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Introduction: Relationships and interplay of an infection burden (IB) and periodontal pathogens or periodontal disease (Pd) markers with Alzheimer's disease (AD) and all-cause dementia among US adults were examined., Methods: Less than or equal to 2997 participants from the National Health and Nutrition Survey III were linked to CMS-Medicare [≥45 years (1988-1994); ≤30 years follow-up]., Results: Hepatitis C (hazard ratio = 3.33, p = 0.004) and herpes simplex virus 2 were strongly associated with greater all-cause dementia risk. Porphyromonas gingivalis and Streptococcus oralis were associated with greater AD risk at higher IB. The red-green periodontal pathogen cluster coupled with higher IB count increased the risk of all-cause dementia among minority racial groups. Pocket probing depth associated with dementia risk at lower IB in the overall sample., Discussion: Select viruses and bacteria were associated with all-cause and AD dementia, while the IB interacted with Pd markers in relation to these outcomes., Highlights: Interplay of infection burden (IB) and periodontal disease with dementia was tested. ≤2997 participants from NHANES III were linked to Medicare. Hepatitis C and herpes simplex virus 2 strongly associated with dementia risk. Tetanus sero-positivity increased Alzheimer's disease (AD) risk. Porphyromonas gingivalis and Streptococcus oralis associated with AD at higher IB. Red-green periodontal cluster at high IB, increased dementia in racial minorities. Pocket probing depth associated with dementia risk at lower IB., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Inflammation can play a role in the pathophysiology of depression, and specific types of antidepressants may have inflammatory or anti-inflammatory properties. Furthermore, depression and antidepressant use has been linked to white blood cell (WBC) count, a routinely measured inflammatory marker. We examined the cross-sectional and longitudinal relationships of depressive symptoms and/or antidepressant use with WBC count among postmenopausal women. Analyses of cross-sectional data at enrollment were performed on 125,307 participants, 50-79 years of age, from the Women's Health Initiative Clinical Trials and Observational Studies who met eligibility criteria, and a subset of those with 3-year follow-up data were examined for longitudinal relationships. Depressive symptoms were defined using the Burnam Algorithm whereas antidepressant use was defined using therapeutic class codes. WBC count (Kcell/ml) was obtained through laboratory evaluations of fasting blood samples. Multivariable regression modeling was performed taking sociodemographic, lifestyle and health characteristics into consideration. At enrollment, nearly 85% were non-users of antidepressants with no depressive symptoms, 5% were antidepressant users with no depressive symptoms, 9% were non-users of antidepressants with depressive symptoms, and 2% were users of antidepressants with depressive symptoms. In fully-adjusted models, cross-sectional relationships were observed whereby women in the 2 nd (OR = 1.06, 95% CI: 1.01, 1.13), 3 rd (OR = 1.06, 95% CI: 1.00, 1.12) or 4 th (OR = 1.10, 95% CI: 1.05, 1.17) quartiles of WBC count were more likely to exhibit depressive symptoms, and women in the 4 th quartile were more likely to be users of antidepressants (OR = 1.07, 95% CI: 1.00, 1.15), compared to women in the 1 st quartile. Compared to women who exhibited no depressive symptoms at either visit, those with consistent depressive symptoms at enrollment and at 3-year follow-up had faster decline in WBC count (β = -0.73, 95% CI: -1.33, -0.14) over time. No significant bidirectional relationships were observed between changes in depressive symptoms score and WBC count over time. In conclusion, depressive symptoms and/or antidepressant use were cross-sectionally related to higher WBC counts among postmenopausal women. Further evaluation of observed relationships is needed in the context of prospective cohort studies involving older adult men and women, with repeated measures of depression, antidepressant use, and WBC count., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Pathways explaining racial/ethnic and socio-economic status (SES) disparities in white matter integrity (WMI) reflecting brain health, remain underexplored, particularly in the UK population. We examined racial/ethnic and SES disparities in diffusion tensor brain magnetic resonance imaging (dMRI) markers, namely global and tract-specific mean fractional anisotropy (FA), and tested total, direct and indirect effects through lifestyle, health-related and cognition factors using a structural equations modeling approach among 36,184 UK Biobank participants aged 40-70 y at baseline assessment (47% men). Multiple linear regression models were conducted, testing independent associations of race/ethnicity, socio-economic and other downstream factors in relation to global mean FA, while stratifying by Alzheimer's Disease polygenic Risk Score (AD PRS) tertiles. Race (Non-White vs. White) and lower SES predicted poorer WMI (i.e. lower global mean FA) at follow-up, with racial/ethnic disparities in FA mean involving multiple pathways and SES playing a central role in those pathways. Mediational patterns differed across tract-specific FA outcomes, with SES-FA mean total effect being partially mediated (41% of total effect = indirect effect). Furthermore, the association of poor cognition with FA mean was markedly stronger in the two uppermost AD PRS tertiles compared to the lower tertile (T 2 and T 3 : β±SE: -0.0009 ± 0.0001 vs. T 1 : β±SE: -0.0005 ± 0.0001, P  < 0.001), independently of potentially confounding factors. Race and lower SES were generally important determinants of adverse WMI outcomes, with partial mediation of socio-economic disparities in global mean FA through lifestyle, health-related and cognition factors. The association of poor cognition with lower global mean FA was stronger at higher AD polygenic risk., Competing Interests: The authors declare no conflict of interest.

Persistent infections, whether viral, bacterial or parasitic, including Helicobacter pylori infection, have been implicated in non-communicable diseases, including dementia and other neurodegenerative diseases. In this cross-sectional study, data on 635 cognitively normal participants from the UK Biobank study (2006-21, age range: 40-70 years) were used to examine whether H. pylori seropositivity (e.g. presence of antibodies), serointensities of five H. pylori antigens and a measure of total persistent infection burden were associated with selected brain volumetric structural MRI (total, white, grey matter, frontal grey matter (left/right), white matter hyperintensity as percent intracranial volume and bi-lateral sub-cortical volumes) and diffusion-weighted MRI measures (global and tract-specific bi-lateral fractional anisotropy and mean diffusivity), after an average 9-10 years of lag time. Persistent infection burden was calculated as a cumulative score of seropositivity for over 20 different pathogens. Multivariable-adjusted linear regression analyses were conducted, whereby selected potential confounders (all measures) and intracranial volume (sub-cortical volumes) were adjusted, with stratification by Alzheimer's disease polygenic risk score tertile when exposures were H. pylori antigen serointensities. Type I error was adjusted to 0.007. We report little evidence of an association between H. pylori seropositivity and persistent infection burden with various volumetric outcomes ( P > 0.007, from multivariable regression models), unlike previously reported in past research. However, H. pylori antigen serointensities, particularly immunoglobulin G against the vacuolating cytotoxin A, GroEL and outer membrane protein antigens, were associated with poorer tract-specific white matter integrity ( P < 0.007), with outer membrane protein serointensity linked to worse outcomes in cognition-related tracts such as the external capsule, the anterior limb of the internal capsule and the cingulum, specifically at low Alzheimer's disease polygenic risk. Vacuolating cytotoxin A serointensity was associated with greater white matter hyperintensity volume among individuals with mid-level Alzheimer's disease polygenic risk, while among individuals with the highest Alzheimer's disease polygenic risk, the urease serointensity was consistently associated with reduced bi-lateral caudate volumes and the vacuolating cytotoxin A serointensity was linked to reduced right putamen volume ( P < 0.007). Outer membrane protein and urease were associated with larger sub-cortical volumes (e.g. left putamen and right nucleus accumbens) at middle Alzheimer's disease polygenic risk levels ( P < 0.007). Our results shed light on the relationship between H. pylori seropositivity, H. pylori antigen levels and persistent infection burden with brain volumetric structural measures. These data are important given the links between infectious agents and neurodegenerative diseases, including Alzheimer's disease, and can be used for the development of drugs and preventive interventions that would reduce the burden of those diseases., Competing Interests: The authors report no competing interests. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of Fort Belvoir Community Hospital, the Defense Health Agency, the Department of Defense or the U.S. Government. Reference to any commercial products within this publication does not create or imply any endorsement by Fort Belvoir Community Hospital, the Defense Health Agency, the Department of Defense or the U.S. Government., (Published by Oxford University Press on behalf of the Guarantors of Brain 2024.)

The plasma proteome can mediate the association of hospital-treated infections with dementia incidence. We screened up to 37,269 UK Biobank participants aged 50-74 years for the presence of a prevalent hospital-treated infection, subsequently tested as a predictor for ≤1,463 plasma proteins and dementia incidence. Four-way decomposition models decomposed infection-dementia total effect into pure mediation, pure interaction, neither or both through the plasma proteome. Hospital-treated infections increased dementia two-fold. The strongest mediation effect was through the growth differentiation factor 15 (GDF15) protein. Top 17 proteomic mediators explained collectively 5% of the total effect, while pathway analysis of all mediators (k = 221 plasma proteins) revealed top pathways including the immune system, signal transduction, metabolism, disease and metabolism of proteins, with the GDF15 cluster reflecting most strongly the "transmembrane receptor protein tyrosine kinase signaling pathway". The association of hospital-treated infections with dementia was partially mediated through GDF15 and other plasma proteomic markers., Competing Interests: The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of AT Augusta Military Medical Center, the Defense Health Agency, Department of Defense, or US Government. Reference to any commercial products within this publication does not create or imply any endorsement by AT Augusta Military Medical Center, the Defense Health Agency, Department of Defense, or US Government. The authors declare no conflict of interest., (© 2023.)

Background: Cardiovascular health is associated with brain magnetic resonance imaging (MRI) markers of pathology and infections may modulate this association., Methods: Using data from 38,803 adults (aged 40-70 years) and followed-up for 5-15 years, we tested associations of prevalent total (47.5%) and hospital-treated infection burden (9.7%) with brain structural and diffusion-weighted MRI (i.e., sMRI and dMRI, respectively) common in dementia phenome. Poor white matter tissue integrity was operationalized with lower global and tract-specific fractional anisotropy (FA) and higher mean diffusivity (MD). Volumetric sMRI outcomes included total, gray matter (GM), white matter (WM), frontal bilateral GM, white matter hyperintensity (WMH), and selected based on previous associations with dementia. Cardiovascular health was measured with Life's Essential 8 score (LE8) converted to tertiles. Multiple linear regression models were used, adjusting for intracranial volumes (ICV) for subcortical structures, and for demographic, socio-economic, and the Alzheimer's Disease polygenic risk score for all outcomes, among potential confounders., Results: In fully adjusted models, hospital-treated infections were inversely related to GM (β ± SE: -1042 ± 379, p = 0.006) and directly related to WMH as percent of ICV (Log e transformed) (β ± SE:+0.026 ± 0.007, p < 0.001). Both total and hospital-treated infections were associated with poor WMI, while the latter was inversely related to FA within the lowest LE8 tertile (β ± SE:-0.0011 ± 0.0003, p < 0.001, P LE8×IB  < 0.05), a pattern detected for GM, Right Frontal GM, left accumbens and left hippocampus volumes. Within the uppermost LE8 tertile, total infection burden was linked to smaller right amygdala while being associated with larger left frontal GM and right putamen volumes, in the overall sample. Within that uppermost tertile of LE8, caudate volumes were also positively associated with hospital-treated infections., Conclusions: Hospital-treated infections had more consistent deleterious effects on volumetric and white matter integrity brain neuroimaging outcomes compared with total infectious burden, particularly in poorer cardiovascular health groups. Further studies are needed in comparable populations, including longitudinal studies with multiple repeats on neuroimaging markers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of Fort Belvoir Community Hospital, the Defense Health Agency, Department of Defense, or U.S. Government. Reference to any commercial products within this publication does not create or imply any endorsement by Fort Belvoir Community Hospital, the Defense Health Agency, Department of Defense, or U.S. Government., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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&#95;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 (LE8 LIFESTYLE ), 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&#95;ETHN(-) → SES(-) → DEMENTIA', 'RACE&#95;ETHN(-) → SES(-) → Poor cognitive performance, COGN(+) → DEMENTIA' and 'RACE&#95;ETHN(-) → SES(+) → LE8 LIFESTYLE (-) → 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.

Elevated plasma neurofilament light chain (NfL) is associated with dementia though underlying mechanisms remain unknown. We examined cross-sectional relationships of time-dependent plasma NfL with selected brain structural magnetic resonance imaging (sMRI) prognostic markers of dementia. The sample was drawn from the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study, selecting participants with complete v 1 (2004-2009) and v 2 (2009-2013) plasma NfL exposure and ancillary sMRI data at v scan (2011-2015, n = 179, mean v 1 to v scan time: 5.4 years). Multivariable-adjusted linear regression models were conducted, overall, by sex, and race, correcting for multiple testing with q-values. NfL (v1) was associated with larger WMLV (both Log e transformed), after 5-6 years' follow-up, overall (β = +2.131 ± 0.660, b = +0.29, p = 0.001, and q = 0.0029) and among females. NfLv 2 was linked to a 125 mm 3 lower left hippocampal volume (p = 0.004 and q = 0.015) in reduced models, mainly among males, as was observed for annualized longitudinal change in NfL (δNfL bayes ). Among African American adults, NfL v1 was inversely related to total, gray and white matter volumes. Plasma NfL may reflect future brain pathologies in middle-aged adults., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: High levels of occupational physical activity (PA) have been linked to an increased risk of dementia. We assessed the association of trajectories of occupational PA at ages 33-65 with risk of dementia and mild cognitive impairment (MCI) at ages 70+., Methods: We included 7005 participants (49.8% were women, 3488/7005) from the HUNT4 70+ Study. Group-based trajectory modelling was used to identify four trajectories of occupational PA based on national registry data from 1960 to 2014: stable low (30.9%, 2162/7005), increasing then decreasing (8.9%, 625/7005), stable intermediate (25.1%, 1755/7005), and stable high (35.2%, 2463/7005). Dementia and MCI were clinically assessed in 2017-2019. We performed adjusted multinomial regression to estimate relative risk ratios (RRR) with 95% confidence intervals (CI) for dementia and MCI., Findings: 902 participants were diagnosed with dementia and 2407 were diagnosed with MCI. Absolute unadjusted risks for dementia and MCI were 8.8% (95% CI: 7.6-10.0) and 27.4% (25.5-29.3), respectively, for those with a stable low PA trajectory, 8.2% (6.0-10.4) and 33.3% (29.6-37.0) for those with increasing, then decreasing PA; while they were 16.0% (14.3-17.7) and 35% (32.8-37.2) for those with stable intermediate, and 15.4% (14.0-16.8) and 40.2% (38.3-42.1) for those with stable high PA trajectories. In the adjusted model, participants with a stable high trajectory had a higher risk of dementia (RRR 1.34, 1.04-1.73) and MCI (1.80, 1.54-2.11), whereas participants with a stable intermediate trajectory had a higher risk of MCI (1.36, 1.15-1.61) compared to the stable low trajectory. While not statistically significant, participants with increasing then decreasing occupational PA had a 24% lower risk of dementia and 18% higher risk of MCI than the stable low PA group., Interpretation: Consistently working in an occupation with intermediate or high occupational PA was linked to an increased risk of cognitive impairment, indicating the importance of developing strategies for individuals in physically demanding occupations to prevent cognitive impairment., Funding: This work was supported by the National Institutes of Health (R01AG069109-01) and the Research Council of Norway (296297, 262700, 288083)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 The Author(s).)

Objective: /Background: The allostatic framework is a theoretical perspective that identifies allostatic load (AL) as a meaningful measure of dysregulation and desynchrony across biological processes due to cumulative stress exposure, thereby increasing disease risk. Research exploring the relationships of AL with sleep quality have yielded inconsistent findings. We examined AL at three visits (2004-2009 [Visit 1], 2009-2013 [Visit 2] and 2013-2017 [Visit 3]) in relation to sleep quality [Visit 3] among urban adults by sex, race and age group., Patients/methods: We analyzed data on 1489 Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) participants [59.6% female, baseline age: 48.2 years, 58.5% African Americans] with available data on cardiovascular, metabolic and inflammatory AL markers and Pittsburgh Sleep Quality Index (PSQI) scores. Least squares regression models were constructed to evaluate AL score at Visit 1 (AL v1 ) and z-transformed probability of higher trajectory in AL score between Visit 1 and Visit 3 (AL traj ) as predictors of PSQI score at Visit 3, controlling for demographic, lifestyle and health characteristics at Visit 1. AL traj was generated using group-based trajectory modeling., Results: In fully adjusted models, AL v1 and PSQI score were positively related among men only (β = 0.43, P = 0.001), whereas higher AL traj was associated with PSQI score among women (β = 0.51, P = 0.001), White (β = 0.45, P = 0.011) and African American (β = 0.33, P = 0.014) populations. There were no statistically significant interactions according to age group (<50 vs. ≥ 50)., Conclusions: Disparities exist whereby AL trajectory predicted sleep quality among women irrespective of race and baseline AL predicted sleep quality among men. Future studies should examine bi-directional AL-sleep relationships., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Apolipoprotein E (APOE) is considered the major susceptibility gene for developing Alzheimer's disease. However, the strength of this risk factor is not well established across diverse Hispanic populations., Methods: We investigated the associations among APOE genotype, dementia prevalence, and memory performance (immediate and delayed recall scores) in Caribbean Hispanics (CH), African Americans (AA), Hispanic Americans (HA) and non-Hispanic White Americans (NHW). Multivariable logistic regressions and negative binomial regressions were used to examine these associations by subsample., Results: Our final dataset included 13,516 participants (5198 men, 8318 women) across all subsamples, with a mean age of 74.8 years. Prevalence of APOE ε4 allele was similar in CHs, HAs, and NHWs (21.8%-25.4%), but was substantially higher in AAs (33.6%; P < 0.001). APOE ε4 carriers had higher dementia prevalence across all groups., Discussion: APOE ε4 was similarly associated with increased relative risk of dementia and lower memory performance in all subsamples., (© 2022 the Alzheimer's Association.)

Serum GDF15 levels are correlated with multiple neurodegenerative diseases. Few studies have tested this marker's association with middle-aged cognitive performance over time, and whether race affects this association is unknown. We examined associations of initial serum GDF15 concentrations with longitudinal cognitive performance, spanning domains of global mental status, visual and verbal memory, attention, fluency, and executive function in a sub-sample of adults participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (n = 776, Age v1 :30-66y, 45.6 % male, 57.0 % African American, 43.0 % below poverty). This analysis consisted of mixed-effects regression models applied to the total selected sample, while also stratifying the analyses by race in the main analyses and further stratifying by sex, age group and poverty status in an exploratory analysis. Our main findings, which passed multiple testing and covariate-adjustment, indicated that GDF15 was associated with poorer baseline performance on several cognitive tests, including animal fluency [overall sample: (Model 1: γ 0  ± SE: -0.664 ± 0.208, P < 0.001; Model 2, γ 0  ± SE: -0.498 ± 0.217, P < 0.05)]. Among White adults, GDF15 was linked to poorer performance on a brief test of attention (Model 1: γ 0  ± SE: -0.426 ± 0.126, P < 0.001; Model 2, γ 0  ± SE: -0.281 ± 0.139, P < 0.05); and Trailmaking test, part B (Model 1: γ 0  ± SE: +0.129 ± 0.040, P < 0.001; Model 2, γ 0  ± SE: +0.089 ± 0.041, P < 0.05), the latter being also linked to higher GDF15 among individuals living below poverty. Among women, GDF15 was associated with poor global mental status (Normalized MMSE: Model 1: γ 0  ± SE: -2.617 ± 0.746, P < 0.001; Model 2: γ 0  ± SE: -1.729 ± 0.709, P < 0.05). GDF15 was not associated with decline on any of the 11 cognitive test scores considered in ∼ 4 years of follow-up. In sum, we detected cross-sectional associations between GDF15 and cognition, although GDF15 did not predict rate of change in cognitive performance over time among a sample of middle-aged adults. More longitudinal studies are needed to address the clinical utility of this biomarker for early cognitive defects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Background: Despite the high burden of Alzheimer's disease and other dementias among the Hispanic population worldwide, little is known about how dementia affects healthcare utilizations among this population outside of the US, in particular among those in the Caribbean region., Objective: This study examines healthcare utilization associated with Alzheimer's disease and other dementias among older adults in the Caribbean as compared to the US., Methods: We conducted harmonized analyses of two population-based surveys, the 10/66 Dementia Group Research data collected in Dominican Republic, Cuba, and Puerto Rico, and the US-based Health and Retirement Study. We examined changes in hospital nights and physician visits in response to incident and ongoing dementias., Results: Incident dementia significantly increased the risk of hospitalization and number of hospital nights in both populations. Ongoing dementia increased the risk of hospitalization and hospital nights in the US, with imprecise estimates for the Caribbean. The number of physician visits was elevated in the US but not in the Caribbean., Conclusions: The concentration of increased healthcare utilization on hospital care and among patients with incident dementia suggests an opportunity for improved outpatient management of new and existing dementia patients in the Caribbean.

Plasma neurofilament light chain (NfL)'s link to dementia may be mediated through white matter integrity (WMI). In this study, we examined plasma NfL's relationships with diffusion tensor magnetic resonance imaging markers: global and cortical white matter fractional anisotropy (FA) and trace (TR). Plasma NfL measurements at 2 times (v 1 : 2004-2009 and v 2 : 2009-2013) and ancillary dMRI (v scan : 2011-2015) were considered (n = 163, mean time v 1 to v scan  = 5.4 years and v 2 to v scan : 1.1 years). Multivariable-adjusted regression models, correcting for multiple-testing revealed that, overall, higher NfL v1 was associated with greater global TR (β ± SE: +0.0000560 ± 0.0000186, b = 0.27, p = 0.003, q = 0.012), left frontal WM TR (β ± SE: + 0.0000706 ± 0.0000201, b ± 0.30, p = 0.001, q = 0.0093) and right frontal WM TR (β ± SE: + 0.0000767 ± 0.000021, b ± 0.31, p < 0.001, q = 0.0093). These associations were mainly among males and White adults. Among African American adults only, NfL v2 was associated with greater left temporal lobe TR. "Tracking high" in NfL was associated with reduced left frontal FA (Model 2, body mass index-adjusted: β ± SE:-0.01084 ± 0.00408, p = 0.009). Plasma NfL is a promising biomarker predicting future brain white matter integrity (WMI) in middle-aged adults., (Published by Elsevier Inc.)

Prior research suggests a relationship between number of sons and maternal long-term health outcomes, including dementia. We assessed the relationship between having sons and parental cognitive aging. Specifically, we investigated the relationship between having at least 1 son and parental baseline cognition level and rate of cognitive decline, accounting for life course sociodemographic characteristics in a cohort of 13 222 adults aged ≥50 years from the US Health and Retirement Study. We included only participants with at least one child. We further explored whether this relationship varies by parental sex and whether the magnitude of the relationship increases with each additional son. Cognition was assessed biennially for a maximum of nine times as a sum of scores from immediate and delayed 10-noun free recall tests, a serial 7s subtraction test, and a backwards counting test. Associations were evaluated using linear mixed-effects models, stepwise adjusting for sociodemographic and health-related factors. In our analytic sample of parents, a total of 82.3% of respondents had at least 1 son and 61.6% of respondents were female. Parents of at least 1 son had a faster rate of cognitive decline in comparison to parents without any son. Our results also suggest that cognitive decline was faster among parents of multiple sons, compared to parents with only daughters. Thus, the results support the theory that having sons might have a long-term negative effect on parental cognition., Competing Interests: Declaration of competing interest None., (Copyright © 2022. Published by Elsevier Ltd.)

Differential racial and socioeconomic disparities in dementia incidence across income groups and their underlying mechanisms remain largely unknown. A retrospective cohort study examining all-cause dementia incidence across income groups was conducted linking third National Health and Nutrition Examination Surveys (NHANES III) to Centers for Medicare and Medicaid Services-Medicare data over ≤26 y of follow-up (1988-2014). Cox regression and generalized structural equations models (GSEM) were constructed among adults aged≥60 y at baseline (N = 4,592). Non-Hispanic Black versus White (NHW) adults had higher risk of dementia in age and sex-adjusted Cox regression models (HR = 1.34, 95%CI: 1.15-1.55, P < 0.001), an association that was attenuated in the SES-adjusted model (HR = 1.15, 95%CI: 1.01-1.34, P = 0.092). SES was inversely related to dementia risk overall (per Standard Deviation, HR = 0.80, 95% CI:0.69-0.92, P = 0.002, Model 2), mainly within the middle-income group. Within the lowest and middle-income groups and in socio-economic status (SES)-adjusted models, Mexican American participants were at lower all-cause dementia risk compared with their NHW counterparts. GSEM models further detected 3 pathways explaining >55% of the total effect of SES on dementia risk (Total effect = -0.160 ± 0.067, p = 0.022), namely SES→LIFESTYLE→DEMENTIA (Indirect effect (IE) = -0.041 ± 0.014, p = 0.004), SES→LIFESTYLE→COGN→DEMENTIA (IE = -0.006 ± 0.001, p < 0.001), SES→COGN→DEMENTIA(IE = -0.040 ± 0.008, p < 0.001), with the last two remaining significant or marginally significant in the uppermost income groups. Diet and social support were among key lifestyle factors involved in socio-economic disparities in dementia incidence. We provide evidence for modifiable risk factors that may delay dementia onset differentially across poverty-income ratio groups, underscoring their importance for future observational and intervention studies., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Neurofilament light chain (NfL) is released into the blood during neuronal damage. NfL is linked to mortality in neurological disorders, remaining unexplored in population studies. We investigated whether initial (v 1 ) and annualized change (δ) in plasma NfL can predict all-cause mortality in middle-aged dementia-free urban adults., Methods: Longitudinal data were from 694 participants in the Healthy Aging in Neighborhoods of Diversity Across the Life Span study (HANDLS, mean age v1 : 47.8 years, 42% male, 55.8% African American). Plasma NfL was measured prospectively at three visits. Analyses included Cox proportional hazards models for all-cause mortality risk and 4-way decomposition testing for interaction and mediation., Results: Unlike men, women exhibited a direct association between δNfL (above vs. below median) and all-cause mortality risk in both the minimally (HR = 3.91, 95% CI 1.10-13.9, p = 0.036) and fully adjusted models (HR = 4.92, 95% CI 1.26-19.2, p = 0.022), and for δNfL (per unit increase) in the full model (HR = 1.65, 95% CI 1.04-2.61, p = 0.034). In both models, and among women, 1 standard deviation of NfL v1 was associated with an increased all-cause mortality risk (reduced model: HR = 2.01, 95% CI 1.24-3.25, p = 0.005; full model: HR = 1.75, 95% CI 1.02-2.98, p = 0.041). Only few interactions were detected for cardio-metabolic risk factors. Notably, NfL v1 was shown to be a better prognostic indicator at normal hsCRP values among women, while HbA1c and δNfL interacted synergistically to determine mortality risk, overall., Conclusions: These findings indicate that plasma NfL levels at baseline and over time can predict all-cause mortality in women and interacts with hsCRP and HbA1c to predict that risk., (© 2022. The Author(s).)

Objectives: An emerging literature suggests that fertility history, which includes measures of parity and birth timing, may influence cognitive health in older ages, especially among women given their differential exposure to pregnancy and sex hormones. Yet, few studies have examined associations between measures of fertility history and incident dementia in population-based samples., Method: We examined the associations between parity, younger age at first birth, and older age at last birth with incident dementia over a 16-year period in a prospective sample of 15,361 men and women aged 51-100 years at baseline drawn from the Health and Retirement Study. We used Cox regression and the Fine and Gray model to obtain cause-specific hazard ratios (csHRs) and subdistribution hazard ratios for incident dementia from gender-stratified models, with the latter method accounting for the semicompeting risk of death., Results: During the follow-up period (median 13.0 years), the crude incidence rate for dementia was 16.6 and 19.9 per 1,000 person-years for men and women, respectively. In crude models estimating csHRs, higher parity (vs parity 2) and younger age at first birth were associated with increased risk of dementia for both genders. These associations did not persist after adjusting for sociodemographic characteristics, smoking status, and health conditions, with much of the attenuation in estimates occurring after adjustment for sociodemographic characteristics., Discussion: In this population-based, multiethnic cohort, we observed limited evidence for an association between measures of fertility history and incident dementia among men and women after adjusting for potential confounders., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Several theories of the life course highlight the importance of social connections and ties for coping with transitions that occur at different ages. Individuals rely on family, friends, and colleagues to adapt to these transitions which may in turn change the composition of their networks. Yet, little is known about the association between life cycle transitions and changes in network characteristics. We used fixed effects regression models with three waves of egocentric network data from the UC Berkeley Social Network Study (UCNets) to examine how career- and family-related life cycle transitions during two key life stages-young adulthood and the transition from middle to old age-are associated with network turnover, the proportion of the network comprised of kin, and confidence in receiving support from personal networks. Younger adults experienced churn following a birth and marriage or partnership, while no life transition was associated with changes in proportion kin, and only with the birth of a child did confidence decline. Among older adults, no transition was associated with any measured event, suggesting that older adults maintain more stable relationships compared to young adults and can weather life events without significant disruptions to their networks., Competing Interests: Competing Interests The authors have no competing interests.

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&#95;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&#95;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&#95;ETHN contrast in women was explained by four main pathways: (1) RACE&#95;ETHN→ poor cognitive performance (COGN, +) → DEMENTIA (+); (2) RACE&#95;ETHN → SES (-) → COGN (-) → DEMENTIA (+); (3) RACE&#95;ETHN → SES (-) → physical activity (PA, +) → COGN (-) → DEMENTIA (+); and (4) RACE&#95;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., Competing Interests: None declared., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

The purpose of this longitudinal study is to construct a prediction model for Covid-19 level of concern using established Covid-19 socio-demographic, lifestyle and health risk characteristics and to examine specific contributions of obesity-related cardiometabolic health characteristics as predictors of Covid-19 level of concern among a representative sample of U.S. older adults. We performed secondary analyses of existing data on 2872 2006-2020 Health and Retirement Study participants and examined 19 characteristics in relation to the outcome of interest using logistic regression and machine learning algorithms. In mixed-effects ordinal logistic regression models, a history of diabetes, stroke as well as 1-2 cardiometabolic risk factors and/or chronic conditions were associated with greater Covid-19 level of concern, after controlling for confounders. Female sex, birth cohort, minority race, Hispanic ethnicity and total wealth as well as depressive symptoms were associated with higher level of Covid-19 concern, and education was associated with lower level of Covid-19 concern in fully adjusted mixed-effects ordinal logistic regression models. The selected socio-demographic, lifestyle and health characteristics accounted for < 70% of the variability in Covid-19 level of concern based on machine learning algorithms. Independent risk factors for Covid-19 level of concern among U.S. older adults include socio-demographic characteristics and depressive symptoms. Advanced research is needed to identify relevant predictors and elucidate underlying mechanisms of observed relationships., (© 2022. The Author(s).)

Extensive literature in the United States documents racial/ethnic and gender disparities in the incidence and prevalence of dementia yet few studies have examined how race/ethnicity and gender intersect to shape inequalities in the risk of dementia. Moreover, few studies have examined heterogeneity in the contribution of known risk factors to dementia across these demographic strata while properly accounting for the semi-competing risk of death. I calculated the proportion of dementia cases attributable to socioeconomic, lifestyle, and medical risk factors across demographic subgroups using nationally representative data from the US-based Health and Retirement Study for the years 2000-2016 and a multistate framework that accounts for the semi-competing risk of death. Socioeconomic resources contributed to the largest number of dementia cases but the magnitude of this contribution varied across strata defined by race/ethnicity and gender. The greatest potential for dementia prevention was observed among non-Hispanic black and Hispanic men and women, supporting an intersectionality approach, and underscoring the need for culturally sensitive intervention and public health initiatives to address the growing burden of dementia. Taken together, work demonstrates the potential benefit of taking an intersectional approach to understanding disparities in dementia., Competing Interests: The author declares no conflicts of interest, financial or otherwise., (© 2021 The Author.)

We examined associations between cognition and mortality and how these relationships vary by race and Apolipoprotein E (APOE) genotype, in a longitudinal study of 2346 middle-aged White and African American adults (30-64 years at baseline) from the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort study. Baseline cognition spanned global mental status, and several domains obtained using principal components analysis (PCA; PCA1: verbal memory/fluency; PCA2: attention/working memory; PCA3: executive function/visuo-spatial abilities). Cox regression models evaluated associations between cognition and all-cause and cardiovascular disease (CVD)-mortality. Interactions between cognition and APOE2 as well as APOE4 allelic dose were tested, and race was a key effect modifier. Higher APOE4 dose was associated with increased CVD-mortality (hazard ratio [HR] per allele = 1.37; 95% CI 1.01-1.86, p = 0.041); APOE2 dosage's association with CVD-mortality was non-significant (HR = 0.60; 95% CI 0.35-1.03, p = 0.065). Higher PCA3 was associated with lower all-cause (HR = 0.93; 95% CI 0.87-0.99, p = 0.030) and CVD (HR = 0.85; 95% CI 0.77-0.95, p = 0.001) mortality risks, the latter association being more pronounced among Whites. PCA2 interacted synergistically with APOE2 dosage, reducing risks for all-cause mortality (PCA2 × APOE2: - 0.33 ± 0.13, p = 0.010) and CVD mortality (PCA2 × APOE2: - 0.73 ± 0.31, p = 0.019). In conclusion, greater executive function/visuo-spatial abilities were associated with reduced CVD-specific mortality, particularly among Whites. Greater "attention/working memory" coupled with higher APOE2 dosage was linked with reduced all-cause and CVD mortality risks., (© 2021. The Author(s).)

Co-infection between Helicobacter pylori (Hp) and groups of periodontal pathogens may alter the onset of Alzheimer's disease (AD) and all-cause dementia. We examined the interactive associations among Hp sero-positivity, periodontal disease (Pd), and infections with incident AD and all-cause dementia, among older adults (≥65 years at baseline). Up to 1431 participants from phase 1 of the National Health and Nutrition Survey III (1988-1991) had complete data till January 1st, 2014 on Hp sero-positivity with a mean follow-up of 10-11 years for AD and all-cause dementia incidence. Exposures consisted of 19 periodontal pathogens, constructed factors and clusters, and two Pd markers- probing depth and clinical attachment loss (CAL). Cox proportional hazards models were performed. Around 55% of the selected sample was Hp + . We found that Prevotella intermedia, Campylobacter Rectus, Factor 2 (Pi/Prevotella nigrescens/Prevotella melaninogenica), and the Orange-Red cluster interacted synergistically with Hp sero-positivity, particularly with respect to AD incidence. The presence of higher levels of Actinomyces Naeslundii (An) enhanced the effect of being Hp + on both AD and all-cause dementia incidence. In contrast, Fusobacterim nucleatum (Fn), and Factor 1 (which included Fn), exhibited an antagonistic interaction with Hp in relation to all-cause dementia. Both probing depth and CAL had direct associations with all-cause dementia among Hp + individuals, despite nonsignificant interaction. Selected periodontal pathogen titers, factors, and clusters interacted mostly synergistically, with Hp sero-positivity, to alter the risk of AD and all-cause dementia. Ultimately, a randomized controlled trial is needed, examining effects of co-eradication of Hp and select periodontal pathogens on neurodegenerative disease., (© 2020. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Introduction: Despite high dementia prevalence in Hispanic populations globally, especially Caribbean Hispanics, no study has comparatively examined the association between education and dementia among Hispanics living in the Caribbean Islands and older adults in the United States., Methods: We used data on 6107 respondents aged 65 and older in the baseline wave of the population-based and harmonized 10/66 survey from Cuba, the Dominican Republic, and Puerto Rico, collected between 2003 and 2008, and 11,032 respondents aged 65 and older from the U.S.-based Health and Retirement Study data in 2014, a total of 17,139 individuals. We estimated multivariable logistic regression models examining the association between education and dementia, adjusted for age, income, assets, and occupation. The models were estimated separately for the Caribbean population (pooled and by setting) and the U.S. population by race/ethnicity (Hispanic, Black, and White), followed by pooled models across all populations., Results: In the Caribbean population, the relative risk of dementia among low versus high educated adults was 1.45 for women (95% confidence interval [CI] 1.17, 1.74) and 1.92 (95% CI 1.35, 2.49) for men, smaller compared to those in the United States, especially among non-Hispanic Whites (women: 2.78, 95% CI 1.94, 3.61; men: 5.98, 95% CI 4.02, 7.95)., Discussion: The differential associations between education and dementia across the Caribbean and US settings may be explained by greater disparities in social conditions in the United States compared to the Caribbean, such as access to health care, healthy behaviors, and social stressors, which serve as potentially important mediators., Competing Interests: WD has provided consultation to Urban Institute, the Robert Wood Johnson Foundation, NIH, and Annual Review of Public Health. JL, IJG, AH, JW, IJV, DA, ML, and JLR have nothing to disclose., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Anemia (blood hemoglobin [Hb] <13 g/dL among males; <12 g/dL among females) and elevated red cell distribution width (RDW) are potential risk factors for reduced brain white matter integrity (WMI), reflected by lower fractional anisotropy or increased mean diffusivity. Cross-sectional data with exposure-outcome lag time was used, whereby hematological exposures (RDW and Hb) and covariates were compiled from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study with available visit 1 (v 1 ; 2004-2009) and/or v 2 (2009-2013) data; while diffusion tensor magnetic resonance imaging (dMRI) outcome data were collected at HANDLS SCAN visit (v scan : 2011-2015, n = 214, mean follow-up from v 1 ±SD: 5.6 ± 1.8 year). Multivariable-adjusted linear regression analyses were conducted, overall, stratifying by sex, and further restricting to the nonanemic for RDW exposures in part of the analyses. Among males, RDW (v1) was linked with lower global mean fractional anisotropy (standardized effect size b = -0.30, p= 0.003, q < 0.05; basic model), an association only slightly attenuated with further covariate adjustment. Anemia was not a risk factor for poor WMI, independently of RDW. Ultimately, pending further longitudinal evidence, initial RDW appears to be associated with poorer WMI among males., (Published by Elsevier Inc.)

Plasma neurofilament light (NfL) is a marker for neurodegenerative diseases. Few studies have examined the association of NfL with middle-aged changes in cognitive performance, and no studies have examined differential NfL effects by race. Using data from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (n = 625, Agev1: 30-66 y, 41.6% male, 56.3% African American, 27.8% below poverty), we investigated the associations of initial NfL levels and annualized change with cognitive performance over time in global mental status, verbal and visual memory, fluency, attention, and executive function. We used ordinary least squares and mixed-effects regressions stratified by race, while exploring differential associations by age group, sex, and poverty status. Over a mean follow-up of 4.3 years, we found initial NfL level was associated with a faster decline on normalized mental status scores in Whites only and in those >50 years old. Annualized increase in NfL was associated with a greater decline in verbal fluency in men. In other exploratory analyses, annualized increase in NfL was associated with a slower decline in verbal memory among individuals living above poverty; in the older group (>50 years), first-visit NfL was linked with better performance at baseline in global mental status and verbal memory. In summary, first-visit NfL was primarily associated with the global mental status decline among Whites, while exhibiting inconsistent relationships in some exploratory analyses. Plasma NfL levels can be detected and quantified in non-demented middle-aged adults and changes can be analyzed over time. More longitudinal studies are needed to address the clinical utility of this biomarker for early cognitive defects., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Associations of Apolipoprotein (APOE) ε2 or ε4 (APOE2 or APOE4) dosages with cognitive change may differ across racial groups., Methods: Longitudinal data on 1770 middle-aged White and African American adults was compiled from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS 2004-2013) study. APOE2 and APOE4 dosages were the two main exposures, while v 1 and annual rate of change in cognitive performance (between v 1 and v 2 ) on 11 test scores were the main outcomes of interest (v1: 2004-2009 and v2: 2009-2013). Mixed-effects linear regression models were conducted adjusting for socio-demographic, lifestyle, and health-related potential confounders. Race (African American vs. White) and sex within racial groups were main effect modifiers., Results: Upon adjustment for multiple testing and potential confounders, APOE4 allelic dosage was associated with faster decline on a test of verbal memory among Whites only (CVLT-List A: γ 12 = - 0.363 ± 0.137, p = 0.008), but not among African Americans. In contrast, among African American women, APOE4 dosage was linked to slower decline on a test of attention (BTA: γ 12 = + 0.106 ± 0.035, p = 0.002), while no association was detected among African American men. APOE2 and APOE4 dosages showed inconsistent results in other domains of cognition overall and across racial groups that did not survive correction for multiple testing., Conclusions: In conclusion, APOE4 dosage was associated with faster decline on a test of verbal memory among Whites only, while exhibiting a potential protective effect among African American women in the domain of attention. Further longitudinal studies are needed to replicate our race and sex-specific findings.

Objective: To evaluate the longitudinal relationship in insomnia symptoms over time with incident memory problems and dementia diagnoses among U.S. adults aged 65 years and older., Methods: Secondary analyses were performed on 9518 elderly participants (≥65 years) who completed the 2006 wave of the Health and Retirement Study (HRS) and were followed-up to determine if insomnia symptom scores (2006-2014) were associated with time-to-onset of [1] physician-diagnosed "memory-related disease", "Alzheimer's disease" and/or "dementia, senility or any other serious memory impairment" and [2] diagnosis of dementia based on HRS-specific criteria. Cox proportional hazards models were constructed adjusting for socio-demographic, lifestyle, and health characteristics., Results: In fully adjusted models, severe insomnia symptoms were associated with increased risk of physician-diagnosed memory problems. Individuals reporting any change (increase or decrease) in insomnia symptoms during the 2006-2010 period were more likely to be diagnosed with dementia based on HRS criteria. Finally, those who experienced an increase in the severity of insomnia symptoms over time exhibited 41-72% increased risks of physician-diagnosed memory problems and 45-58% increased risks of dementia diagnosis based on HRS criteria., Conclusions: When severe insomnia symptoms increased over time, physician-diagnosed memory problems and dementia diagnoses also increased among U.S. elderly people over a 10-year follow-up period. More studies are required to confirm these findings using large prospective cohort designs and validated tools., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The responsibility and stress of being a family caregiver are associated with reduced physical and mental health., Purpose: To examine whether a 24-week aerobic exercise program improves multiple aspects of psychological functioning in family caregivers., Methods: Family caregivers of patients with Alzheimer's disease and other dementias (n = 68) were recruited and randomized into either an aerobic exercise group (n = 34) or a waitlist control group (n = 34). The exercise group was assigned a 24-week aerobic training program that incrementally increased the intensity, duration, and frequency of the exercise program until 150 min of moderate to vigorous activity were completed per week by the ninth week. Twelve measures of psychological functioning were administered at baseline and compared with responses completed following the intervention., Results: Multilevel modeling revealed significant decreases in caregiver burden (β = -4.60, 95% confidence interval [CI] = [-8.82, -0.38], RLMM2 = 0.11) and depression (β = -2.59, 95% CI = [-4.79, -0.38], RLMM2 = 0.13), as well as increases in mastery (β = 1.78, 95% CI = [0.09, 3.46], RLMM2 = .04) in the exercise intervention group compared to the control group., Conclusion: Family caregivers report high levels of depression and caregiver burden. Engagement in a 24-week exercise intervention can ameliorate the perceived burden of caregiving, symptoms of depression, and their sense of mastery., (© Society of Behavioral Medicine 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Few studies have explored whether gait measured continuously within a community setting can identify individuals with Alzheimer's disease (AD). This study tests the feasibility of this method to identify individuals at the earliest stage of AD., Methods: Mild AD (n = 38) and cognitively normal control (CNC; n = 48) participants from the University of Kansas Alzheimer's Disease Center Registry wore a GT3x+ accelerometer continuously for 7 days to assess gait. Penalized logistic regression with repeated five-fold cross-validation followed by adjusted logistic regression was used to identify gait metrics with the highest predictive performance in discriminating mild AD from CNC., Results: Variability in step velocity and cadence had the highest predictive utility in identifying individuals with mild AD. Metrics were also associated with cognitive domains impacted in early AD., Discussion: Continuous gait monitoring may be a scalable method to identify individuals at-risk for developing dementia within large, population-based studies., Competing Interests: Authors have no competing interests to declare., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Behavioral and social scientists have identified many nonbiological predictors of mortality. An important limitation of much of this research, however, is that risk factors are not studied in comparison with one another or from across different fields of research. It therefore remains unclear which factors should be prioritized for interventions and policy to reduce mortality risk. In the current investigation, we compare 57 factors within a multidisciplinary framework. These include ( i ) adverse socioeconomic and psychosocial experiences during childhood and ( ii ) socioeconomic conditions, ( iii ) health behaviors, ( iv ) social connections, ( v ) psychological characteristics, and ( vi ) adverse experiences during adulthood. The current prospective cohort investigation with 13,611 adults from 52 to 104 y of age (mean age 69.3 y) from the nationally representative Health and Retirement Study used weighted traditional (i.e., multivariate Cox regressions) and machine-learning (i.e., lasso, random forest analysis) statistical approaches to identify the leading predictors of mortality over 6 y of follow-up time. We demonstrate that, in addition to the well-established behavioral risk factors of smoking, alcohol abuse, and lack of physical activity, economic (e.g., recent financial difficulties, unemployment history), social (e.g., childhood adversity, divorce history), and psychological (e.g., negative affectivity) factors were also among the strongest predictors of mortality among older American adults. The strength of these predictors should be used to guide future transdisciplinary investigations and intervention studies across the fields of epidemiology, psychology, sociology, economics, and medicine to understand how changes in these factors alter individual mortality risk., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Systemic inflammation may influence trajectories of depressive symptoms over time, perhaps differentially by sex and race. Inflammatory markers and the Center for Epidemiologic Studies-Depression scale [total score: CES-D total and four distinctive domains: somatic complaints, depressed affect, positive affect and interpersonal problems] were examined among African-American (AA) and White urban adults participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study [2004-2013, Age base :30-64 y, mean ± SD follow-up time: 4.64 ± 0.93 y, N = 150 (with cytokine data) to N = 1,767 (with other inflammatory markers)]. Findings suggest that serum concentrations of high-sensitivity C-reactive protein (hsCRP), z-inflammation composite score [ICS, combining elevated hsCRP and ESR with low serum albumin and iron], and serum interleukin (IL) 1β were positively associated with ΔCES-D total (Δ: annual rate of increase) among Whites only. IL-12 was directly related to ΔCES-D total among men and AA. The race-specific associations of hsCRP, ICS, IL-1β and the sex-specific association of IL-12 with ΔCES-D total were replicated for the "depressed affect" domain. Similarly, among men, lower serum albumin and higher ICS were linked with higher baseline "somatic complaints". IL-10 among AA and IL-12 among men were inversely related to Δ"positive affect", while "interpersonal problems" were cross-sectionally associated with IL-6 among AA and IL-10 among Whites. Finally, baseline ICS was positively associated with incident "elevated depressive symptoms" (EDS: CES-D total  ≥ 16) among AA (HR = 1.28, 95% CI: 1.04-1.56, P = 0.017). Overall, systemic inflammation was directly linked to increased depressive symptoms over time and at baseline, differentially across sex and race groups. More longitudinal research is needed to replicate our findings.

Body mass index (BMI) is commonly used as a proxy for adiposity in epidemiological and public health studies. However, BMI may suffer from issues of misreporting and, because it fluctuates over the life course, its association with morbidities such as diabetes is difficult to measure. We examined the associations between actual BMI, genetic propensity for high BMI, and diabetes to better understand whether a BMI polygenic score (PGS) explained more variation in diabetes than self-reported BMI. We used a sample of non-Hispanic white adults from the longitudinal Health and Retirement Study (1992-2016). Structural equation models were used to determine how much variation in BMI could be explained by a BMI PGS. Then, we used logistic regression models (n = 12,086) to study prevalent diabetes at baseline and Cox regression models (n = 11,129) to examine incident diabetes with up to 24 years of follow-up. We observed that while both actual BMI and the BMI PGS were significantly associated with diabetes, actual BMI had a stronger association than its genetic counterpart and resulted in better model performance. Moreover, actual BMI explained more variation in baseline and incident diabetes than its genetic counterpart which may suggest that actual BMI captures more than just adiposity as intended.

Background: Chronic systemic inflammation has been positively associated with structural and functional brain changes representing early markers of Alzheimer's Disease (AD) and cognitive decline. The current study examined associations between systemic inflammation and cognitive performance among African-Americans and Whites urban adults., Methods: Participants were selected from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (2004-2013, baseline age: 30-64 y, mean ± SD follow-up time of 4.64 ± 0.93 y, N = 189-222, k = 1.5-1.7 observations/participant). Cytokines known to be positively linked to AD incidence among others were tested against cross-sectional and longitudinal cognitive function, stratifying by age group (≤50 y vs. >50 y), sex and race. A series of mixed-effects regression models were conducted, adjusting for key confounders., Results: Among key findings, IL1β was positively associated with a faster rate of decline on a test of executive functioning, among older adults (age >50 y, γ 11  = +2.49 ± 0.89, p = 0.005), while in the total population, IL-6 was linked to a faster decline on a test of verbal memory (γ 11  = -0.011 ± 0.004, p = 0.009). Among younger participants, IL-18 was linked to a poorer performance on a test of attention at baseline (age ≤50 y, γ 01  = -0.007 ± 0.0025, p = 0.004) though a slower rate of decline with higher IL-18 was detected for a test of psychomotor speed in older adults (age >50 y, γ 11  = +0.0010 ± 0.0004, p = 0.008). Finally, among Whites, unlike among African-Americans, IL-6 was associated with a better baseline performance on two tests of verbal and working memory., Conclusions: Cytokines were shown to be associated with age-related cognitive decline among middle-aged and older urban adults in an age group and race-specific manner. Further longitudinal studies are needed to replicate our findings and mediation through relevant biological and psychosocial factors need to be studied as well., (Published by Elsevier Inc.)

Study Design: Family members caring for chronically ill relatives are typically sedentary, chronically stressed, and at high risk of disease. Observational reports suggest caregivers have accelerated cellular aging as indicated by shorter leukocyte telomere lengths. We performed a randomized controlled trial to examine the effect of aerobic exercise on changes in telomerase levels (primary outcome) and telomere lengths (secondary outcome) in inactive caregivers., Methods: 68 female and male community dwelling dementia caregivers who reported high stress and physical inactivity were randomly assigned to a highly supervised aerobic exercise intervention vs. waitlist control group for 24 weeks. Average leukocyte telomere lengths and peripheral blood mononuclear cells' telomerase activity were measured pre- and post-intervention. All staff completing blood draws, fitness testing and bioassays were blinded to group assignment., Results: The intervention group completed approximately 40 min of aerobic exercise 3-5 times per week, verified by actigraphy. There was high (81%) adherence to 120 min/week of aerobic exercise. Groups did not significantly differ in telomerase activity changes across time, but had significant different telomere length changes across time (67.3 base pairs, 95%CI 3.1, 131.5). There were also significant reductions in body mass index and perceived stress and an increase in cardiorespiratory fitness (i.e., VO 2peak ) in the exercising caregivers versus controls., Conclusion: In the context of a highly controlled intervention, exercise can induce apparent telomere lengthening, though the mechanisms remain elusive. Our study underscores the importance of increasing participation in aerobic exercise to improve markers of health and attenuate cellular aging in high-risk samples., (Copyright © 2018. Published by Elsevier Ltd.)