Framingham Heart Study Offspring Cohort Research Articles

Identifying Proteomic Prognostic Markers for Alzheimer's Disease with Survival Machine Learning: the Framingham Heart Study.

Protein abundance levels, sensitive to both physiological changes and external interventions, are useful for assessing the Alzheimer's disease (AD) risk and treatment efficacy. However, identifying proteomic prognostic markers for AD is challenging by their high dimensionality and inherent correlations. Our study analyzed 1128 plasma proteins, measured by the SOMAscan platform, from 858 participants 55 years and older (mean age 63 years, 52.9% women) of the Framingham Heart Study (FHS) Offspring cohort. We conducted regression analysis and machine learning models, including LASSO-based Cox proportional hazard regression model (LASSO) and generalized boosted regression model (GBM), to identify protein prognostic markers. These markers were used to construct a weighted proteomic composite score, the AD prediction performance of which was assessed using time-dependent area under the curve (AUC). The association between the composite score and memory domain was examined in 339 (of the 858) participants with available memory scores, and in an independent group of 430 participants younger than 55 years (mean age 46, 56.7% women). Over a mean follow-up of 20 years, 132 (15.4%) participants developed AD. After adjusting for baseline age, sex, education, and APOE ε4+ status, regression models identified 309 proteins (P ≤ 0.2). After applying machine learning methods, nine of these proteins were selected to develop a composite score. This score improved AD prediction beyond the factors of age, sex, education, and APOE ε4+ status across 15 to 25 years of follow-up, achieving its peak AUC of 0.84 in the LASSO model at the 22-year follow-up. It also showed a consistent negative association with memory scores in 339 participants (beta = -0.061, P = 0.046), 430 independent participants (beta = -0.060, P = 0.018), and the pooled 769 samples (beta = -0.058, P = 0.003). These findings highlight the utility of proteomic markers in improving AD prediction and emphasize the complex pathology of AD. The composite score may aid early AD detection and efficacy monitoring, warranting further validation in diverse populations.

Plasma proteins associated with plant-based diets: Results from the Atherosclerosis Risk in Communities (ARIC) study and Framingham Heart Study (FHS)

Background & AimsPlant-based diets are associated with a lower risk of chronic diseases. Large-scale proteomics can identify objective biomarkers of plant-based diets, and can improve our understanding of the pathways that link plant-based diets to health outcomes. This study investigated the plasma proteome of four different plant-based diets [overall plant-based diet (PDI), provegetarian diet, healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI)] in the Atherosclerosis Risk in Communities (ARIC) Study and replicated the findings in the Framingham Heart Study (FHS) Offspring cohort. MethodsARIC Study participants at visit 3 (1993-1995) with completed food frequency questionnaire (FFQ) data and proteomics data were divided into internal discovery (n=7,690) and replication (n=2,543) data sets. Multivariable linear regression was used to examine associations between plant-based diet indices (PDIs) and 4,955 individual proteins in the discovery sample. Then, proteins that were internally replicated in the ARIC Study were tested for external replication in FHS (n=1,358). Pathway overrepresentation analysis was conducted for diet-related proteins. C-statistics were used to predict if the proteins improved prediction of plant-based diet indices beyond participant characteristics. ResultsIn ARIC discovery, a total of 837 diet-protein associations (PDI=233; provegetarian=182; hPDI=406; uPDI=16) were observed at false discovery rate (FDR) <0.05. Of these, 453 diet-protein associations (PDI=132; provegetarian=104; hPDI=208; uPDI=13) were internally replicated. In FHS, 167/453 diet-protein associations were available for external replication, of which 8 proteins (PDI=1; provegetarian=0; hPDI=8; uPDI=0) replicated. Complement and coagulation cascades, cell adhesion molecules, and retinol metabolism were over-represented. C-C motif chemokine 25 for PDI and 8 proteins for hPDI modestly but significantly improved the prediction of these indices individually and collectively (P value for difference in C-statistics<0.05 for all tests) ConclusionsUsing large-scale proteomics, we identified potential candidate biomarkers of plant-based diets, and pathways that may partially explain the associations between plant-based diets and chronic conditions.

Clinical risk factors and blood protein biomarkers of 10-year pneumonia risk.

Chronic inflammation may increase susceptibility to pneumonia. To explore associations between clinical comorbidities, serum protein immunoassays, and long-term pneumonia risk. Framingham Heart Study Offspring Cohort participants ≥65 years were linked to their Centers for Medicare Services claims data. Clinical data and 88 serum protein immunoassays were evaluated for associations with 10-year incident pneumonia risk using Fine-Gray models for competing risks of death and least absolute shrinkage and selection operators for covariate selection. We identified 1,370 participants with immunoassays and linkage to Medicare data. During 10 years of follow up, 428 (31%) participants had a pneumonia diagnosis. Chronic pulmonary disease [subdistribution hazard ratio (SHR) 1.87; 95% confidence interval (CI), 1.33-2.61], current smoking (SHR 1.79, CI 1.31-2.45), heart failure (SHR 1.74, CI 1.10-2.74), atrial fibrillation/flutter (SHR 1.43, CI 1.06-1.93), diabetes (SHR 1.36, CI 1.05-1.75), hospitalization within one year (SHR 1.34, CI 1.09-1.65), and age (SHR 1.06 per year, CI 1.04-1.08) were associated with pneumonia. Three baseline serum protein measurements were associated with pneumonia risk independent of measured clinical factors: growth differentiation factor 15 (SHR 1.32; CI 1.02-1.69), C-reactive protein (SHR 1.16, CI 1.06-1.27) and matrix metallopeptidase 8 (SHR 1.14, CI 1.01-1.30). Addition of C-reactive protein to the clinical model improved prediction (Akaike information criterion 4950 from 4960; C-statistic of 0.64 from 0.62). Clinical comorbidities and serum immunoassays were predictive of pneumonia risk. C-reactive protein, a routinely-available measure of inflammation, modestly improved pneumonia risk prediction over clinical factors. Our findings support the hypothesis that prior inflammation may increase the risk of pneumonia.

Flavonoid-Rich Fruit Intake in Midlife and Late-Life and Associations with Risk of Dementia: The Framingham Heart Study

BackgroundFruits are an important source of flavonoids, and greater intake of dietary flavonoids in older adults has been shown to be associated with decreased risk of dementia. It is unclear whether this relationship is similar or different between younger adults and older adults.ObjectivesWe examined for associations between midlife and late-life intake of flavonoid-rich fruits and incident dementia. We hypothesized that greater total cumulative intake of flavonoid-rich fruits in midlife and late-life adults would be associated with reduced risk of all-cause dementia.DesignLongitudinal, cohort study design.SettingFramingham Heart Study, which is a longitudinal, multi-generational community-based cohort based in Framingham, Massachusetts, USA.ParticipantsParticipants from the Framingham Heart Study Offspring cohort were included (n = 2,790) who attended the fifth core exam between 1991 to 1995, and were dementiafree and at least 45 years of age at that time, as well as had valid food frequency questionnaires from the fifth to ninth core exams.MeasurementsConsumption of fruits with high flavonoid content or are important contributors to overall flavonoid intake was collected via food frequency questionnaire. Flavonoid-rich fruits from the food frequency questionnaire included raisins or grapes, prunes, bananas, fresh apples or pears, apple juice or cider, oranges, orange juice, grapefruit, grapefruit juice, strawberries, blueberries, and peaches, apricots, or plums. Dementia ascertainment was based on a multidisciplinary consensus committee, and included all-cause dementia and Alzheimer’s disease dementia diagnoses based on research criteria. Cox models were used to examine associations between cumulative fruit intake and incident dementia, stratified by midlife (45–59 years; n = 1,642) and late-life (60–82 years; n = 1,148).ResultsGreater cumulative total fruit intake in midlife, but not late-life, was significantly associated with a 44% decreased risk of all-cause dementia (HR = 0.56; 95% CI = 0.32–0.98; p = 0.044). Decreased risk of all-cause dementia was also associated with higher intake of apples or pears in midlife and late-life, as well as higher intake of raisins or grapes in midlife only, and higher intake of oranges, grapefruit, blueberries, and peaches, apricots, or plums in late-life only.ConclusionsAmong participants from the Framingham Heart Study, greater overall consumption of flavonoid-rich fruits in midlife was associated with reduced risk of dementia, though intake of specific fruits in midlife and late-life may have a protective role against developing dementia. These findings may help to inform future recommendations on when dietary interventions may be most beneficial to healthy brain aging across the life course.

Concurrent nutrient deficiencies are associated with dementia incidence.

While observational research suggests a protective role for nutrition in brain aging, intervention studies remain inconclusive. This failing translation from observational to interventional research may result from overlooking nutrient interactions. We developed a nutrient status index capturing the number of suboptimal statuses of omega-3 fatty acids, homocysteine, and vitamin D (range 0 to 3). We associated this index with dementia incidence in a subsample (age ≥ 50 years) of the Framingham Heart Study Offspring cohort. Among 968 participants, 79 developed dementia over 15.5 years (median follow-up). Each point increase in nutrient status index was associated with a 50% higher risk of dementia (hazard ratio [HR]=1.50; 95% confidence interval [CI]=1.16, 1.96). Participants with three high-risk statuses had a four-fold increased risk of dementia compared to participants without high-risk status (HR=4.68; 95% CI=1.69, 12.94). Concurrent nutrient deficiencies are associated with the risk of dementia. The potential of optimizing nutritional status to lower dementia risk warrants further study. Nutrition and dementia research calls for multiple-nutrient approaches. We studied combined suboptimal statuses of omega-3 polyunsaturated fatty acids, homocysteine, and vitamin D. Suboptimal status of the three nutrients was associated with dementia risk. The risk estimate was larger than for other factors (ie, diabetes, apolipoprotein Eε4 carrier). Future studies should assess the effect of improving nutrient status on dementia risk.

Immune cell phenotypes and mortality in the Framingham Heart Study

BackgroundGlobal life expectancy is rising, with the 60 + age group projected to hit 2 billion by 2050. Aging impacts the immune system. A notable marker of immune system aging is the presence of Aging-Related Immune Cell Phenotypes (ARIPs). Despite their importance, links between immune cell phenotypes including ARIPs and mortality are underexplored. We prospectively investigated 16 different immune cell phenotypes using flow cytometry and IL-6 in relation to survival outcome among dementia-free Framingham Heart Study (FHS) offspring cohort participants who attended the seventh exam (1998–2001).ResultsAmong 996 participants (mean age 62 years, range 40 to 88 years, 52% female), the 19-year survival rate was 65%. Adjusting for age, sex, and cytomegalovirus (CMV) serostatus, higher CD4/CD8 and Tc17/CD8 + Treg ratios were significantly associated with lower all-cause mortality (HR: 0.86 [0.76–0.96], 0.84 [0.74–0.94], respectively), while higher CD8 regulatory cell levels (CD8 + CD25 + FoxP3 +) were associated with increased all-cause mortality risk (HR = 1.17, [1.03–1.32]). Elevated IL-6 levels correlated with higher all-cause, cardiovascular, and non-cardiovascular mortality (HR = 1.43 [1.26–1.62], 1.70 [1.31–2.21], and 1.36 [1.18–1.57], respectively). However, after adjusting for cardiovascular risk factors and prevalent cancer alongside age, sex, and CMV, immune cell phenotypes were no longer associated with mortality in our cohort. Nonetheless, IL-6 remained significantly associated with all-cause and cardiovascular mortality (HRs: 1.3 [1.13–1.49], 1.5 [1.12–1.99], respectively).ConclusionsIn 19-year follow-up, higher Tc17/CD8 + Treg and CD4/CD8 ratios were associated with lower all-cause mortality, while the CD8 + CD25 + FoxP3 + (CD8 + Treg) phenotype showed increased risk. Elevated IL-6 levels consistently correlated with amplified mortality risks. These findings highlight the links between immune phenotypes and mortality, suggesting implications for future research and clinical considerations.

Abstract P251: Circulating Immune Cell Phenotypes Are Associated With Inflammatory Biomarkers in the Framingham Heart Study Offspring Cohort

Age-related changes in circulating immune cells have been associated with inflammation and immunosenescence, increasing susceptibility to cardiovascular disease. This study investigated the association between circulating immune cell phenotypes and inflammatory biomarkers in the Framingham Heart Study Offspring cohort. Participants (N=865, 52% female, mean age 62) were immunophenotyped using peripheral blood mononuclear cells with 37 immune cell phenotypes and 6 composite ratio measures, including T cells, B cells, NK cells, and monocytes. The inflammatory biomarkers were profiled in plasma samples using the OLINK Proteomics inflammation panel. Pairwise cross-sectional associations between 43 circulating immune cell phenotypes and 68 protein biomarkers were investigated using linear mixed-effect models accommodating familial correlations and adjusting for covariates (sex, age, number of apolipoprotein E ( APOE) ε2 and ε4 alleles, and cytomegalovirus levels), with FDR ≤0.05 to declare significant associations. Age-stratified analyses were performed to explore effect modification. CD8 T naïve cells (CD8Tn) were negatively associated with several proteins ( Figure ). Significant associations were also observed for CD4 T cell subtypes including higher levels of CD4 T helper cells associated with lower Flt3L and TNFRSF9, higher levels of CD4 T central memory (Tcm) and CD4 T effector (Teff) cells associated with lower TNFB, and higher CD4 Teff associated with lower CD40 levels. Among associations identified in the full sample, we observed a large proportion of associations between CD4 T cell subtypes and CD8 Tn in the older age group (&gt;60 years) but not the younger age group. Our results suggest that people tend to have more inflammation-associated immune responses during aging. Future studies are needed to improve understanding of the contribution of these inflammation-immune cell associations to cardiovascular disease.

Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol

Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified. To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults. A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023. LDL-C, cumulative past LDL-C, FH variant status. Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults. Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant. In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

Sex-specific blood biomarkers linked to memory changes in middle-aged adults: The Framingham Heart Study.

The relationship between sex-specific blood biomarkers and memory changes in middle-aged adults remains unclear. We aimed to investigate this relationship using the data from the Framingham Heart Study (FHS). We conducted association analysis, partial correlation analysis, and causal dose-response curves using blood biomarkers and other data from 793 middle-aged participants (≤ 60 years) from the FHS Offspring Cohort. The results revealed associations of adiponectin and fasting blood glucose with midlife memory change, along with a U-shaped relationship of high-density lipoprotein cholesterol with memory change. No significant associations were found for the other blood biomarkers (e.g., amyloid beta protein 42) with memory change. To our knowledge, this is the first sex-specific network analysis of blood biomarkers related to midlife memory change in a prospective cohort study. Our findings highlight the importance of targeting cardiometabolic risks and the need to validate midlife-specific biomarkers that can accelerate the development of primary preventive strategies.

Impact of midlife intake of flavonoid‐rich fruits on dementia risk in the Framingham Heart Study

AbstractBackgroundConsumption of foods with high flavonoid content may be protective against dementia in older adults, but it is unclear whether this relationship is consistent earlier in life. We investigated the relationship between consumption of flavonoid‐rich fruits in midlife and risk of dementia, including Alzheimer’s disease (AD).Method1,642 participants from the Framingham Heart Study Offspring cohort who were aged 45‐59 years and did not have prevalent dementia at Exam 5 (1991‐1995), and had a valid food frequency questionnaire data were included. Intake of 12 fruit items with high flavonoid content or are important contributors to overall flavonoid intake at Exam 5 were examined. Total fruit intake was calculated by summing intake of each fruit item. Diagnoses of all‐cause dementia and AD dementia were adjudicated by a multi‐disciplinary consensus committee through 2019. Cox models were used to evaluate the association between higher intake (&gt;30th percentile) versus lower intake (≤30th percentile) of total fruit consumption, as well for each fruit item, and incident dementia, adjusting for demographic, behavior and lifestyle, dietary, genetic, and clinical factors.ResultThe sample was, on average, 52 years of age, 53% female, and had 14 years of education, with an average follow up time of 24 years in the study. Higher intake of total fruits was associated with decreased risk of all‐cause dementia (HR = 0.56; 95% CI = 0.32 – 0.98), but not with AD dementia. Decreased risk of all‐cause dementia was associated with higher intake of apples or pears (HR = 0.47; 95% CI = 0.27 – 0.81), and oranges (HR = 0.55; 95% CI = 0.32 – 0.95). Higher intakes of apples or pears (HR = 0.50; 95% CI = 0.25 – 1.00), and oranges (HR = 0.43; 95% CI = 0.22 – 0.85), were also associated with decreased risk of AD dementia. Sex modified the association between total fruit intake in midlife and dementia risk (HRfemale = 0.46; 95% CI = 0.21 – 0.97; HRmale = 0.65; 95% CI = 0.27 – 1.60).ConclusionGreater consumption of flavonoid‐rich fruits in midlife, particularly apples or pears, as well as oranges, were significantly associated with reduced dementia risk.

Abstract 14427: Subclinical Age- and Sex-Differences in Ventricular Strain in the Community: A Framingham Heart Study Cardiac Magnetic Resonance Study

Introduction: Myocardial strain is a measure of deformation and a marker of cardiovascular disease (CVD). The subclinical age- and sex-associations of left and right ventricular (LV, RV) strain by feature tracking cardiovascular magnetic resonance (FT-CMR) are not well established in the community. Methods: Framingham Heart Study Offspring cohort participants (n=1077) without prevalent CVD, hypertension, diabetes, or use of treatment for these conditions underwent 1.5T CMR. Steady-state free precession cine images spanning the entirety of both ventricles were acquired in the short-axis, 2-chamber, and 4-chamber views. Global longitudinal (GLS), circumferential (GCS), and radial (GRS) strains were measured by FT-CMR (Circle cvi42 v.5.11.1). Comparisons among age groups (&lt;45 years, 45-54 years, 55-65 years, and &gt;65 years) were performed by one-way analysis of variance and between sexes by independent samples t -test. Results: Clinical characteristics, CMR measures, and LV and RV strain by age and sex for the cohort are presented in the Table . Across increasing age groups, we observed more favorable LV GLS, GCS, and GRS (p=0.010, p&lt;0.001, and p&lt;0.001, respectively). Similar trends were present for RV strain for GCS and GRS (both p&lt;0.001) but not GLS (p=0.22). Compared with men, women had greater magnitude (more favorable) LV and RV strain values for GLS, GCS, and GRS (all p≤0.013). Conclusions: In this large community based study of individuals without CVD, LV and RV strains by FT-CMR were greater (more favorable) with increasing age and in women. The associations and long-term implications of these differences in myocardial mechanics between groups require further investigation.

Abstract 17170: Association of Plasma Homocysteine Levels in Cancer Survivors - Data From Framingham Heart Study Offspring Cohort

Introduction: Cancer survivors experience a high prevalence of vascular remodeling from their anti-cancer therapies, which can lead to arterial stiffness. High plasma homocysteine (Hcy) is associated with increased cardiovascular disease risk via its role in decreasing nitric oxide bioavailability and impairing vascular function. However, there is limited work on its role in cancer survivorship. We, therefore, hypothesized that survivors of breast, gastrointestinal, and prostate cancer with elevated plasma Hcy values have higher arterial stiffness and lower endothelial function compared to those with low plasma Hcy. Methods: We evaluated cardiovascular disease-free cancer survivors in the Framingham Heart Study Offspring Cohort (n=196, 66±8 years old, 55.1% women, 26.4±1.2 years from cancer diagnosis, Range: [23.8 - 29.6 years]) with plasma Hcy measurements. The cohort median plasma Hcy was used to define low (&lt;8.16 μmol/L) and high Hcy (≥8.16 μmol/L) groups. Arterial stiffness was assessed via carotid-femoral pulse wave velocity (cfPWV). Peripheral vascular endothelial function was assessed via endothelium-dependent brachial artery flow-mediated dilation (FMD). Differences in cfPWV, FMD, and cardiovascular risk factors were assessed via independent sample t-test or chi-square test. Differences in cfPWV and FMD were further assessed via one-way ANCOVA with age, sex, and cardiovascular medications included as covariates. Results: cfPWV was significantly higher in the high Hcy (9.9±1.5m/s) vs. low Hcy group (8.5±1.9m/s, p=0.005); however, there were no differences in FMD between groups (2.4±1.7 vs. 2.7±2.0%, p=0.42). After controlling for our covariates, cfPWV was still significantly higher in the high Hcy group (Mean[95% CI]): (9.8[9.0-10.61]) compared to the low Hcy group (8.5[8-9.1]) (p=0.015). Conclusions: Our findings suggest an association between elevated Hcy and an increase in arterial stiffness in cancer survivors. This supports the potential adverse consequences of vascular stiffening following cancer diagnosis and treatment which could have long-term cardiovascular health implications.

Abstract 12346: Atherosclerotic Cardiovascular Disease Risk Associated With Social Determinants of Health at Individual and Area Levels

Introduction: Adverse social determinants of health (SDOH) are associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD). However, it is unclear if the ASCVD risks associated with area-level SDOH are similar to those with individual-level measures. Further, SDOH are not included in the Pooled Cohort Equations (PCEs) when estimating 10-year ASCVD risk. Studies have shown that PCEs systematically underestimate risk for socially deprived individuals. Aims To examine the association of individual- and area-level SDOH including education, income, and employment with incident ASCVD. Also, we assessed if adding SDOH to the PCEs improves risk prediction accuracy. Methods: We pooled data from four cohorts: Jackson Heart Study, Multi-Ethnic Study of Atherosclerosis, Framingham Heart Study Offspring Cohort, and Reasons for Geographic and Racial Differences in Stroke Study. We excluded participants with a history of ASCVD. Individual-level SDOH were based on participants’ self-report and area-level SDOH were derived by linking participants’ addresses to US Census tract data. We used Cox proportional hazards models to assess the associations between SDOH and ASCVD. We also assessed the changes in discrimination (Harrell’s C-index) and calibration (Integrated Brier Score) after adding SDOH to risk prediction models. Results: We analyzed data from 27,603 participants (mean age 61.4 years, 59% women, and 49% White). During a median follow-up of 13 years, 2,839 incident ASCVD events occurred. Both individual- and area-level SDOH were associated with ASCVD ( Figure, Panel A ). Adding both individual- and area-level SDOH to risk prediction modestly improved model discrimination and calibration in Black men and women ( Figure, Panels B &amp; C ), and also improved calibration in non-Black women. Conclusions: The findings suggest that SDOH may be considered in the development of future ASCVD risk assessment tools, particularly among Black individuals.

The association of circulating endocannabinoids with neuroimaging and blood biomarkers of neuro-injury

BackgroundPreclinical studies highlight the importance of endogenous cannabinoids (endocannabinoids; eCBs) in neurodegeneration. Yet, prior observational studies focused on limited outcome measures and assessed only few eCB compounds while largely ignoring the complexity of the eCB system. We examined the associations of multiple circulating eCBs and eCB-like molecules with early markers of neurodegeneration and neuro-injury and tested for effect modification by sex.MethodsThis exploratory cross-sectional study included a random sample of 237 dementia-free older participants from the Framingham Heart Study Offspring cohort who attended examination cycle 9 (2011–2014), were 65 years or older, and cognitively healthy. Forty-four eCB compounds were quantified in serum, via liquid chromatography high-resolution mass spectrometry. Linear regression models were used to examine the associations of eCB levels with brain MRI measures (i.e., total cerebral brain volume, gray matter volume, hippocampal volume, and white matter hyperintensities volume) and blood biomarkers of Alzheimer’s disease and neuro-injury (i.e., total tau, neurofilament light, glial fibrillary acidic protein and Ubiquitin C-terminal hydrolase L1). All models were adjusted for potential confounders and effect modification by sex was examined.ResultsParticipants mean age was 73.3 ± 6.2 years, and 40% were men. After adjustment for potential confounders and correction for multiple comparisons, no statistically significant associations were observed between eCB levels and the study outcomes. However, we identified multiple sex-specific associations between eCB levels and the various study outcomes. For example, high linoleoyl ethanolamide (LEA) levels were related to decreased hippocampal volume among men and to increased hippocampal volume among women (β ± SE = − 0.12 ± 0.06, p = 0.034 and β ± SE = 0.08 ± 0.04, p = 0.026, respectively).ConclusionsCirculating eCBs may play a role in neuro-injury and may explain sex differences in susceptibility to accelerated brain aging. Particularly, our results highlight the possible involvement of eCBs from the N-acyl amino acids and fatty acid ethanolamide classes and suggest specific novel fatty acid compounds that may be implicated in brain aging. Furthermore, investigation of the eCBs contribution to neurodegenerative disease such as Alzheimer’s disease in humans is warranted, especially with prospective study designs and among diverse populations, including premenopausal women.

Peripheral inflammatory biomarkers are associated with cognitive function and dementia: Framingham Heart Study Offspring cohort.

Inflammatory protein biomarkers induced by immune responses have been associated with cognitive decline and the pathogenesis of Alzheimer's disease (AD). Here, we investigate associations between a panel of inflammatory biomarkers and cognitive function and incident dementia outcomes in the well-characterized Framingham Heart Study Offspring cohort. Participants aged ≥40 years and dementia-free at Exam 7 who had a stored plasma sample were selected for profiling using the OLINK proteomics inflammation panel. Cross-sectional associations of the biomarkers with cognitive domain scores (N = 708, 53% female, 22% apolipoprotein E (APOE) ε4 carriers, 15% APOE ε2 carriers, mean age 61) and incident all-cause and AD dementia during up to 20 years of follow-up were tested. APOE genotype-stratified analyses were performed to explore effect modification. Higher levels of 12 and 3 proteins were associated with worse executive function and language domain factor scores, respectively. Several proteins were associated with more than one cognitive domain, including IL10, LIF-R, TWEAK, CCL19, IL-17C, MCP-4, and TGF-alpha. Stratified analyses suggested differential effects between APOE ε2 and ε4 carriers: most ε4 carrier associations were with executive function and memory domains, whereas most ε2 associations were with the visuospatial domain. Higher levels of TNFB and CDCP1 were associated with higher risks of incident all-cause and AD dementia. Our study found that TWEAK concentration was associated both with cognitive function and risks for AD dementia. The association of these inflammatory biomarkers with cognitive function and incident dementia may contribute to the discovery of therapeutic interventions for the prevention and treatment of cognitive decline.

Association of the Triglyceride-Glucose Index With Risk of Alzheimer's Disease: A Prospective Cohort Study

Triglyceride-glucose index (TyG) is a reliable surrogate marker of insulin resistance, and insulin resistance has been implicated in Alzheimer's disease pathophysiology. However, the relationship between the TyG index and Alzheimer's disease remains unclear. This study aimed to evaluate the association of the TyG index with the risk of Alzheimer's disease. This prospective study included 2,170 participants free of Alzheimer's disease from the Framingham Heart Study Offspring Cohort Exam 7 (1998-2001), whose follow-up data were collected until 2018. The TyG index was calculated as Ln(fasting triglyceride [mg/dL]×fasting glucose [mg/dL]/2). The association of the TyG index with Alzheimer's disease was evaluated by competing risk regression model. Statistical analyses were performed in 2023. During a median follow-up of 13.8 years, 163 (7.5%) participants developed Alzheimer's disease. When compared with the reference (TyG index ≤8.28), a significantly elevated risk of Alzheimer's disease was seen in the group with a triglyceride-glucose index of 8.68-9.09 (adjusted hazard ratio=1.69, 95% CI=1.02, 2.81). When the TyG index was considered as a continuous variable, each unit increment in the TyG index was not significantly associated with the risk of Alzheimer's disease (adjusted hazard ratio=1.32, 95% CI=0.98, 1.77). This study showed that moderately elevated TyG index was independently associated with a higher incidence of Alzheimer's disease. TheTyG index might be used to define a high-risk population of Alzheimer's disease.

Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and DNA-methylation based PAI1

Sex hormones are hypothesized to drive sex-specific health disparities. Here, we study the association between sex steroid hormones and DNA methylation-based (DNAm) biomarkers of age and mortality risk including Pheno Age Acceleration (AA), Grim AA, and DNAm-based estimators of Plasminogen Activator Inhibitor 1 (PAI1), and leptin concentrations. We pooled data from three population-based cohorts, the Framingham Heart Study Offspring Cohort, the Baltimore Longitudinal Study of Aging, and the InCHIANTI Study, including 1,062 postmenopausal women without hormone therapy and 1,612 men of European descent. Sex-stratified analyses using a linear mixed regression were performed, with a Benjamini-Hochberg (BH) adjustment for multiple testing. Sex Hormone Binding Globulin (SHBG) was associated with a decrease in DNAm PAI1 among men (per 1 standard deviation (SD): -478 pg/mL; 95%CI: -614 to -343; P:1e-11; BH-P: 1e-10), and women (-434 pg/mL; 95%CI: -589 to -279; P:1e-7; BH-P:2e-6). The testosterone/estradiol (TE) ratio was associated with a decrease in Pheno AA (-0.41 years; 95%CI: -0.70 to -0.12; P:0.01; BH-P: 0.04), and DNAm PAI1 (-351 pg/mL; 95%CI: -486 to -217; P:4e-7; BH-P:3e-6) among men. In men, testosterone was associated with a decrease in DNAm PAI1 (-481 pg/mL; 95%CI: -613 to -349; P:2e-12; BH-P:6e-11). SHBG was associated with lower DNAm PAI1 among men and women. Higher testosterone and testosterone/estradiol ratio were associated with lower DNAm PAI and a younger epigenetic age in men. A decrease in DNAm PAI1 is associated with lower mortality and morbidity risk indicating a potential protective effect of testosterone on lifespan and conceivably cardiovascular health via DNAm PAI1.Graphical

Association of the Mediterranean Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) Diet With the Risk of Dementia

Dementia threatens the well-being of older adults, making efforts toward prevention of great importance. To evaluate the association of the Mediterranean-Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay (MIND) diet with the risk of dementia in 3 prospective studies and a meta-analysis. Cohort analyses included the Whitehall II study (WII), the Health and Retirement Study (HRS), and the Framingham Heart Study Offspring cohort (FOS), and the meta-analysis included 11 cohort studies. Participants were middle-aged and older women and men from WII in 2002 to 2004, HRS in 2013, and FOS in 1998 to 2001 without dementia at the study baseline. Data were analyzed from May 25 to September 1, 2022. MIND diet score was measured using food frequency questionnaires, and scores ranged from 0 to 15, with a higher score indicating higher adherence to the MIND diet. Incident all-cause dementia, with cohort-specific definitions. Included in this study were 8358 participants (mean [SD] age, 62.2 [6.0] years; 5777 male [69.1%]) from WII, 6758 participants (mean [SD] age, 66.5 [10.4] years; 3965 female [58.7%]) from HRS, and 3020 participants (mean [SD] age, 64.2 [9.1] years; 1648 female [54.6%]) from FOS. The mean (SD) baseline MIND diet score was 8.3 (1.4) in WII, 7.1 (1.9) in HRS, and 8.1 (1.6) in FOS. Over 166 516 person-years, a total of 775 participants (220 in WII, 338 in HRS, and 217 in FOS) developed incident dementia. In the multivariable-adjusted Cox proportional hazard model, higher MIND diet score was associated with lower risk of dementia (pooled hazard ratio [HR] for every 3-point increment, 0.83; 95% CI, 0.72-0.95; P for trend = .01; I2 = 0%). The associations were consistently observed in subgroups defined by sex, age, smoking status, and body mass index. In the meta-analysis of 11 cohort studies with 224 049 participants (5279 incident dementia cases), the highest tertile of MIND diet score was associated with lower risk of dementia compared with the lowest tertile (pooled HR, 0.83; 95% CI, 0.76-0.90; I2 = 35%). Results suggest that adherence to the MIND diet was associated with lower risk of incident dementia in middle-aged and older adults. Further studies are warranted to develop and refine the specific MIND diet for different populations.

Optimizing Arteriovenous Fistula Care in Kidney Transplant Recipients: A Complex Task.

Optimizing Arteriovenous Fistula Care in Kidney Transplant Recipients: A Complex Task.

Circulating immune cell phenotypes are associated with age, sex, CMV, and smoking status in the Framingham Heart Study offspring participants.

Understanding the composition of circulating immune cells with aging and the underlying biologic mechanisms driving aging may provide molecular targets to slow the aging process and reduce age-related disease. Utilizing cryopreserved cells from 996 Framingham Heart Study (FHS) Offspring Cohort participants aged 40 and older (mean 62 years, 48% female), we report on 116 immune cell phenotypes including monocytes, T-, B-, and NK cells and their subtypes, across age groups, sex, cytomegalovirus (CMV) exposure groups, smoking and other cardiovascular risk factors. The major cellular differences with CMV exposure were higher Granzyme B+ cells, effector cells, and effector-memory re-expressing CD45RA (TEMRA) cells for both CD4+ and CD8+. Older age was associated with lower CD3+ T cells, lower naïve cells and naïve/memory ratios for CD4+ and CD8+. We identified many immune cell differences by sex, with males showing lower naïve cells and higher effector and effector memory cells. Current smokers showed lower pro-inflammatory CD8 cells, higher CD8 regulatory type cells and altered B cell subsets. No significant associations were seen with BMI and other cardiovascular risk factors. Our cross-sectional observations of immune cell phenotypes provide a reference to further the understanding of the complexity of immune cells in blood, an easily accessible tissue.