Introduction: HDL subspecies defined by functional apolipoproteins (apo) exhibit different associations with coronary heart disease (CHD) risk; however, the underlying mechanism, particularly from a lipidomic perspective, is unclear. Hypothesis: Apo-defined HDL subspecies may be characterized by distinct lipid profiles that are associated with differential CHD risk. Methods: We measured the apoA1 concentrations of 15 apo-defined HDL subspecies and 176 plasma lipids among 446 women in Nurses’ Health Study (NHS). The proportion of each HDL subspecies was calculated as the ratio of apoA1 concentrations in HDL containing a specific protein to total plasma apoA1 concentration. Linear regression was used to identify individual lipids associated with the proportions of HDL subspecies, and elastic net regression was used to define predictive lipidomic signatures. Associations between lipidomic signatures and CHD risk were examined using conditional logistic regression in a nested case-control study (400 matched pairs) and Cox regression in 13,495 participants from NHS, NHSII, and Health Professionals Follow-Up Study. Results: HDL subspecies showed different associations with lipidomic features: proportions of HDL containing apoC1, apoE, apoL1, apoC3, and apoJ were associated with specific lipids, while few associations were found for the other ten subspecies. The lipid profile of HDL containing apoC1 closely resembled that of total apoA1, whereas HDL containing apoL1 showed a distinct pattern. Several TAGs and DAGs were negatively associated with apoC1 but positively with apoL1; conversely, certain phospholipids showed positive associations with apoC1 and negative associations with apoL1. The Pearson r between the lipidomic signatures and their corresponding HDL subspecies was 0.76 for total apoA1 (total HDL), 0.67 for apoC1, 0.63 for apoE, 0.55 for apoC3, 0.50 for apoL1, and 0.34 for apoJ. Multivariable-adjusted ORs (95% CIs) for CHD risk per 1-SD increase in lipidomic signatures were 0.85 (0.72, 1.00) for total apoA1, 0.77 (0.65, 0.91) for apoC1, 0.79 (0.66, 0.94) for apoE, 0.92 (0.79, 1.08) for apoC3, 1.30 (1.10, 1.53) for apoL1, and 0.97 (0.81, 1.15) for apoJ ( Figure ). Individual lipids positively associated with HDL containing apoL1, including specific TAGs, DAGs, and ceramides, were also related to a higher CHD risk in the cohorts. Conclusions: Lipid profiles vary across apo-defined HDL subspecies and may contribute to their different associations with CHD risk.

Background: The effects of reducing dietary carbohydrate intake and glycemic index (GI) levels on temporal changes in blood metabolomic profiles and their impact on improving glucose tolerance remain unclear. Aim: We examined temporal changes in circulating metabolites induced by lowering dietary carbohydrate content and GI levels and aimed to identify specific metabolites associated with improved glucose tolerance and insulin sensitivity. Methods: We analyzed data from 162 adults in the OmniCarb trial, a crossover feeding study of diets varying in carbohydrate amount and GI levels. Each diet was consumed for 5 weeks, with at least a 2-week washout period. Global metabolomics was repeatedly performed to calculate temporal changes. Oral glucose tolerance tests (OGTTs) were conducted for all participants; 12-hour meal tests were performed in a subsample (n=59). To validate and explore long-term associations in an independent study (n=670), we analyzed 6-month changes in metabolites in response to weight-loss diets varying in macronutrient composition among participants in the POUNDS Lost trial. Results: At baseline, 189 of 906 analyzed metabolites showed suggestive associations (crude p <0.05) for the area under the curve of glucose during the OGTT, and 51 metabolites remained significant after correcting for multiple testing (P-FDR <0.05). We found that 170 metabolites (19%) after overnight fasting were significantly modified by lowering carbohydrate amount and GI. In addition, at 30 minutes post-meal (after breakfast), 101 metabolites changed significantly, indicating that the low-carbohydrate, low-GI diet altered postprandial metabolite responses. Particularly, changes in gut microbiota-related metabolites, including 3-hydroxybutyrate, 3-aminoisobutyrate, kynurenate, N-acetylglycine, and hippurate, were associated with improved 12-hour postprandial glucose responses following the low-carbohydrate, low-GI diet. In the POUNDS Lost trial, 6-month increases in 3-hydroxybutyrate, 3-aminoisobutyrate, and N-acetylglycine were associated with greater reductions in fasting glucose and insulin resistance at 6 months. These initial (6-month) metabolite changes were associated with 2-year improvements in glucose metabolism and insulin sensitivity. Conclusions: Dietary interventions focusing on carbohydrate amount and GI altered circulating metabolites, including gut microbiota-related metabolites, which were linked to improved glucose tolerance and insulin sensitivity.

INTRODUCTION:Observational studies link the MIND diet to reduced risk of Alzheimer's disease (AD) and slower cognitive decline. However, a recent randomized controlled trial found no differential cognitive benefit of the MIND diet over a control diet in the context of shared caloric restriction. Given that both groups achieved significant weight loss and metabolic improvements, this study aimed to disentangle the impact of the MIND diet and host metabolic improvements on the intestinal microbiome. METHODS:A subset of participants (n = 213) from the MIND trial were analyzed in this study. Clinical data and stool samples were collected at baseline, Year 1, Year 2, and Year 3, and longitudinal changes in microbiome composition were assessed via shotgun metagenomics. RESULTS:Both groups exhibited significant, transient microbiome remodeling at Year 1 (the period of most active weight loss). The control group demonstrated a broad range of altered metabolic pathways, whereas the MIND diet group showed only one, suggesting a functional buffering effect of the MIND diet. Prospective modeling independent of diet group revealed that a poorer cognitive trajectory was significantly associated with increased inositol degradation (PWY-7237) and purine nucleotide salvage (PWY66-409); conversely, a better cognitive trajectory was associated with increased degradation of deoxy sugars (FUC-RHAMCAT-PWY). DISCUSSION:Caloric restriction, weight loss, and host metabolic improvement are the dominant factors shaping the intestinal microbiome, overshadowing diet-specific taxonomic shifts. The MIND diet appeared to provide a modest stabilizing effect on the microbial functional profile against perturbations during active weight loss; however, these dietary associations did not persist in covariate-adjusted models, suggesting that host metabolic improvements remained the primary driver of functional shifts.

INTRODUCTION:We examined whether participant characteristics, including sociodemographics, APOE ε4 allele, lifestyle factors, and cardiovascular risk factors, modified the effect of the Mediterranean-Dietary Approach to Systolic Hypertension Intervention for Neurodegenerative Delay (MIND). METHODS:The MIND trial (NCT02817074) randomized adults 65 to 85 years who were overweight or obese to the MIND diet or control diet conditions. A linear mixed-effects model was used to examine whether participant characteristics modified the effect of MIND on the annual change in a global cognition score derived from a battery of 12 neurocognitive tests. RESULTS:On average, participants (N = 604) were 70.4 years old, 65.5% female, and with a body mass index (BMI) of 33.9 kg/m2. In multivariable-adjusted models, BMI was the only significant modifier (p = 0.009); only among individuals with BMI ≥ 35 kg/m2 (n = 213) was the MIND diet group associated with higher cognitive scores by 0.040 (standard error = 0.017, p = 0.018) standardized units per year versus control. DISCUSSION:The MIND diet may have cognitive benefits in people with obesity, particularly BMI ≥ 35. CLINICAL TRIAL REGISTRATION NUMBER:NCT02817074 HIGHLIGHTS: This study examined potential effect modifiers of the MIND diet on cognition. BMI emerged as a significant effect modifier. In those with BMI ≥ 35 kg/m2, the MIND diet group had higher cognitive scores. The MIND diet may have cognitive benefits for people with obesity.

Observational studies have shown a protective association between antioxidant nutrients and lower risk of Alzheimer’s disease. Results from dietary intervention trials remain inconclusive. The effect of APOE-e4, the strongest risk factor for AD, on responsiveness to dietary interventions remains largely uninvestigated. We examined whether the association of plasma nutrient levels and changes in global cognition over three years differed by the APOE-e4 allele among MIND trial participants. The study included 601 participants from the MIND trial with APOE-e4 genotype. Plasma nutrients were analyzed using HPLC at Harvard School of Public Health. Cognitive function was evaluated with a 12-test battery from which a composite of global cognition was derived. Mixed-effect regression model was used to examine the association of plasma nutrient levels, the APOE-e4 allele and cognitive decline. The mean age was 70.4 years for the 428 APOE-e4 non -carriers and 69.8 years for the 174 carriers (p = 0.08) ( Table 1 ). Among APOE-e4 carriers, individuals in the highest tertile of lutein and zeaxanthin, alpha-carotene, and beta-carotene had a significantly slower cognitive decline by 0.16 standardized unit (SU) [SE = 0.07, p = 0.03], 0.16 SU [SE = 0.07, p = 0.02], and 0.18 SU [SE = 0.07, p = 0.01], respectively, when compared with the lowest tertile ( Figure 1 ). Among APOE-e4 carriers, individuals in both the moderate and the highest tertiles of lycopene (0.24 ± 0.07, p = 0.001, 0.19 ± 0.07, p = 0.01) and beta-cryptoxanthin (0.26 ± 0.07, p = 0.000, 0.20 ± 0.07, p = 0.01) had slower cognitive decline than those in the lowest tertile Among APOE-e4 non- carriers, there was no association, except individuals in the moderate tertile of lutein and zeaxanthin which showed slower declines (0.08 ± 0.04, p = 0.04) compared to the lowest tertile. When comparing APOE-e4 carriers and non -carriers at high plasma levels (75 th percentile) of alpha-tocopherol, lutein and zeaxanthin, beta-carotene, lycopene, and beta-cryptoxanthin, APOE-e4 carriers had slower global cognitive decline ranging from 4.7% to 21% (p<0.05 for all). Higher plasma antioxidant nutrients were associated with significantly slower cognitive decline among APOE-e4 carriers in the MIND trial participants, suggesting the potential effects of antioxidant nutrients in mitigating the genetic risk posed by APOE-e4.

Plasma amyloid-beta (Abeta) reflects brain amyloid pathology, with a lower plasma Abeta42/40 ratio linked to a higher risk of Alzheimer's disease and related dementias (ADRD). This study investigates the effect of the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet on the longitudinal changes in plasma Abeta 42/40 levels. MIND trial was a 3-year, two-site, randomized controlled clinical trial comparing the MIND diet with a usual diet in 604 participants aged 65 to 85 years with a family history of dementia but without cognitive impairment, being overweight and with suboptimal diets at baseline; both diets promoted weight loss through mild caloric restriction. MIND diet intervention promoted 9 brain-healthy food groups (e.g., green leafy vegetables, nuts, berries) and limited consumption of 5 unhealthy food groups (e.g., red and processed meats, fried foods). Multivariable-adjusted linear mixed-effect models with a random intercept were utilized to estimate the effect of dietary interventions on the rate of change in plasma Abeta42/40 levels during the 3-year trial period. Of 604 individuals enrolled in the trial, 598 had measured plasma levels of A 42 and 40 at the baseline and 504 (84.3%) at the end of the trial (year 3). The average (SD) age at enrollment was 70.4 (4.2) years; 388 (64.9%) were female, and 524 (87.6%) were white individuals. At the baseline, Abeta42/40 levels were similar in people randomized to the MIND diet group (mean = 0.069 pg/ml) and those in the control group (mean = 0.068 pg/ml). At year 3, Abeta42/40 levels decreased in the control group while remaining statistically unchanged in the MIND diet group. Compared to the individuals in the MIND diet group, those in the control group showed an average 2.8% decline in plasma Abeta42/40 levels (beta= -0.012; SE = 0.005; p -value=0.024) over a 3-year follow-up period. This study showed that dietary intervention influences longitudinal changes in plasma Abeta 42/40 levels. Compared to the MIND diet group, individuals in the control group showed a modest decline in plasma Abeta 42/40 levels, suggesting that the MIND diet intervention may reduce Alzheimer's disease pathology in the brain and, potentially, the risk of ADRD.

Background and aims: Meal timing has been suggested as a circadian disruptor that may be linked cardiovascular disease by influencing fatty acid metabolism and specific metabolomic pathways. We aimed to test associations of diurnal postprandial glucose responses (PPGRs) after consuming diets varying in carbohydrate amount (Carb) and glycemic index (GI) with comprehensive lipid subtypes and lipidomic signatures. Materials and methods: This ancillary analysis included 61 adults from the OmniCarb trial, a randomized crossover, controlled feeding trial of 4 diets that differed in Carb and GI levels. Each diet was based on a healthful DASH-type diet and was provided for 5 weeks, with a 2-week washout. Twelve-hour meal tests were conducted at the end of each intervention. Participants were given the same diet type for that diet period for breakfast, lunch, and dinner, which had a mean 486, 610, 618 kcal, respectively, for a typical 2000-kcal diet. The area under the curve (AUC) of glucose after each meal was calculated and analyses were performed per 1 SD higher of AUC-glucose. Lipid subtypes considering the presence of apolipoprotein C-III (apoC-III) were measured in fasting samples collected at the end of the intervention. Serum lipid metabolites were analyzed using Metabolon's complex lipids targeted panel. Results: At the end of high-carb and high-GI diet interventions, PPGRs after dinner, but not after lunch, were associated with higher levels of atherogenic apoC-III (β [SE]: 0.3 [0.1]; p=0.035), apoB (β 0.2 [0.1]; p=0.04), and cholesterol (β 1.2 [0.5]; p=0.018) in LDL with apoC-III. PPGRs after breakfast were not significantly related to cholesterol in LDL with apoC-III. When analyzing effects on lipid class concentrations, a low-carb and low-GI diet compared to high-carb and high-GI diet lowered triacylglycerol (TAG) and phosphatidylcholines but slightly increased phosphatidylethanolamines (PE) and lactosylceramides ( p <0.05 for all). At the end of low-carb and low-GI diet interventions, greater AUC-glucose after dinner and AUC-glucose differences between lunch and dinner showed significant associations with higher levels of cholesteryl esters, dihydroceramides, TAG, and PE. Conclusion: Greater PPGRs were associated with atherogenic lipid subtypes and lipidomic pathways after evening meals but not after daytime meals. The atherogenic lipid pathways associated with PPGRs in the evening may vary depending on Carb content and dietary GI of the meals.

Recent advancements in machine learning (ML) for analyzing heterogeneous treatment effects (HTE) are gaining prominence within the medical and epidemiological communities, offering potential breakthroughs in the realm of precision medicine by enabling the prediction of individual responses to treatments. This paper introduces the methodological frameworks used to study HTEs, particularly based on a single randomized controlled trial (RCT). We focus on methods to estimate conditional average treatment effect (CATE) for multiple covariates, aiming to predict individualized treatment effects. We explore a range of methodologies from basic frameworks like the T-learner, S-learner, and Causal Forest, to more advanced ones such as the DR-learner and R-learner, as well as cross-validation for CATE estimation to enhance statistical efficiency by estimating CATE for all RCT participants. We also provide a practical application of these approaches using the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial, which compared the effects of high versus low-fat diet interventions on 2-year weight changes. We compared different sets of covariates for CATE estimation, showing that the DR- and R-learners are useful for the estimation of CATE in high-dimensional settings. This paper aims to explain the theoretical underpinnings and methodological nuances of ML-based HTE analysis without relying on technical jargon, making these concepts more accessible to the clinical and epidemiological research communities.

BACKGROUND:With the increasing prevalence of obesity and its negative consequences on health, weight management emerges as a priority for public health, especially in older adults, in whom obesity is linked to increased risks of chronic diseases such as cardiovascular disease. We performed a study investigating the association of intentional weight loss through dietary intervention on cardiometabolic health among older adults participating in the MIND trial. METHODS:The MIND trial enrolled overweight individuals aged 65-84 who self-reported a suboptimal diet. Participants were randomized to the MIND or a control diet for 3 years; both diets promoted weight loss through mild caloric restriction (250 kcal). Of 604 individuals enrolled in the trial, 518 were included in the analysis. We calculated the percentage of weight loss based on measured weight at the baseline and year 3 and categorized individuals into four groups: no weight loss (e.g., weight gain), <5%, 5-10%, and >10% weight loss. Cardiometabolic health included traditional lipid biomarkers, biomarkers of inflammation, and glycosylated hemoglobin. Linear mixed-effect models were used to evaluate the associations of weight loss with cardiometabolic health. RESULTS:At the baseline, mean age was 70 (SD = 4.1) years, 332 (65%) were women, and BMI was 33.8 (SD = 5.9) kg/m2. Compared to people who did not lose weight, those with >10% weight loss significantly improved their biomarkers of cardiometabolic health at the year 3 visit as follows: LDL cholesterol levels decreased by 8.3%, triglycerides by 28.2%, and HDL increased by 12.4%. As for biomarkers of inflammation, GlycA decreased by 7.5%, hs-IL6 by 33.0%, hs-CRP by 59.4%, and adiponectin increased by 53.7%. These improvements in biomarkers of cardiometabolic health did not differ by dietary intervention. CONCLUSION:Weight loss through dietary interventions with mild calorie restriction resulted in favorable changes in cardiometabolic risk factors among older adults with overweight and obesity. CLINICAL TRIAL REGISTRATION NUMBER:NCT02817074.

With the increasing prevalence of obesity and its negative consequences on health, weight management has emerged as a priority for public health. We conducted a study to investigate the association of intentional weight loss through dietary intervention on cognition among older adults participating in the MIND trial. MIND trial enrolled overweight older adults aged 65-85 years with a family history of dementia but without cognitive impairment and self-reporting a suboptimal diet. Participants were randomized to the MIND diet or a control (usual) diet for 3 years; both diets promoted weight loss through mild caloric restriction. Of 604 individuals enrolled in the MIND trial, 520 had measured weight at the baseline and year 3 visit and were included in the analysis. We computed the percentage of weight loss based on baseline and last assessment and grouped individuals into 4 categories: weight gainers, <5% weight loss, 5-10% weight loss, and >10% weight loss. Linear mixed-effect models were used to estimate the 3-year change in global cognitive scores. Models were adjusted by age, sex, race, apolipoprotein E (APOE) e4 allele, baseline BMI, and dietary assignment. The mean age was 70 years, 65% were women, and the mean BMI was 34 kg/m 2 . During 3 years of dietary intervention, 78.5% of participants lost weight. The average weight loss ranged from 2.3 kg to 15kg. Compared to people who gained weight, those with >10% weight loss significantly improved their cognitive scores by 0.103 SD/units (95%CI 0.008, 0.199) at year 3 visit. In addition, individuals who lost weight had improved plasma levels of inflammation, lipids, and glucose during the trial period. Among people in the MIND diet group, those with >10% weight loss significantly improved their cognitive scores by 0.171 SD/units (95%CI 0.028, 0.314) compared to people who gained weight; there was no significant association in the control diet group. Among overweight and cognitively unimpaired individuals at the baseline with a family history of dementia, a weight loss of 10% (average 15 kg) or more during 3 years of dietary interventions was associated with improved cognitive scores when compared to people who gained weight.

BACKGROUND:Alzheimer disease (AD) prevention is a public health priority, yet the impact of dietary carotenoids on cognitive decline, particularly in apolipoprotein E (APOE) ε4 carriers, remains unclear. OBJECTIVES:The objective of this study was to examine whether the APOE ε4 genotype modifies the relationship between blood carotenoid concentrations and global cognition. METHODS:This study was conducted within the Mediterranean-Dietary Approaches to Stop Hypertension intervention for neurodegenerative delay trial, a 3-y randomized controlled trial comparing the effects of the Mediterranean-Dietary Approaches to Stop Hypertension intervention for neurodegenerative delay diet with the usual diet on global cognition in older adults. Eligible participants were ≥65 y, had a body mass index (in kg/m2) >25, a family history of AD, suboptimal diets, and a Montreal cognitive assessment score ≥22. The primary outcome was 3-y change in global cognitive function, assessed using a validated composite cognitive score converted to standardized units (SUs). Baseline plasma carotenoid concentrations were measured in a subgroup of participants (n = 442). Mixed-effects models were used to test the interaction between APOE ε4 status and baseline carotenoid concentrations on cognitive trajectories. RESULTS:The mean age was 70.0 y for noncarriers (n = 308) and 69.4 y for APOE ε4 carriers (n = 134). Among APOE ε4 carriers, a 1-unit increment in plasma total carotenoids at baseline was associated with higher global cognitive scores [β = 0.17 SU; 95% confidence interval (CI): 0.06, 0.28 SU; P = 0.009]. Similar associations were observed for β-carotene (β = 0.13 SU; 95% CI: 0.05, 0.21 SU; P = 0.001), α-carotene (β = 0.09 SU; 95% CI: 0.02, 0.15 SU; P = 0.008), lutein plus zeaxanthin (β = 0.14 SU; 95% CI: 0.04, 0.25 SU; P = 0.008), lycopene (β = 0.17 SU; 95% CI: 0.07, 0.28 SU; P = 0.005), and β-cryptoxanthin (β = 0.13 SU; 95% CI: 0.05, 0.21 SU; P = 0.03). Associations in noncarriers were weaker or nonsignificant. CONCLUSIONS:Higher plasma carotenoid concentrations were associated with slower cognitive decline in APOE ε4 carriers, potentially mitigating genetic risk. This trial was registered at clinicaltrials.gov as NCT02817074.

People with type 2 diabetes and hypertension are at high risk for blood pressure–related cardiovascular events. Few trials have tested the blood pressure–lowering effects of dietary interventions other than weight loss in this population. To determine the effects of dietary patterns and sodium reduction on blood pressure in adults with type 2 diabetes. Dietary Approaches to Stop Hypertension for Diabetes (DASH4D) was a randomized 4-period crossover feeding study conducted at a community-based study center from June 2021 to June 2024. It included adults with type 2 diabetes, a systolic blood pressure of 120 to 159 mm Hg, and a diastolic blood pressure of less than 100 mm Hg. The DASH4D diet is a Dietary Approaches to Stop Hypertension (DASH)–style diet optimized for people with type 2 diabetes (lower carbohydrates, higher unsaturated fats, and lower potassium than the original DASH diet). Participants were provided all of their food and ate no outside food. Weight was held constant. Data analysis was completed in November 2024. Participants were randomized to a sequence of 4 diets, each for 5 weeks: (1) DASH4D diet with lower sodium, (2) DASH4D diet with higher sodium, (3) comparison (typical US) diet with lower sodium, and (4) comparison diet with higher sodium (reference). The primary and secondary outcomes were end-of-period systolic and diastolic blood pressure, respectively. The primary dietary contrast compared the DASH4D lower sodium diet vs a comparison higher sodium diet. Of 102 participants, 85 (83.3%) completed all diet periods. The mean (SD) age was 66 (8.8) years, 67 (66%) were women, 6 (6%) were self-reported Asian, 89 (87%) were Black, 2 (2%) were Hispanic, 6 (6%) were White, mean (SD) baseline blood pressure was 135 (9)/75 (9) mm Hg, and 67 (66%) used 2 or more antihypertensive medications. Compared with the comparison diet with higher sodium, the DASH4D diet with lower sodium reduced end-of-period systolic blood pressure by 4.6 mm Hg (95% CI, 7.2-2.0; P < .001) and diastolic blood pressure by 2.3 mm Hg (95% CI, 3.7-0.9). Most blood pressure reduction occurred during the first 3 weeks of each diet, and the effect of sodium reduction appeared stronger than the effect of the DASH4D diet. Adverse events were infrequent in each diet. This randomized clinical trial found that, for adults with type 2 diabetes, most of whom were treated with multiple antihypertensive medications, the DASH4D diet combined with sodium reduction achieved a clinically relevant reduction in blood pressure, primarily from sodium reduction. ClinicalTrials.gov Identifier: NCT04286555

With increasing prevalence of obesity in the United States, dietary interventions that promote weight loss have high public health significance. In the recently completed clinical trial (i.e., MIND diet trial), both the MIND diet intervention and control diet groups received mild caloric restriction and showed clinically significant weight loss and improved cognition over 3 years. In the current study, we examined whether the effect of the MIND diet intervention on cognition differs across people with different body mass index (BMI) at enrollment. The MIND trial enrolled older adults without cognitive impairment but with a family history of dementia, BMI>25, and a suboptimal diet. A linear mixed-effect model was used to examine if BMI modified the effect of MIND on cognition, specifically annual change in a global cognition score derived from a battery of 12 neurocognitive tests. Participants (N = 604) were, on average, 70.4 years old, 65.5% female, and with a BMI of 33.9 kg/m2 at baseline. In a multivariable-adjusted model, there was a significant interaction between intervention x BMI x time (p= .011); as such, among individuals with BMI>35 kg/m2 (n = 213), those within the MIND diet group showed a slower rate of decline in global cognition by 0.040 (SE = 0.017, p=.018) standardized units per year when compared to people in the control diet group. In people with BMI< 35, there were no differences between the MIND diet and the control group in global cognition. Future work should examine underlying mechanisms that explain the cognitive benefits of the MIND diet among people with obesity.

Metabolomics captures net influences of exposome, diet, gut microbiome, and genome, informing about individuality and how we respond to interventions. Applications of metabolomics in pharmacology are starting to enable a Systems Pharmacology approach, where the outcome of a treatment is considered to evolve from effects on complex molecular networks, enabling insights into response variations. We bring the power of these approaches to the study of the MIND, a Mediterranean DASH diet for prevention of cognitive decline. We evaluate if metabolomics can reveal beneficial metabolic effects linked to improved cognition in all participants or subgroups of individuals. Serum samples were collected from participants enrolled in the MIND trial at the Rush University Medical Center site. Participants were randomized to either the MIND diet or control diet group for three years with study visits, cognitive testing, and sample collection occurring at baseline, Years 1, 2, and 3. A total of 746 serum samples from 243 participants were profiled using targeted and non-targeted metabolomics, lipidomics, metagenomics, and foodomics approaches. The longitudinal effects of the diet on the metabolome were evaluated. We identified metabolic signatures of participants on the MIND diet that were unique compared to the control diet. Major changes in lipid metabolism including ceramides, sphingomyelins, PUFAs, and plasmalogens were noted along with changes in energy metabolism and one carbon metabolism (Figure 1). Food components and exposome-related metabolites were changed. For example, tryptophan betaine (lower in cognitive dysfunction) was increased in the MIND diet group with strongest effects in individuals with low levels at baseline. Additionally, glycoprotein acetyls (GlycA, an inflammation marker associated with AD, cognitive decline, reduced brain volume) was decreased in the MIND diet group compared to controls. Detailed mapping of influences on the gut microbiome are being defined and linked to changes in metabolome. The metabolomics data highlighted alterations in metabolism in response to MIND diet. These alterations suggest metabolic benefit for cognitive function and inflammation based on big metabolomics data in ADNI and other cohorts. The variation among individuals seen in our analysis warrants stratification of people enrolled in the MIND study before final conclusions are made on its outcome.

Plasma levels of phosphorylated tau (pTau-181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) as biomarkers of brain pathology and neurodegeneration have been associated with cognition and Alzheimer’s dementia. Whether a dietary intervention modifies these relationships by potentially promoting cognitive reserve is unknown. We conducted a posthoc analysis of the MIND trial to investigate whether dietary intervention modifies the association of longitudinal changes in pTau-181, NfL, and GFAP with cognition during 3 years of follow-up. MIND trial was a 3-year, two-site, randomized controlled clinical trial comparing the MIND diet with a usual diet on cognitive changes among 604 older participants (65 to 85 years) with a family history of dementia but without cognitive impairment, overweight, and with suboptimal diets at enrollment. pTau-181, NfL, and GFAP were measured in plasma from blood collected after an overnight fast. Relative change in biomarkers (i.e., %change) from baseline to Year 3 were computed [(year 3 - baseline)/baseline)*100]. Global cognition was derived from a standardized 12-test cognitive battery. We included 508 individuals with biomarkers and cognitive assessments at the baseline and year 3. Changes in pTau-181 and NfL were associated with global cognition. One SD increase in %change of pTau-181 was associated with 0.049 SD units lower in cognition at year 3 ($∖beta$ -0.049; 95%CI -0.081 to -0.016). For NfL, cognition was 0.044 SD units lower at year 3 (β -0.044; 95%CI 0.076 to -0.012). The strength of these associations differed by the dietary arm (p for interaction = 0.063), such that effects were attenuated in the MIND diet arm and more robust in the control arm. Specifically, pTau-181 in the MIND diet group was -0.027 (p = 0.264), and in the control group, -0.076 (p = 0.001). For NfL, these estimates were -0.022 (p = 0.263) and -0.087 (p = 0.002) in the MIND and control diet arms, respectively. Levels of biomarkers reflecting neurodegeneration increase with age, and we showed that the greater increase was associated with lower cognitive scores. Among individuals with greater changes in biomarkers, MIND diet intervention attenuated the association with cognition, suggesting that the MIND diet may promote cognitive reserve in older adults.

Diet is a complex exposure that affects health across the lifespan. Objective biomarkers that can reliably reflect intake of nutrients, foods, and dietary patterns with sufficient accuracy are an important tool for assessing associations of diet with health outcomes. Advances in metabolomics, coupled with feeding trials and high-dimensional bioinformatics analyses, pave the way for discovering compounds that can serve as sensitive and specific biomarkers of dietary exposures. The Dietary Biomarkers Development Consortium (DBDC) is leading the first major effort to improve dietary assessment through the discovery and validation of biomarkers for foods commonly consumed in the United States diet. To achieve this goal, a 3-phase approach will be implemented to identify, evaluate, and validate food biomarkers. In phase 1, 3 controlled feeding trial designs will be implemented by administering test foods in prespecified amounts to healthy participants, followed by metabolomic profiling of blood and urine specimens collected during the feeding trials to identify candidate compounds. Data from these studies will characterize the pharmacokinetic parameters of candidate biomarkers associated with specific foods. In phase 2, the ability of candidate biomarkers to identify individuals eating the biomarker-associated foods will be evaluated using controlled feeding studies of various dietary patterns. In phase 3, the validity of candidate biomarkers to predict recent and habitual consumption of specific test foods will be evaluated in independent observational settings. Data generated during all study phases will be archived in a publicly accessible database as a resource for the research community. The DBDC aims to significantly expand the list of validated biomarkers of intake for foods consumed in the United States diet, which can help advance understanding of how diet influences human health. This manuscript discusses the DBDC’s organizational infrastructure, study design, laboratory methods, and strategies for dietary biomarker discovery and validation. Trial registration number: This trial was registered at Phase 1 Seattle Dietary Biomarkers Development Center (P1-SDBDC) as NCT05580653, at Fruit and Vegetable Biomarker Discovery (UCD-DBDC) as NCT05621863, and at Dietary Biomarkers Intervention Core as NCT05616585.

[This corrects the article DOI: 10.1016/j.cdnut.2025.107435.].

Background and Aims: Low-calorie weight loss diets with different macronutrient compositions have shown to result in clinically meaningful long-term weight loss. We aimed to identify plasma metabolites that significantly changed over two years in an intervention trial of low-calorie weight-loss diets with varying amounts of fats, carbohydrates, and proteins, and to investigate which changes in plasma metabolites are linked to better long-term weight loss. Materials and methods: The present study included participants who were randomly assigned to one of 4 diets in the POUNDS Lost trial. Untargeted plasma metabolomics was performed; changes in 856 metabolites across various metabolic pathways from baseline to the end of the two-year intervention were calculated in 533 participants. Results: We observed 571 metabolites (67%) showing statistically significant changes ( P- FDR < 0.05) following the two-year diet intervention (Figure panel a). We also identified core metabolites that significantly changed across all diet groups as well as specific metabolites that changed only in each of the 4 diet groups (panel b). Of the significantly modified metabolites by diets, 239 were significantly associated with 2-year weight changes, while others were not linked to weight loss (panel c). When stratifying by diet group, we identified 230 metabolites related to weight loss in response to one of the 4 diet interventions, including 22 metabolites within the lactoyl amino acid pathways, which showed the strongest sub-pathway associations with weight changes over two years in all diet groups. Conclusion: Our study identified core and specific metabolic pathways associated with changes in all or each of three macronutrients that contribute to better long-term weight loss.