Plasma proteomic biomarkers and the association between poor cardiovascular health and incident dementia: The UK Biobank study.

BACKGROUND: The study examined how plasma proteome indicators may explain the link between poor cardiovascular health (CVH) and dementia risk. METHODS: The present study involved 28,974 UK Biobank participants aged 50-74y at baseline (2006-2010) who were followed-up for ≤ 15 y for incidence of dementia. CVH was calculated using Life's Essential 8 (LE8) total scores. The scores were standardized and reverse coded to reflect poor CVH (LE8z_rev). OLINK proteomics was available on this sample (k = 1,463 plasma proteins). The study primarily tested the mediating effects of the plasma proteome in LE8z_rev-dementia effect. The total effect was decomposed into "mediation only" or pure indirect effect (PIE), "interaction only" or interaction referent (INTREF), "neither mediation nor interaction" or controlled direct effect (CDE), and "both mediation and interaction" or mediated interaction (INTMED). RESULTS: The study found poorer CVH assessed by LE8z_rev increased the risk of all-cause dementia by 11 % [per 1 SD, hazard ratio, (HR) = 1.11, 95 % CI: 1.03-1.20, p = 0.005). The study identified 11 plasma proteins with strong mediating effects, with GDF15 having the strongest association with dementia risk (per 1 SD, HR = 1.24, 95 % CI: 1.16, 1.33, P < 0.001 when LE8z_rev is set at its mean value) and the largest proportion mediated combining PIE and INTMED (62.6 %; 48 % of TE is PIE), followed by adrenomedullin or ADM. A first principal component with 10 top mediators (TNFRSF1A, GDF15, FSTL3, COL6A3, PLAUR, ADM, GFRAL, ACVRL1, TNFRSF6B, TGFA) mediated 53.6 % of the LE8z_rev-dementia effect. Using all the significant PIE (k = 526) proteins, we used OLINK Insight pathway analysis to identify key pathways, which revealed the involvement of the immune system, signal transduction, metabolism, disease, protein metabolism, hemostasis, membrane trafficking, extracellular matrix organization, developmental biology, and gene expression among others. STRING analysis revealed that five top consistent proteomic mediators were represented in two larger clusters reflecting numerous interconnected biological gene ontology pathways, most notably cytokine-mediated signaling pathway for GDF15 cluster (GO:0019221) and regulation of peptidyl-tyrosine phosphorylation for the ADM cluster (GO:0050730). CONCLUSION: Dementia is linked to poor CVH mediated by GDF15 and ADM among several key proteomic markers which collectively explained âˆ¼ 54 % of the total effect.

Serum neurofilament light chain as a prognostic marker of all-cause mortality in a national sample of US adults.

Neurofilament light chain (NfL) is a neuron-specific structural protein released into the extracellular space, including body fluids, upon neuroaxonal damage. Despite evidence of a link in neurological disorders, few studies have examined the association of serum NfL with mortality in population-based studies. Data from the National Health and Nutrition Survey were utilized including 2,071 Non-Hispanic White, Non-Hispanic Black and Hispanic adult participants and adult participants of other ethnic groups (20-85 years) with serum NfL measurements who were followed for ≤ 6 years till 2019. We tested the association of serum NfL with mortality in the overall population and stratified by sex with the addition of potential interactive and mediating effects of cardio-metabolic risk factors and nutritional biomarkers. Elevated serum NfL levels (above median group) were associated with mortality risk compared to the below median NfL group in the overall sample (P = 0.010), with trends observed within each sex group (P < 0.10). When examining Loge NfL as a continuum, one standard deviation of Loge NfL was associated with an increased mortality risk (HR = 1.88, 95% CI 1.60-2.20, P < 0.001) in the reduced model adjusted for age, sex, race, and poverty income ratio; a finding only slightly attenuated with the adjustment of lifestyle and health-related factors. Four-way decomposition indicated that there was, among others, mediated interaction between NfL and HbA1c and a pure inconsistent mediation with 25(OH)D3 in predicting all-cause mortality, in models adjusted for all other covariates. Furthermore, urinary albumin-to-creatinine ratio interacted synergistically with NfL in relation to mortality risk both on the additive and multiplicative scales. These data indicate that elevated serum NfL levels were associated with all-cause mortality in a nationally representative sample of US adults.

Pathways explaining racial/ethnic disparities in incident all-cause dementia among middle-aged US adults.

INTRODUCTION: Racial disparities in dementia incidence exist, but less is known about their presence and drivers among middle-aged adults. METHODS: We used time-to-event analysis among a sample of 4378 respondents (age 40-59 years at baseline) drawn from the third National Health and Nutrition Examination Surveys (NHANES III) with administrative linkage-spanning the years 1988-2014-to evaluate potential mediating pathways through socioeconomic status (SES), lifestyle, and health-related characteristics. RESULTS: Compared with Non-Hispanic White (NHW) adults, Non-White adults had a higher incidence of AD-specific (hazard ratio [HR] = 2.05, 95% confidence interval [CI]: 1.21, 3.49) and all-cause dementia (HR = 2.01, 95% CI: 1.36, 2.98). Diet, smoking, and physical activity were among characteristics on the pathway between race/ethnicity, SES, and dementia, with health-mediating effects of smoking and physical activity on dementia risk. DISCUSSION: We identified several pathways that may generate racial disparities in incident all-cause dementia among middle-aged adults. No direct effect of race was observed. More studies are needed to corroborate our findings in comparable populations.

Dietary factors are associated with serum uric acid trajectory differentially by race among urban adults.

Serum uric acid (SUA), a causative agent for gout, is linked to dietary factors, perhaps differentially by race. Cross-sectional (SUAbase, i.e. baseline SUA) and longitudinal (SUArate; i.e. annual rate of change in SUA) associations of SUA with diet were evaluated across race and sex-race groups, in a large prospective cohort study of urban adults. Of 3720 African American (AA) and White urban adults participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span study, longitudinal data (2004-2013, k=1·7 repeats, follow-up, 4·64 (sd 0·93) years) on n 2138 participants were used. The main outcome consisted of up to two repeated measures on SUA. Exposures included the dietary factors such as 'added sugar', 'alcoholic beverages', 'red meat', 'total fish', 'legumes', 'total dairy product', 'caffeine', 'vitamin C' and a composite measure termed 'dietary urate index'. Mixed-effects linear regression models were conducted, stratifying by race and by race×sex. A positive association between legume intake and SUArate was restricted to AA, whereas alcohol intake was positively associated with SUAbase overall without racial differences. Added sugars were directly related to SUAbase among White men (P<0·05 for race×sex interaction), whereas dairy product intake was linked with slower SUArate among AA women, unlike among White women. Nevertheless, dairy product intake was associated with a lower SUAbase among Whites. Finally, the dietary urate index was positively associated with both SUAbase and SUArate, particularly among AA. In sum, race and sex interactions with dietary intakes of added sugars, dairy products and legumes were detected in determining SUA. Similar studies are needed to replicate these findings.

Dairy product consumption and its association with metabolic disturbance in a prospective study of urban adults.

The role of dairy foods and related nutrients in cardiometabolic health aetiology is poorly understood. We investigated longitudinal associations between the metabolic syndrome (MetS) and its components with key dairy product exposures. We used prospective data from a bi-racial cohort of urban adults (30-64 years at baseline (n 1371)), the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS), in Baltimore City, MD (2004-2013). The average of two 24-h dietary recalls measured 4-10 d apart was computed at baseline (V1) and follow-up (V2) waves. Annual rates of change (Δ) in dairy foods and key nutrients were estimated. Incident obesity, central obesity and the MetS were determined. Among key findings, in the overall urban adult population, both cheese and yogurt (V1 and Δ) were associated with an increased risk of central obesity (hazard ratio (HR) 1·13; 95 % CI 1·05, 1·23 per oz equivalent of cheese (V1); HR 1·21; 95 % CI 1·01, 1·44 per fl oz equivalent of yogurt (V1)]. Baseline fluid milk intake (V1 in cup equivalents) was inversely related to the MetS (HR 0·86; 95 % CI 0·78, 0·94), specifically to dyslipidaemia-TAG (HR 0·89; 95 % CI 0·81, 0·99), although it was directly associated with dyslipidaemia-HDL-cholesterol (HR 1·10; 95 % CI 1·01, 1·21). Furthermore, ΔCa and ΔP were inversely related to dyslipidaemia-HDL and MetS incidence, respectively, whereas Δdairy product fat was positively associated with incident TAG-dyslipidaemia and HDL-cholesterol-dyslipidaemia and the MetS. A few of those associations were sex and race specific. In sum, various dairy product exposures had differential associations with metabolic disturbances. Future intervention studies should uncover how changes in dairy product components over time may affect metabolic disorders.

Genetic risk scores, sex and dietary factors interact to alter serum uric acid trajectory among African-American urban adults.

Serum uric acid (SUA), a causative agent for gout among others, is affected by both genetic and dietary factors, perhaps differentially by sex. We evaluated cross-sectional (SUAbase) and longitudinal (SUArate) associations of SUA with a genetic risk score (GRS), diet and sex. We then tested the interactive effect of GRS, diet and sex on SUA. Longitudinal data on 766 African-American urban adults participating in the Healthy Aging in Neighborhood of Diversity across the Lifespan study were used. In all, three GRS for SUA were created from known SUA-associated SNP (GRSbase (n 12 SNP), GRSrate (n 3 SNP) and GRStotal (n 15 SNP)). Dietary factors included added sugar, total alcohol, red meat, total fish, legumes, dairy products, caffeine and vitamin C. Mixed-effects linear regression models were conducted. SUAbase was higher among men compared with that among women, and increased with GRStotal tertiles. SUArate was positively associated with legume intake in women (γ=+0·14; 95 % CI +0·06, +0·22, P=0·001) and inversely related to dairy product intake in both sexes combined (γ=-0·042; 95 % CI -0·075, -0·009), P=0·010). SUAbase was directly linked to alcohol consumption among women (γ=+0·154; 95 % CI +0·046, +0·262, P=0·005). GRSrate was linearly related to SUArate only among men. Legume consumption was also positively associated with SUArate within the GRStotal's lowest tertile. Among women, a synergistic interaction was observed between GRSrate and red meat intake in association with SUArate. Among men, a synergistic interaction between low vitamin C and genetic risk was found. In sum, sex-diet, sex-gene and gene-diet interactions were detected in determining SUA. Further similar studies are needed to replicate our findings.

Alternative Pathway Analyses Indicate Bidirectional Relations between Depressive Symptoms, Diet Quality, and Central Adiposity in a Sample of Urban US Adults.

BACKGROUND: Temporality between socioeconomic status (SES), depressive symptoms (DS), dietary quality (DQ), and central adiposity (CA) is underexplored. OBJECTIVES: Alternative pathways linking SES to DQ, DS, and CA were tested and models compared, stratified by race and sex. METHODS: With the use of data from the Healthy Aging in Neighborhoods of Diversity across the Life Span (baseline age: 30-64 y; 2 visits; mean follow-up: 4.9 y), 12 structural equation models (SM) were conducted and compared. Time-dependent factors included the Center for Epidemiologic Studies-Depression [CES-D total score, baseline or visit 1 (v1), follow-up or visit 2 (v2), mean across visits (m), and annual rate of change (Δ)], 2010 Healthy Eating Index (HEI) (same notation), and central adiposity principal components' analysis score of waist circumference and trunk fat (kg) (Adipcent) (same notation). Sample sizes were white women (WW, n = 236), white men (WM, n = 159), African American women (AAW, n = 395), and African American men (AAM, n = 274), and a multigroup analysis within the SM framework was also conducted. RESULTS: In the best-fitting model, overall, ∼31% of the total effect of SES→Adipcent(v2) (α ± SE: -0.10 ± 0.03, P < 0.05) was mediated through a combination of CES-D(v1) and ΔHEI. Two dominant pathways contributed to the indirect effect: SES→(-)CES-D(v1)→(+)Adipcent(v2) (-0.015) and SES→(+) ΔHEI→(-)Adipcent(v2) (-0.017), with a total indirect effect of -0.031 (P < 0.05). In a second best-fitting model, SES independently predicted Adipcent(v1, -0.069), ΔHEI(+0.037) and CES-D(v2, -2.70) (P < 0.05), with Adipcent(v1) marginally predicting ΔHEI(-0.014) and CES-D(v2, +0.67) (P < 0.10). These findings were indicative of DS's and CA's marginally significant bidirectional association (P < 0.10). Although best-fit-selected models were consistent across race × sex categories, path coefficients differed significantly between groups. Specifically, SES→Adipcent[v1(+0.11), v2(+0.14)] was positive among AAM (P < 0.05), and the overall positive association of Adipcent(v1)→CES-D(v2) was specific to AAW (+0.97, P < 0.10). CONCLUSIONS: Despite consistent model fit, pathways linking SES to DQ, DS, and CA differed markedly among the race × sex groups. Our findings can inform the potential effectiveness of various mental health and dietary interventions.

Associations of the Ratios of n-3 to n-6 Dietary Fatty Acids With Longitudinal Changes in Depressive Symptoms Among US Women.

In the present study, we examined longitudinal changes in self-reported depressive symptoms (and related domains) in relation to baseline intakes of n-3 fatty acids (absolute and relative to n-6 fatty acids). Sex-specific associations were evaluated in a prospective cohort of adults (n = 2,053) from Baltimore, Maryland, who were 30-64 years of age at baseline and were followed for a mean of 4.65 (standard deviation, 0.93) years (2004-2013). Using mean intakes of n-3 and n-6 fatty acids reported on two 24-hour dietary recalls, we estimated the ratios of n-3 to n-6 fatty acids for both highly unsaturated fatty acids (≥20 carbon atoms) (HUFAs) and polyunsaturated fatty acids (≥18 carbon atoms) (PUFAs). Outcomes included total and domain-specific scores on the 20-item Center for Epidemiologic Studies-Depression scale. Based on mixed-effects regression models, among women, both higher n-3 HUFA:n-6 PUFA and n-3 PUFA:n-6 PUFA ratios were associated with a slower rate of increase in total Center for Epidemiologic Studies-Depression scores over time. Higher n-3 HUFA:n-6 HUFA ratios were associated with slower increases in somatic complaints in men, whereas among women, higher n-3 HUFA:n-6 PUFA and n-3 PUFA:n-6 PUFA ratios were both linked to putative longitudinal improvement in positive affect over time. Among US adults, n-3:n-6 dietary fatty acid ratio was associated with longitudinal changes in depressive symptoms, with a higher ratio linked to a slower increase in depressive symptoms over time, particularly among women.

Dietary antioxidant intake and its association with cognitive function in an ethnically diverse sample of US adults.

BACKGROUND: Dietary antioxidants can inhibit reactions accompanying neurodegeneration and thus prevent cognitive impairment. We describe associations of dietary antioxidants with cognitive function in a large biracial population, while testing moderation by sex, race, and age and mediation by depressive symptoms. METHODS: This was a cross-sectional analysis of 1274 adults (541 men and 733 women) aged 30 to 64 years at baseline (mean [standard deviation] = 47.5 [9.3]) in the Healthy Aging in Neighborhoods of Diversity Across the Lifespan Study, Baltimore city, MD. Cognitive performance in the domains of memory, language/verbal, attention, spatial, psychomotor speed, executive function, and global mental status were assessed. The 20-item Center for Epidemiologic Studies Depression Scale was used to measure depressive symptoms. Dietary intake was assessed with two 24-hour recalls, estimating daily consumption of total carotenoids and vitamins A, C, and E per 1000 kcal. RESULTS: Among key findings, 1 standard deviation (∼ 2.02 mg/1000 kcal) higher vitamin E was associated with a higher score on verbal memory, immediate recall (ß = +0.64 [0.19], p = .001), and better language/verbal fluency performance (ß = +0.53 [0.16], p = .001), particularly among the younger age group. Women with higher vitamin E intake (ß = +0.68 [0.21], p = .001) had better performance on a psychomotor speed test. The vitamin E-verbal memory association was partially mediated by depressive symptoms (proportion mediated = 13%-16%). CONCLUSIONS: In sum, future cohort studies and dietary interventions should focus on associations of dietary vitamin E with cognitive decline, specifically for domains of verbal memory, verbal fluency, and psychomotor speed.

ω-3 fatty acid intakes are inversely related to elevated depressive symptoms among United States women.

Evidence that depressive symptoms are inversely related to n-3 (ω-3) fatty acids is growing among United States adults. We assessed whether self-reported depressive symptoms were inversely associated with n-3 fatty acid intakes by using a cross-sectional study in 1746 adults (aged 30-65 y) in Baltimore City, MD (2004-2009). The 20-item Center for Epidemiologic Studies-Depression Scale (CES-D) was used, with a CES-D score ≥16 suggestive of elevated depressive symptoms (EDS). By using the mean of two 24-h dietary recalls, n-3 highly unsaturated fatty acids (HUFAs; ≥20 carbons), n-3 polyunsaturated fatty acids (PUFAs; ≥18 carbons), and plausible ratios with n-6 (ω6) fatty acids were estimated. EDS prevalence was 18.1% among men and 25.6% among women. In women, the uppermost tertile (tertile 3) of n-3 PUFAs (compared with tertile 1) was associated with reduced odds of EDS by 49%, with a substantial sex differential. The n-3 PUFA:n-6:PUFA ratio was inversely related to EDS among women (tertile 2 vs. tertile 1, OR: 0.74; 95% CI: 0.41, 1.32; tertile 3 vs. tertile 1, OR: 0.47; 95% CI: 0.27, 0.83). A similar pattern was noted for n-3 HUFA:n-6 HUFA among women. For CES-D subscales, n-3 PUFA (% of energy) was inversely related to somatic complaints, whereas positive affect was directly related to n-3 HUFA (% of energy; total population and among women), n-3 HUFA:n-6 HUFA (women), and n-3 HUFA:n-6 PUFA (total population and among women). In sum, among United States women, higher intakes of n-3 fatty acids [absolute (n-3) and relative to n-6 fatty acids (n-3:n-6)] were associated with lower risk of elevated depressive symptoms, specifically in domains of somatic complaints (mainly n-3 PUFAs) and positive affect (mainly n-3 HUFAs).

Allostatic Load and Cognitive Function Among Urban Adults in the Healthy Aging in Neighborhoods of Diversity across the Life Span Study.

BACKGROUND: Cross-sectional studies have linked cognition to allostatic load (AL) which reflects multisystem dysregulation from life course exposure to stressors. OBJECTIVE: To examine baseline and changes in AL and their relationships with 11 cognitive function test scores, while exploring health disparities according to sex and race. METHODS: Longitudinal [Visit 1 (2004-2009) and Visit 2 (2009-2013)] data were analyzed from 2,223 Healthy Aging in Neighborhoods of Diversity across the Life Span participants. We calculated AL total score using cardiovascular, metabolic, and inflammatory risk indicators, and applied group-based trajectory modeling to define AL change. RESULTS: Overall and stratum-specific relationships were evaluated using mixed-effects linear regression models that controlled for socio-demographic, lifestyle, and health characteristics. Baseline AL was significantly associated with higher log-transformed Part A Trail Making Test score [Loge (TRAILS A)] (ß= 0.020, p = 0.004) and increasing AL was associated with higher Benton Visual Retention Test score [BVRT] (ß= 0.35, p = 0.002) at baseline, in models that controlled for age, sex, race, poverty status, education, literacy, smoking, drug use, the 2010 healthy eating index and body mass index. Baseline AL and AL change were not related to change in cognitive function between visits. There were no statistically significant interaction effects by sex or race in fully-adjusted models. CONCLUSION: At baseline, AL was associated with worse attention or executive functioning. Increasing AL was associated with worse non-verbal memory or visuo-constructional abilities at baseline. AL was not related to change in cognitive function over time, and relationships did not vary by sex or race.

Longitudinal association of allostatic load with depressive symptoms among urban adults: Healthy Aging in Neighborhoods of Diversity across the Life Span study.

BACKGROUND: Evidence suggests that lifetime exposure to stressful life events and chronic stressors may be linked to geriatric depression. Allostatic load (AL) is considered a mediator of the stress-health relationship and has been linked to psychosocial factors reflecting health disparities. The purpose of this study was to examine the longitudinal associations of AL with depressive symptoms scores among urban adults, before and after stratifying by sex and race. METHODS: Secondary analyses were performed using Visit 1 (2004-2009), Visit 2 (2009-2013) and Visit 3 (2013-2017) data collected on 2298 Healthy Aging in Neighborhoods of Diversity across the Life Span study participants (baseline age: 30-64 y). AL at Visit 1 (ALv1) and z-transformed probability of higher AL trajectory (ALtraj) between Visits 1 and 3 were calculated using cardiovascular, metabolic and inflammatory risk indicators. The 20-item Center for Epidemiologic Studies Depression (CES-D) scale was used to calculate total and domain-specific depressive symptoms scores. Mixed-effects linear models controlled for socio-demographic, lifestyle and health characteristics. RESULTS: In fully adjusted models, a positive cross-sectional relationship was observed between ALv1 and "somatic complaints" depressive symptoms (ß = 0.21, P = 0.006) score at Visit 1, whereas ALtraj was associated with increasing depressive symptoms score (ß = 0.086, P = 0.003) between Visits 1 and 3. An inverse relationship was observed between ALtraj and "positive affect" depressive symptoms score at Visit 1 among women (ß = -0.31, P < 0.0001) and White adults (ß = -0.32, P = 0.004). Among women, ALtraj was also positively related to change in "somatic complaints" depressive symptoms score between Visits 1 and 3 (ß = 0.043, P = 0.020). CONCLUSIONS: Among urban adults, AL may be associated with "somatic complaints" depressive symptoms at baseline. Higher AL trajectories may predict increasing depressive symptoms (overall) and increasing "somatic complaints" depressive symptoms (among women). A higher AL trajectory may be associated with lower "positive affect" depressive symptoms at baseline among women and White adults only.

Life's simple 7 and its association with trajectories in depressive symptoms among urban middle-aged adults.

BACKGROUND: The American Heart Association Life's Simple 7 (LS7) is a composite metric assessing cardiovascular health on a scale of 0-14 comprised of nutrition, physical activity, cigarette use, body mass index, blood pressure, cholesterol and glucose. METHODS: Using data from the Healthy Aging in Neighborhoods of Diversity across the Life Span study [n = 1465, Age at visit 1 (v1: 2004-2009): 30-66 y, 41.7 % male, 60.6 % African American], we investigated associations of trajectories in depressive symptoms (2004-2017) with Life's simple 7 scores after ∼8.6 years follow-up (2013-2017). Analyses used group-based zero-inflated Poisson trajectory (GBTM) models and multiple linear or ordinal logistic regression. GBTM analyses generated two classes of depressive symptoms trajectories ("low declining" and "high declining"), based on intercept and slope direction and significance. RESULTS: Overall, "high declining depressive symptoms" vs. the "low declining" group was associated with -0.67 ± 0.10 lower scores on LS7 total score (P < 0.001) in analyses adjusted for age, sex, race and the inverse mills ratio. This effect was markedly attenuated to -0.45 ± 0.10 score-points (P < 0.001) upon adjustment for socio-economic factors and to -0.27 ± 0.10 score-points (P < 0.010) in fully adjusted analyses, with a stronger association detected among women (ß ± SE: -0.45 ± 0.14, P = 0.002). An association between elevated depressive symptoms over time ("high declining" vs "low declining") and LS7 total score was detected among African American adults (ß ± SE: -0.281 ± 0.131, p = 0.031, full model). Moreover, the "high declining" vs. "low declining" depressive symptoms group was associated with a lower score on LS7 physical activity (ß ± SE: -0.494 ± 0.130, P < 0.001). CONCLUSIONS: Poorer cardiovascular health was linked to higher depressive symptoms over time.

Pathways explaining racial/ethnic and socio-economic disparities in dementia incidence: the UK Biobank study.

BACKGROUND: Pathways explaining racial/ethnic disparities in dementia risk are under-evaluated. METHODS: We examine those disparities and their related pathways among UK Biobank study respondents (50-74 y, N = 323,483; 3.6% non-White minorities) using a series of Cox proportional hazards and generalized structural equations models (GSEM). RESULTS: After ≤15 years, 5,491 all-cause dementia cases were diagnosed. Racial minority status (RACE_ETHN, Non-White vs. White) increased dementia risk by 24% (HR = 1.24, 95% CI: 1.07-1.45, P = 0.005), an association attenuated by socio-economic status (SES), (HR = 1.12, 95% CI: 0.96-1.31). Total race-dementia effect was mediated through both SES and Life's Essential 8 lifestyle sub-score (LE8LIFESTYLE), combining diet, smoking, physical activity, and sleep factors. SES was inversely related to dementia risk (HR = 0.69, 95% CI: 0.67, 0.72, P < 0.001). Pathways explaining excess dementia risk among racial minorities included 'RACE_ETHN(-) → SES(-) → DEMENTIA', 'RACE_ETHN(-) → SES(-) → Poor cognitive performance, COGN(+) → DEMENTIA' and 'RACE_ETHN(-) → SES(+) → LE8LIFESTYLE(-) → DEMENTIA'. CONCLUSIONS: Pending future interventions, lifestyle factors including diet, smoking, physical activity, and sleep are crucial for reducing racial and socio-economic disparities in dementia.

Association of Serum Antioxidant Vitamins and Carotenoids With Incident Alzheimer Disease and All-Cause Dementia Among US Adults.

BACKGROUND AND OBJECTIVES: Serum antioxidant vitamins and carotenoids may protect against neurodegeneration with age. We examined associations of these nutritional biomarkers with incident all-cause and Alzheimer disease (AD) dementia among US middle-aged and older adults. METHODS: Using data from the third National Health and Nutrition Examination Surveys (1988-1994), linked with Centers for Medicare & Medicaid follow-up data, we tested associations and interactions of serum vitamins A, C, and E and total and individual serum carotenoids and interactions with incident AD and all-cause dementia. Cox proportional hazards regression models were conducted. RESULTS: After ≤26 years follow-up (mean 16-17 years, 7,283 participants aged 45-90 years at baseline), serum lutein+zeaxanthin was associated with reduced risk of all-cause dementia (65+ age group), even in the lifestyle-adjusted model (per SD: hazard ratio [HR] 0.93, 95% CI 0.87-0.99; p = 0.037), but attenuated in comparison with a socioeconomic status (SES)-adjusted model (HR 0.92, 95% CI 0.86-0.93; p = 0.013). An inverse relationship was detected between serum ß-cryptoxanthin (per SD increase) and all-cause dementia (45+ and 65+) for age- and sex-adjusted models (HR 0.86, 95% CI 0.80-0.93; p < 0.001 for 45+; HR 0.86, 95% CI 0.80-0.93; p = 0.001 for 65+), a relationship remaining strong in SES-adjusted models (HR 0.89, 95% CI 0.82-0.96; p = 0.006 for 45+; HR 0.88, 95% CI 0.81-0.96; p = 0.007 for 65+), but attenuated in subsequent models. Antagonistic interactions indicate putative protective effects of 1 carotenoid may be observed at lower levels other carotenoids or antioxidant vitamin. DISCUSSION: Incident all-cause dementia was inversely associated with serum lutein+zeaxanthin and ß-cryptoxanthin levels. Further studies with time-dependent exposures and randomized trials are needed to test neuroprotective effects of supplementing the diet with select carotenoids. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that incident all-cause dementia was inversely associated with serum lutein+zeaxanthin and ß-cryptoxanthin levels.

APOE gene region methylation is associated with cognitive performance in middle-aged urban adults.

Apolipoprotein (APOE) ε4 allele is a strong risk factor for Alzheimer's disease (AD) and cognitive decline. Epigenetic modifications such as DNA methylation (DNAm) play a central role in cognition. This study sought to identify DNAm sites in the APOE genomic region associated with cognitive performance in a racially diverse middle-aged cohort (n = 411). Cognitive performance was measured by 11 standard neuropsychological tests. Two CpG sites were associated with the Card Rotation and Benton Visual Retention cognitive tests. The methylation level of the CpG site cg00397545 was associated with Card Rotation Test score (p = 0.000177) and a novel CpG site cg10178308 was associated with Benton Visual Retention Test score (p = 0.000084). Significant associations were observed among the dietary inflammatory index, which reflects the inflammatory potential of the diet, cognitive performance and the methylation level of several CpG sites. Our results indicate that DNAm in the APOE genomic area is correlated with cognitive performance and may presage cognitive decline.

Pathways explaining racial/ethnic disparities in incident all-cause and Alzheimer's disease dementia among older US men and women.

Introduction: Racial disparities in Alzheimer's disease (AD) and all-cause dementia (DEMENTIA) incidence may exist differentially among men and women, with unknown mechanisms. Methods: A retrospective cohort study examining all-cause and AD dementia incidence was conducted linking Third National Health and Nutrition Examination Survey (NHANES III) to Centers for Medicare & Medicaid Services Medicare data over ≤26 years of follow-up (1988 to 2014). Cox regression and generalized structural equation models (GSEMs) were constructed among men and women ≥60 years of age at baseline (N = 4592). Outcomes included onset ages of all-cause and AD dementia, whereas the main exposures were race/ethnicity contrasts (RACE_ETHN). Potential mediators) included socio-economic status (SES), lifestyle factors (dietary quality [DIET] nutritional biomarkers [NUTR], physical activity [PA], social support [SS], alcohol [ALCOHOL], poor health [or HEALTH], poor cognitive performance [or COGN]. In addition to RACE_ETHN, the following were exogenous covariates in the GSEM and potential confounders in Cox models: age, sex, urban-rural, household size, and marital status. Results: Non-Hispanic Black (NHB) women had a higher risk of DEMENTIA versus non-Hispanic White (NHW) women in GSEM, consistent with Cox models (age-adjusted model: hazard ratio [HR] = 1.34, 95% confidence interval [CI]: 1.10 to 1.61). The total effect of this RACE_ETHN contrast in women was explained by four main pathways: (1) RACE_ETHN→ poor cognitive performance (COGN, +) → DEMENTIA (+); (2) RACE_ETHN → SES (-) → COGN (-) → DEMENTIA (+); (3) RACE_ETHN → SES (-) → physical activity (PA, +) → COGN (-) → DEMENTIA (+); and (4) RACE_ETHN → SES (-) → DIET (+) → COGN (-) → DEMENTIA (+). A reduced AD risk in Mexican American (MA) women versus NHW women upon adjustment for SES and downstream factors (HR = 0.53, 95% CI: 0.35 to 0.80). For the non-White versus NHW contrast in incident DEMENTIA, pathways involved lower SES, directly increasing cognitive deficits (or indirectly through lifestyle factors), which then directly increases DEMENTIA . Discussion: Socioeconomic and lifestyle factors explaining disparities between NHB and NHW in dementia onset among women are important to consider for future observational and intervention studies.

Usual Intake of Flavonoids Is Inversely Associated with Metabolic Syndrome in African American and White Males but Not Females in Baltimore City, Maryland, USA.

Despite research that suggests flavonoids protect against metabolic syndrome (MetS) and evidence that intake of these compounds differs by race, knowledge about whether flavonoid-MetS associations vary among racial groups is limited. This study sought to estimate usual total flavonoid intake in African American and White adults and assess its sex- and sex/race-specific associations with MetS and its risk factors. Analysis of cross-sectional data from 1837 adults participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study were analyzed. Usual total flavonoid intake was estimated using the NCI Method, and logistic regression measured its linkages with health outcomes. Among males overall and when stratified by race, odds of MetS and its risk factors low high-density lipoprotein cholesterol (HDL-C) and elevated glucose were lower at the 75th percentile of usual total flavonoid intake than at the 25th percentile (OR for MetS = 0.62; 95% CI = 0.53, 0.71). However, low HDL-C and elevated glucose were positively associated with usual flavonoid intake among females. The comparable associations by race within sex imply that the relationships between flavonoid and health outcomes may be evident across an array of intakes.

Vitamin D status and its longitudinal association with changes in patterns of sleep among middle-aged urban adults.

OBJECTIVE: We examined relationships of vitamin D status with over time changes in patterns of sleep in a longitudinal study of Whites and African-American urban middle-aged adults, while further testing effect modification by age group, sex and race and the potential roles of dietary and supplemental vitamin D. METHODS: Data on 1,760 middle-aged participants in the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS study: Age range at v2: 33-71y, mean±SD:53.0±8.8, % women: 58.4%, % African-American:60.3%) were used, with complete baseline 25-hydroxyvitamin D [25(OH)D] serum concentration data, initial selected covariates and mediators, and initial and/or follow-up data on five sub-scales (sleep duration, daytime dysfunction, sleep disturbance, sleep latency and sleep quality) of the Pittsburgh Sleep Quality Index. Mean±SD time between initial and follow-up visits: 4.1±1.5 years. Time-interval multiple mixed-effects linear regression models were used. RESULTS: Upon multiple testing adjustment, among Whites, initial 25(OH)D was associated with better sleep duration [25(OH)D × TIME γ±SE: -0.027±0.011, P=0.017] and sleep quality [25(OH)D × TIME γ±SE: -0.026±0.010, P=0.008] over time, with heterogeneity by race found for both relationships (P<0.05 for 25(OH)D × TIME × Race in the un-stratified model). These relationships remained unaltered after further adjustment for dietary and supplemental vitamin D, indicating that this association may be largely explained by sunlight exposure. LIMITATIONS: Limitations included small sample size, selection bias, residual confounding and lack of objective sleep measures. Conclusions Vitamin D status, possibly through mechanisms involving sunlight exposure, was linked to a potential improvement in sleep duration and quality among White urban adults.

The sex-specific role of plasma folate in mediating the association of dietary quality with depressive symptoms.

Folate deficiency has been implicated in the etiology of unipolar depression. In this study, we attempted to cross-link plasma folate, depressive symptoms, and dietary quality (or dietary intake of folate) together in a comprehensive framework, while examining effect modification of those associations by sex. This was a cross-sectional, population-based study of 1681 participants aged 30-64 y (Healthy Aging in Neighborhoods of Diversity across the Lifespan Study). Participants were administered the Center for Epidemiologic Studies Depression scale (CES-D). Measures of plasma folate and dietary intakes (2 24-h recalls) from which the 2005-Healthy Eating Index (HEI) was computed were available. Multivariate logistic regression and structural equation modeling (SM) were conducted. Compared with the lowest tertile, the middle and uppermost tertiles of plasma folate were associated with a 39-40% reduced odds of elevated CES-D (> or =16) among women [adjusted odds ratio (T(3) vs. T(1)) = 0.60 (95% CI = 0.42-0.86); P = 0.006]. Confounding of this association by HEI(total) was noted among both men and women, although dietary folate did not confound this association appreciably. In SM, plasma folate completely mediated the inverse HEI(total)-CES-D association among men only, specifically for HEI(2) (higher intakes of whole fruits), HEI(3) (total vegetables), HEI(5) (total grains), HEI(6) (whole grains), HEI(7) (milk), and HEI(12) (lower discretionary energy). Among women, HEI(total) and 4 components had an inverse direct effect on CES-D score, suggesting a mechanism that is independent of plasma folate. Depressive symptoms in our study may be alleviated by improving overall dietary quality, with plasma folate playing a potential mediating role only among men.