Tau217 concentrations were significantly higher in A- participants with an eGFR of <60 (mL/min/1.73 m2), as compared with those with eGFR >60 A- participants. For an eGFR of 45 vs 60 in the A- cohort, the calculated percentage changes were +31%, +55%, and +19%, for ALZpath p-tau217, C2N p-tau217, and C2N %p-tau217, respectively. For the A+ cohort, the corresponding calculated percentage changes were +17%, +15%, and -5%, respectively. Discussion: CKD was associated with increased p-tau217 concentrations when measuring p-tau217 by ALZpath and C2N methodologies, but the effect was mitigated by the use of %p-tau217. These results indicate limitations for the utility of plasma p-tau217 measurements in individuals with significant renal impairment (eGFR <45 or CKD stage 3b or greater). Determination of eGFR should be considered to avoid inaccurate classification of the presence of AD-related pathology by plasma p-tau217 in individuals with CKD. Classification of evidence: This study provides Class II evidence that in individuals with CKD stage 3 (especially stage 3b) or higher, p-tau217 concentrations are increased, with a greater increase in amyloid-PET-negative individuals.

The functional activation of the androgen receptor (AR) and its interplay with the aberrant Hh/Gli cascade are pivotal in the progression of castration-resistant prostate cancer (CRPC) and resistance to AR-targeted therapies. Our study unveiled a novel role of the truncated form of Gli (t-Gli3) in advancing CRPC. Investigation into Gli3 regulation revealed a Smo-independent mechanism for its activation. Despite lacking a transactivation domain, t-Gli3 relies on androgen receptor variant 7 (AR-V7) for its action. Mechanistically, Gsk3β activation led to the t-Gli3 generation, and inhibition of Gsk3β supported the accumulation of full-length Gli3 expression through a non-canonical mechanism. Knockdown of Gsk3β (Gsk3β KD) reduces CRPC cell proliferation, induces apoptosis via mitochondrial fragmentation, and triggers metabolomic reprogramming. The in vivo studies with Gsk3β KD cells in the mouse prostate resulted in tumor growth retardation compared to scramble cells. RNA-seq HALLMARK Gene Set Enrichment Analysis (GSEA) analysis of Gsk3β KD revealed a positive enrichment of apoptosis, tumor suppressor gene, and negative enrichment of oncogenic pathway. Furthermore, combinational use of a Gsk3β inhibitor with anti-Smo or Gli1 significantly inhibited the CRPC cell growth, which is resistant to individual Smo or Gli1 inhibitor targeting. Intriguingly, solely targeting Gli3 showed effectiveness in inhibiting CRPC cell growth. Overall, our study underscores the clinical significance of Gli3, emphasizing t-Gli3, and provides novel insights into the interplay of the Gsk3β/t-Gli3/AR-V7 axis in CRPC.

Objectives To examine the rate of skin color reporting in randomized controlled trials (RCTs) involving melanoma in the top ten highest dermatology journals by impact factor over the past four decades. Methods A systematic review of RCTs involving melanoma within the top ten dermatology journals, as determined by impact factor, was conducted from inception to July 10th, 2023. Studies were included if they reviewed the diagnosis and/or treatment of melanoma, were RCTs, directly involved patients and were written in English. Studies were characterized as positive for reporting skin of color (SOC) if the demographic data in the results or methods sections included any of the following: race, ethnicity, skin of color, Fitzpatrick scale, sunburn tendency, phototype, skin type, or skin tone. Results Out of 76 studies initially identified, only 49 articles met inclusion criteria. Of these 49 articles, only 24 articles recorded data of skin color from their demographics (49%). Subgroup analysis showed no statistically significant difference in the rate of reporting between studies grouped by decade (p = 0.779) or by study location (p = 0.763). Conclusion Darker skin tones can disguise melanotic skin lesions. Less than 50% of RCTs related to melanoma in the top ten international dermatology journals included skin color within their results section to characterize study participants. This has a negative impact on our understanding of this potentially devastating disease.

Background Declining gait performance is seen in aging individuals, due to neural and systemic factors. Plasma biomarkers provide an accessible way to assess evolving brain changes; non-specific neurodegeneration (NfL, GFAP) or evolving Alzheimer’s disease (Aβ 42/40 ratio, P-Tau181). Methods In a population-based cohort of older adults, we evaluate the hypothesis that plasma biomarkers of neurodegeneration and Alzheimer’s Disease pathology are associated with worse gait performance. A sample of 2641 Mayo Clinic Study of Aging participants with measurements of plasma biomarkers and gait parameters was analyzed in this cross-sectional study. Linear regression models using plasma biomarkers as predictors of gait parameters and adjusted for age, sex, BMI, Charlson Comorbidity Index, and cognitive diagnosis were evaluated. Results In this study multiple statistically significant relationships are observed for GFAP, NfL, and P-Tau181 with gait parameters. Each standard deviation increase in GFAP, NfL, and P-Tau181 is associated with a reduction in velocity of 2.100 (95% CI: −3.004, −1.196; p = 5.4 × 10⁻⁶), 4.400 (−5.292, -3.507; p = 9.5 × 10⁻²²), and 2.617 (−3.414, −1.819; p = 1.5 × 10⁻¹⁰) cm/sec, respectively. Overall, NfL has the strongest associations with poor gait performance. Models with age interactions show that the strength of associations between the plasma biomarkers and the gait parameters became stronger with increasing age. There are no specific gait parameters that associate with individual plasma biomarkers. Conclusion Plasma biomarkers of neurodegeneration and Alzheimer’s Disease pathology are not only markers of cognitive decline but also indicate motor decline in the aging population.

Background Pediatric respiratory syncytial virus (RSV)-related acute lower respiratory tract infection (LRTI) commonly requires hospitalization. The Clinical Progression Scale Pediatrics (CPS-Ped) measures level of respiratory support and degree of hypoxia across a range of disease severity, but it has not been applied in infants hospitalized with severe RSV-LRTI. Methods We analyzed data from a prospective surveillance registry of infants hospitalized for RSV-related complications across 39 U.S. PICUs from October through December 2022. We assigned CPS-Ped (0=discharged home at respiratory baseline to 8=death) at admission, days 2-7,10, and 14. We identified predictors of clinical improvement (CPS-Ped≤2 or 3-point decrease) by day 7 using multivariable log-binomial regression models and estimated the sample size (80% power) to detect 15% between-group clinical improvement with CPS-Ped versus hospital length of stay (LOS). Results Of 585 hospitalized infants, 138 (23.6%) received invasive mechanical ventilation (IMV). Of the 49 (8.4%) infants whose CPS-Ped score worsened by 2 points after admission, one died. Failure to clinically improve by day 7 occurred in 205 (35%) infants and was associated with age <3 months, prematurity, underlying respiratory condition, and IMV in the first 24 hours in the multivariable analysis. The estimated sample size per arm required for detecting a 15% clinical improvement in a potential study was 584 using CPS-Ped clinical improvement versus 2,031 for hospital LOS. Conclusions CPS-Ped can be used to capture a range of disease severity and track clinical improvement in infants who develop RSV-related critical illness and could be useful for evaluating therapeutic interventions for RSV.

Background The Academic Medical Center earned a 1-Star CMS designation and received an F on the Leapfrog Safety Grade in 2015, which led to leadership setting Clinical Quality Improvement as the #1 Strategic Priority. This paper presents the evolution of a structured patient safety program as a component of this plan to direct and motivate employees to succeed in reducing patient harm. Methods Data-driven quality improvement using simple, timely, actionable data drillable scorecards available to all employees was the cornerstone of the above strategic priority. A comprehensive patient safety program was developed utilizing three phases: Error Prevention Training, Improved Event Reporting, and the Chasing Zero Harm initiative. Results Improvement was achieved in Culture of Safety Survey domains of overall safety, event reporting, nonpunitive response to errors, and hand-off communication. Patient safety indicators and hospital-acquired infections improved on the Medical Center's internal scorecard and public reported data by >60%. These resulted in improvement in Leapfrog Safety Score from an F in 2015 to a B in 2023, and increase from CMS 1-Star to 2-Star rank in 2023. Adverse event reports and review with follow up increased by 45% between 2018 and 2023. A Chasing Zero harm program was initiated following establishment of these steps. Discussion A successful patient safety program, predicated on high reliability, can successfully be built with leadership commitment, development of safety culture, and performance improvement.

Background Since older adults spend significant time in their neighborhood environment, environmental factors such as neighborhood socioeconomic disadvantage, high racial segregation, low healthy food availability, low access to recreation, and minimal social engagement may have adverse effects on cognitive function and increase susceptibility to dementia. DNA methylation, which is associated with neighborhood characteristics as well as cognitive function and white matter hyperintensity (WMH), may act as a mediator between neighborhood characteristics and neurocognitive outcomes. Methods In this study, we examined whether DNA methylation in peripheral blood leukocytes mediates the relationship between neighborhood characteristics and cognitive function (N = 542) or WMH (N = 466) in older African American (AA) participants without preliminary evidence of dementia from the Genetic Epidemiology Network of Arteriopathy (GENOA). Results For a 1-mile buffer around a participant’s residence, each additional fast food destination or unfavorable food store with alcohol per square mile was nominally associated with a 0.05 (95%CI: 0.01, 0.09) and a 0.04 (0.00, 0.08) second improvement in visual conceptual tracking score, respectively. Also, each additional alcohol drinking place per square mile was nominally associated with a 0.62 (0.05, 1.19) word increase in delayed recall score, indicating better memory function (all p < 0.05). Neighborhood characteristics were not associated with WMH. We did not find evidence that DNA methylation mediates the observed associations between neighborhood characteristics and cognitive function. Conclusions The presence of fast food destinations and unfavorable food stores with alcohol was associated cognitive measures, possibly due to greater social interaction provided in these venues. However, replication of these findings is necessary. Further examination of the potential pathways between the neighborhood environment and cognitive function/WMH may allow the development of potential behavioral, infrastructural, and pharmaceutical interventions to facilitate aging in place and healthy brain aging in older adults, especially in marginal populations that are most at risk.

Importance Cardiovascular health outcomes associated with noncigarette tobacco products (cigar, pipe, and smokeless tobacco) remain unclear, yet such data are required for evidence-based regulation. Objective To investigate the association of noncigarette tobacco products with cardiovascular health outcomes. Design, Setting, and Participants This cohort study was conducted within the Cross Cohort Collaboration Tobacco Working Group by harmonizing tobacco-related data and conducting a pooled analysis from 15 US-based prospective cohorts with data on the use of at least 1 noncigarette tobacco product ranging between 1948 and 2015. The analysis for this study was conducted between September 2023 and February 2024. The median (IQR) follow-up time for the all-cause mortality outcome was 13.8 (10.2-19.2) years. Exposure Current, sole, and exclusive use of noncigarette tobacco products. Sole use refers to using a noncigarette tobacco product without currently smoking cigarettes. Exclusive use means using only the noncigarette tobacco product and never having smoked cigarettes. Main Outcomes and Measures Myocardial infarction, stroke, heart failure, atrial fibrillation, total coronary heart disease, total cardiovascular disease (CVD), coronary heart disease mortality, CVD mortality, and all-cause mortality. Results Of 103 642 participants (mean [SD] age, 55.7 [13.2] years; 49 550 female [47.8%] and 54 092 male [52.2%]), current use rates were 26 962 participants (26.3%) for cigarettes, 1147 participants (2.1%) for cigars, 530 participants (1.2%) for pipes, and 1410 participants (2.1%) for smokeless tobacco. Current cigar use was associated with stroke (hazard ratio [HR], 1.25; 95% CI, 1.01-1.55), atrial fibrillation (HR, 1.32; 95% CI, 1.13-1.53), and heart failure (HR, 1.29; 95% CI, 1.10-1.51) compared with never using cigars in the model adjusted for demographic and socioeconomic factors, cardiovascular risk factors, and cohort. Sole (HR, 1.34; 95% CI, 1.12-1.62) and exclusive (HR, 1.53; 95% CI, 1.20-1.96) cigar use was associated with stroke compared with never using cigars or cigarettes. Current pipe use was associated with heart failure (HR, 1.23; 95% CI, 1.01-1.49) compared with never using pipes, and sole pipe use was associated with myocardial infarction (HR, 1.43; 95% CI, 1.17-1.74) compared with never using pipes or cigarettes. Current use of smokeless tobacco was associated with coronary heart disease mortality (HR, 1.31; 95% CI, 1.08-1.59) and myocardial infarction (HR, 1.20; 95% CI, 1.03-1.39) compared with never using smokeless tobacco. Sole and exclusive smokeless tobacco use demonstrated associations with total CVD (HR, 1.34; 95% CI, 1.19-1.50 and HR, 1.34; 955 CI, 1.13-1.59, respectively), total coronary heart disease (HR, 1.41; 95% CI, 1.21-1.64 and HR, 1.36; 95% CI, 1.08-1.70, respectively), heart failure (HR, 1.41; 95% CI, 1.22-1.64 and HR, 1.70; 95% CI, 1.40-2.06, respectively), and cardiovascular (HR, 1.41; 95% CI, 1.20-1.65 and HR, 1.54; 95% CI, 1.24-1.91, respectively) and all-cause (HR, 1.46; 95% CI, 1.34-1.60 and HR, 1.39; 95% CI, 1.22-1.58, respectively) mortality compared with never using smokeless tobacco or cigarettes. Conclusions and Relevance In this study, there were distinct risk patterns associated with the use of noncigarette tobacco products. These findings may carry implications for public health and regulation of noncigarette tobacco products.

Understanding the lifetime risk of dementia can inform public health planning and improve patient engagement in prevention. Using data from a community-based, prospective cohort study (n = 15,043; 26.9% Black race, 55.1% women and 30.8% with at least one apolipoprotein E4 (APOE ε4) allele), we estimated the lifetime risk of dementia (from age 55 years to 95 years), with mortality treated as a competing event. We applied lifetime risk estimates to US Census projections to evaluate the annual number of incident dementia cases from 2020 to 2060. The lifetime risk of dementia after age 55 years was 42% (95% confidence interval: 41–43). Rates were substantially higher in women, Black adults and APOE ε4 carriers, with lifetime risks ranging from approximately 45% to 60% in these populations. The number of US adults who will develop dementia each year was projected to increase from approximately 514,000 in 2020 to approximately 1 million in 2060. The relative growth in new dementia cases was especially pronounced for Black adults. These results highlight the urgent need for policies that enhance healthy aging, with a focus on health equity.

Importance Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening complication of COVID-19 infection. Data on midterm outcomes are limited. Objective To characterize the frequency and time course of cardiac dysfunction (left ventricular ejection fraction [LVEF] <55%), coronary artery aneurysms ( z score ≥2.5), and noncardiac involvement through 6 months after MIS-C. Design, Setting, and Participants This cohort study enrolled participants between March 2020 and January 2022 with a follow-up period of 2 years. Participants were recruited from 32 North American pediatric hospitals, and all participants met the 2020 Centers for Disease Control and Prevention case definition of MIS-C. Exposure MIS-C after COVID-19 infection. Main Outcomes and Measures Outcomes included echocardiography core laboratory (ECL) assessments of LVEF and maximum coronary artery z scores (zMax); data collection on cardiac and noncardiac sequelae during hospitalization and at 2 weeks, 6 weeks, and 6 months after discharge; and age-appropriate Patient-Reported Outcomes Measurement Information Systems (PROMIS) Global Health Instruments at follow-up. Descriptive statistics, linear regression models, and Kaplan-Meier analysis were used. Results Of 1204 participants (median [IQR] age, 9.1 [5.6-12.7] years; 724 male [60.1%]), 325 self-identified with non-Hispanic Black race (27.0%) and 324 with Hispanic ethnicity (26.9%). A total of 548 of 1195 participants (45.9%) required vasoactive support, 17 of 1195 (1.4%) required extracorporeal membrane oxygenation, and 3 (0.3%) died during hospitalization. Of participants with echocardiograms reviewed by the ECL (n = 349 due to budget constraints), 131 of 322 (42.3%) had LVEF less than 55% during hospitalization; of those with follow-up, all but 1 normalized by 6 months. Black race (vs other/unknown race), higher C-reactive protein level, and abnormal troponin level were associated with lowest LVEF (estimate [SE], −3.09 [0.98]; R ² = 0.14; P =.002). Fifteen participants had coronary artery z scores of 2.5 or greater at any time point; 1 participant had a large/giant aneurysm. Of the 13 participants with z scores of 2.5 or greater during hospitalization, 12 (92.3%) had normalized by 6 months. Return to greater than 90% of pre–MIS-C health status (energy, sleep, appetite, cognition, and mood) was reported by 711 of 824 participants (86.3%) at 2 weeks, increasing to 548 of 576 (95.1%) at 6 months. Fatigue was the most common symptom reported at 2 weeks (141 of 889 [15.9%]), falling to 3.4% (22 of 638) by 6 months. PROMIS Global Health parent/guardian proxy median T scores for fatigue, global health, and pain interference improved significantly from 2 weeks to 6 months (fatigue, 56.1 vs 48.9; global health, 48.8 vs 51.3; pain interference, 53.0 vs 43.3; P < .001) and by the 6-week visit were at least equivalent to prepandemic population norms. Conclusions and Relevance Results of this cohort study suggest that although children and young adults with MIS-C can have severe disease during the acute phase, most recovered quickly and had a reassuring midterm prognosis.

Background Weakened white matter (WM) integrity is highly associated with dementia risk. Still, not everyone with WM changes develops dementia, suggesting the important role modifiable lifestyle factors may have in reducing dementia risk. We investigated how social relationships in mid‐life may modify the association between WM integrity and incident dementia risk within race and sex subgroups. Method In 1,679 Atherosclerosis Risk in Community (ARIC) study participants who were dementia‐free in mid‐life, psychosocial health was assessed via self‐reported questionnaires and participants were classified as having strong or poor social relationships in mid‐life (visit 2: 1990‐1992). Through diffusion tensor imaging, WM integrity was evaluated with 3T brain MRI (visit 5: 2011 – 2013); fractional anisotropy (FA) and mean diffusivity (MD) were estimated. Incident dementia cases were identified from visit 5 through December 31, 2019, with ongoing surveillance. Relative contributions of social relationships and WM integrity to incident dementia were evaluated in Cox‐proportional hazard regression models with race and race‐sex as interaction terms, and in stratified models (White Females, Black Females, White Males, Black Males). Result Significant three‐way interactions were observed between race, WM integrity, and mid‐life social relationships (p‐interaction<0.01). In Black participants with strong mid‐life social relationships, higher MD (hazard ratio (HR): 0.93, 95% CI: 0.63 – 1.38) and lower FA (HR: 1.25, 95% CI: 0.84 – 1.86) were not associated with the risk of dementia, although in Black participants with poor social relationships, higher MD remained a significant risk factor for dementia. However, across all White participants, higher MD and lower FA were associated with the risk of dementia, regardless of mid‐life social relationships (Table 1; Figure 1). Analysis of three‐way interactions between race‐sex, WM integrity, and mid‐life social relationships suggested that effect modification by mid‐life social relationships was most evident in Black Females, respective to other groups (Table 2; Figure 1). Conclusion The contribution of WM integrity to dementia risk may be lower in Black participants with strong social relationships in mid‐life, particularly in Black Females. Further understanding of how contextual social factors may influence brain health in diverse populations should be examined in future studies and intervention efforts.

Background Current blood biomarkers of Alzheimer’s disease (AD) neuropathology and neurodegeneration include the ratio of amyloid‐β 42 to 40 (Aβ42/Aβ40), phosphorylated tau at threonine 181 (p‐Tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Prior studies have reported that hypertension is cross‐sectionally associated with lower levels of Aβ42/Aβ40 and longitudinally associated with faster accumulation of NfL. In this longitudinal investigation, we expanded on prior research by examining whether mid‐life blood pressure status was associated with change in AD biomarkers from mid‐ to late‐life. Method In the Atherosclerosis in Communities Study (ARIC) cohort, 1424 participants had blood pressure measurements at Visit 3 (baseline, 1993‐95) and two or more measurements of AD blood biomarkers from Visit 3, Visit 5 (2011‐13), and Visit 6 or 7 (2016‐2019). Linear mixed effects models quantified the association of mid‐life blood pressure status (hypotension, SBP<90 or DBP<60; hypertension, SBP>130 or DBP>90; normotension) with the rate of change in each AD blood biomarker. Models were adjusted for age, sex, race, education, the presence of apolipoprotein ε4 (APOE ε4) alleles, time‐varying body mass index and estimated glomerular filtration rate, and baseline cardiovascular and lifestyle risk factors. Result The sample included 860 women (60.4%) and 364 Black participants (25.6%). At baseline, 143 participants (10.0%) had hypotension and 449 (31.5%) had hypertension. Compared to participants with normotension, mid‐life hypertension was associated with accelerated accumulation of NfL from mid‐ to late‐life (Table 2). Both mid‐life hypotension and hypertension were associated with accelerated accumulation of pTau‐181 from mid‐ to late‐life. In subgroup analyses, these associations were greater among women, Black participants, and individuals without APOE ε4 alleles. Conclusion Mid‐life hypotension and hypertension are associated with faster changes in both AD‐specific (pTau‐181) and neurodegenerative (NfL) biomarkers from midlife to late‐life. Future investigation is needed to determine whether hypotension and hypertension are on the causal pathway relating AD neuropathology to dementia or if abnormal blood pressure and faster accumulation of pTau‐181 are shared characteristics of other comorbidities.