INTRODUCTION:Multidomain lifestyle interventions have been demonstrated to benefit cognitive function but it is unknown whether they reduce risk for clinically significant cognitive impairment sCI (mild cognitive impairment or dementia). METHODS:The Action for Health in Diabetes administered repeated cognitive assessments in adults who had been enrolled in a 10-year clinical trial of a multidomain Intensive Lifestyle Intervention (ILI) versus Diabetes Support and Education (DSE). RESULTS:N = 3655 underwent at least one assessment of cognitive status during 12-14 years of post-trial follow-up. The relative impact of ILI on sCI incidence varied by baseline body mass index (BMI, interaction p = 0.004): hazard ratio (HR) = 0.64 [0.46,0.89] for BMI 25-29 kg/m2, HR = 0.98 [0.85,1.16] for BMI 30-39 kg/m2, and HR = 1.40 [1.01,1.93] for BMI ≥ 40 kg/m2. DISCUSSION:A long-term multidomain lifestyle intervention may markedly reduce the risk of incident sCI among adults with type 2 diabetes and overweight but not obesity.

INTRODUCTION:The Diabetes Prevention Program (DPP) was a randomized clinical trial designed to prevent type 2 diabetes (T2D) in adults with prediabetes. The DPP Outcomes Study (DPPOS) is the 30-year follow-up of this cohort, focusing on T2D, prediabetes, and related complications. Cognitive assessments began in 2009 and expanded in 2022 to examine cognitive impairment, including Alzheimer's disease (AD) and AD related dementias (ADRD), in the surviving cohort. To support these aims, the National Alzheimer's Coordinating Center Uniform Data Set version 3 (NACC-UDSv3), the standardized framework used by Alzheimer's Disease Research Centers, was implemented in DPPOS in 2022 to enable data sharing with NACC. These forms were complemented by cognitive tests administered in DPPOS. We aimed to integrate the NACC-UDSv3 into the existing longitudinal DPPOS framework while maintaining fidelity to its structure and developing automated reports to streamline cognitive outcomes adjudication. METHODS:Items from the 16 NACC-UDSv3 data forms were compared with those already collected within DPPOS to integrate overlapping similar items, add missing NACC-UDSv3 items, and create a dataset harmonized with NACC-UDSv3. Forms were adapted for electronic data capture (EDC) using the MIDAS (Multimodal Integrated Data Acquisition System, George Washington University). Automated reports integrated current and prior neuropsychological scores to support adjudications. In the first wave of the DPPOS-AD/ADRD study, 1561 cognitive adjudications were successfully completed using the harmonized DPPOS and NACC-UDSv3 data implemented into MIDAS. DISCUSSION:The DPPOS-AD/ADRD project demonstrated that NACC-UDSv3 can be successfully integrated into a long-standing longitudinal cohort not originally designed for AD/ADRD research. The harmonization, electronic capture, and automated adjudication processes may provide a practical framework for other cohorts seeking to incorporate NACC-UDSv3 to align with national AD/ADRD research standards.

Introduction and Objective: PA, a lifestyle target for preventing and treating T2D, may lower risk of CI. We examined longitudinal trajectories of PA and their association with CI in the Diabetes Prevention Program Outcomes Study (DPPOS). Methods: Participants (n=1,560) at high T2D risk randomized to lifestyle, metformin, or placebo (1996-1999) had ~3y of active intervention (DPP) and ~21y of unmasked follow-up (DPPOS). CI status was determined ~25y post-randomization using NACC-UDS (v3) criteria. PA (metabolic equivalent [MET] hours/week) was assessed using the Modifiable Activity Questionnaire at up to 15 visits. Linear mixed-effects models summarized PA during the study period (mean and slope). Multinomial logistic regression assessed associations between PA parameters and CI risk (Dementia, Mild CI [MCI] vs no CI). Results: At cognitive assessment, participants were ~74 years (IQR 68-80); 72% women, and 71% had T2D. Higher mean PA was associated with 19% decreased odds of dementia per additional 10 MET-h/wk (Table, global p=0.023). PA slope was not associated with CI. No significant heterogeneity was observed by diabetes status at time of assessment. Conclusion: Higher mean PA over 21 years was associated with decreased risk of dementia. In the context of prediabetes and T2D, these findings underscore PA throughout mid- to late-life as a critical modifiable protective factor for dementia. Disclosure A.H. Tjaden: None. J.P. Crandall: None. H.P. Hazuda: None. E.M. Venditti: None. Q. Pan: None. B. Laferrère: Consultant; Ended; Azurity. E.S. Strotmeyer: Research Support; Current; Amgen Inc. O. Carmichael: Research Support; Current; Eli Lilly and Company. D. Dabelea: None. E. Groessl: None. W. Knowler: None. N. Nadkarni: None. J.M. Noble: None. B. Rockette-Wagner: None. J.A. Luchsinger: Consultant; Current; Merck KGaA, Novo Nordisk. Other - Merck KGaA provides investigational product including matching placebo free of charge for an NIH funded clinical trial.; Current; Merck KGaA. P. Palta: None. D. Research Group: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) U01 DK048489, National Institute on Aging of the NIH 5 U19 AG078558.

Introduction and Objective: Whether metformin affects dementia risk is unclear. We examined the association of randomized metformin (MET) vs placebo (PBO) and Intensive Lifestyle (ILS) interventions in the Diabetes Prevention Program (DPP) with cognitive impairment (CI) in the DPP Outcomes Study (DPPOS). Methods: Participants (n=1483, mean age 74 ± 8.4) were evaluated for prevalent CI in 2022-2024. Randomization to MET, ILS or PBO (1996-1999) was followed by masked MET (1996-2002) and then open label MET in the original MET group until 2022. CI syndromes, using the National Alzheimer’s Coordinating Center Uniform Dataset version 3 forms, included (in order of severity) no CI, CI-not-Mild Cognitive Impairment (MCI), non-amnestic MCI (naMCI), amnestic MCI (aMCI), dementia. We examined the association of randomization to MET with CI syndromes using multinomial logistic regression. Results: MET exposure was 15.5 ± 7.7 person years in the MET group and after developing type 2 diabetes out-of-study MET was 4.5 ± 5.1 person years in PBO and 3.8 ± 4.8 person years in ILS groups. Randomization to MET was associated with 59-62% and 60% lower odds of dementia compared with PBO and ILS, respectively (Table). Conclusion: Long-term exposure to metformin may prevent dementia among persons with pre-diabetes and type 2 diabetes. Longer follow-up with more dementia cases is needed to confirm our finding. Disclosure P. Wander: None. L. Doherty: None. Q. Pan: None. O. Carmichael: Research Support; Current; Eli Lilly and Company. D. Dabelea: None. R.S. Turner: Research Support; Current; Lilly, Eisai Inc. Speaker's Bureau; Current; Lilly. Consultant; Current; Re:Cognition Health. S. Kuo: None. M. Munshi: Advisory Panel; Current; Abbott Diabetes. Research Support; Ended; Dexcom, Inc. A. Wallia: Research Support; Current; UnitedHealth Group. J.M. Noble: None. V. Shah: None. N. Nadkarni: None. S. Mudaliar: None. M. Temprosa: None. W. Knowler: None. J.A. Luchsinger: Consultant; Current; Merck KGaA, Novo Nordisk. Other - Merck KGaA provides investigational product including matching placebo free of charge for an NIH funded clinical trial.; Current; Merck KGaA. D. Research Group: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) (U01 DK048489), National Institute on Aging of the NIH (5 U19 AG078558).

Background Variability in vascular risk factor (VRF) levels in adulthood has been associated with higher dementia risk. Whether VRF variability from childhood influences midlife cognitive function (CF) is unclear. We aimed to evaluate the association of long-term VRF variability from childhood with midlife CF, independent of mean levels. Methods In this cohort study, participants in the Bogalusa Heart Study with ≥ 3 VRF (systolic blood pressure [SBP], fasting glucose, non-high-density lipoprotein cholesterol [non-HDL], and body mass index [BMI]) measurements from childhood and midlife CF assessment were included. VRF variability was measured using indices reflecting variability around the mean (SD, coefficient of variation [CV]) and around the age-adjusted slope (deviation from age-predicted values [DEV], residual SD [RSD]). CF was assessed using a global cognitive score (GCS) averaging eight standardized neuropsychological tests, and three cognitive domain performances. Associations between tertiles of VRF variability and CF were evaluated using multivariable linear regression with the lowest tertile as reference. Results Among 1,010 participants (mean age 48 years, 61% women, 34% Black, mean follow-up 39 years), being in highest tertiles of SBP and glucose variability were associated with poorer GCS (SBP by DEV: β = -0.10, 95% CI = -0.17, -0.02; glucose by CV: β = -0.12, 95% CI = -0.20, -0.04), after adjusting for covariates. Being in middle and highest tertiles of SBP variability (by DEV) and glucose variability (by SD, CV) were associated with poorer episodic memory and executive function, with effect sizes increasing across higher degrees of variability. Association between non-HDL variability and CF was non-linear: only being in the middle tertile was associated with poorer executive function (by CV, β = -0.12, 95% CI = -0.23, -0.01). Association between BMI variability and CF was bidirectional across degrees of variability: being in the middle tertile of variability was associated with better GCS (by CV, β = 0.09, 95% CI = 0.02, 0.16); whereas being in the highest tertile (by DEV) was associated with poorer executive function, although attenuated after adjusting for APOE ε4 status. Conclusions VRF variability from early life is a potential target for lowering risk of late-life cognitive dysfunction.

Importance:Metformin may influence risk of dementia, with prior conflicting observations of protection or harm. Objective:To determine the association of randomization to metformin vs. placebo or intensive lifestyle intervention (ILS) in the Diabetes Prevention Program (DPP) with cognitive outcomes (cognitive impairment syndromes and trajectories of cognitive test performance) during the DPP Outcomes Study (DPPOS). Design Setting & Participants:Prospective long-term follow-up of DPP/DPPOS participants at 27 U.S. centers among adults who were at high risk for type 2 diabetes (T2D) at baseline. Exposures:Randomization to metformin, placebo, or ILS (1996-1999) for 3.2 years followed by open-label metformin in the original randomized metformin group until 2021. Main Outcomes & Measures:Cognitive impairment syndromes were adjudicated in 2022- 2024 in 1,483 participants (median age 74 [IQR 68, 80]) using the National Alzheimer's Coordinating Center Uniform Dataset version 3. Cognitive performance in executive and memory domains was ascertained with repeated cognitive tests between 2009 and 2024. Multinomial logistic regression and mixed-effects models were fit to examine associations of randomization to metformin with cognitive outcomes. Results:Total metformin exposure (mean ± SD) was 15.5 ±7.7 years/person in the metformin group. Persons in the placebo and ILS groups received out-of-study metformin usually after developing diabetes with mean metformin total exposure of 4.5 ±5.1 and 3.8 ±4.8 years/person in the placebo and ILS groups, respectively. Overall, the frequency distributions of the cognitive syndromes did not differ significantly by treatment group; however, randomization to metformin was associated with a 60% (OR 0.40 [95%CI 0.17, 0.97]) and 62% (OR 0.38 [95%CI 0.16, 0.89]) lower odds of dementia compared with placebo and ILS, respectively, after adjustment for demographics, education, income, and APOE-ε4 genotype. Randomization to metformin was also associated with significantly better memory performance over time (β=0.58; 95%CI: 0.09, 1.1; p=0.02; Cohen's d=0.1). Conclusions and Relevance:Long-term metformin treatment is associated with a reduced risk of dementia and better memory performance among persons with pre-diabetes or T2D. Estimates were imprecise due to a limited number of dementia cases. Longer follow-up with more dementia cases is needed to confirm our findings. KEY POINTS:Question: Is chronic metformin treatment related to the risk of dementia and cognitive impairment?Findings: Randomization to metformin in the Diabetes Prevention Program was associated with a lower risk of dementia in the Diabetes Prevention Program Outcomes Study compared with the randomization to placebo or randomization to intensive lifestyle intervention, but the overall distribution of cognitive impairment syndromes did not differ significantly by treatment group. Randomization to metformin was also related to modestly better longitudinal performance in a memory test.Meaning: Chronic metformin treatment may decrease the risk of dementia.

OBJECTIVES:The NIH Toolbox Cognition Battery (NIHTB-CB) has shown promising results in older adult populations, though more research is needed to examine its relationship with important clinical outcomes (i.e. everyday function, depression). Particularly, additional research on potential disparities in self vs. informant reports in these outcomes is of importance. The aim of the present study was to examine the NIHTB-CB's relationship with both self and informant-reported everyday functioning and depression in older adults. METHOD:Forty-three cognitively healthy older adults completed the NIHTB-CB. Participants and their informants completed questionnaires related to the participants' everyday functioning (Everyday Cognition Scale; ECog) and depression (Geriatric Depression Scale-30; GDS-30). Correlation between NIHTB-CB, ECog, and GDS-30 was conducted. Then, simultaneous regression analyses of total ECog controlling for GDS-30 and significant NIHTB-CB scores identified in the prior aim were conducted. RESULTS:Worse performance on NIHTB-CB tests of processing speed, working memory (WM), inhibitory control, and conceptual flexibility (CF) were all related to worse self-reported everyday functioning and greater depression (all p < 0.05). Further, associations between WM and CF remained significantly associated with worse everyday functioning even after accounting for self-reported depression. While NIHTB-CB episodic memory was associated with informant-rated participant depression, there was no association of any NIHTB-CB measures with informant-rated everyday functioning. CONCLUSION:The NIHTB-CB is associated with functional changes in cognitively healthy older adults and may be useful in early identification of risk for a pathological cognitive aging trajectory. Further exploration of informant-reported participant depression in cognitive aging is warranted.

Skeletal muscle is a crucial facilitator of many of the effects of exercise on metabolic health. Intrinsic myocellular mechanisms, exercise-induced myokine secretion, and crosstalk between multiple organ systems contribute to the maintenance of energy homeostasis, cardiovascular health, strength, cognition, and quality of life. Investigating the molecular underpinnings of the skeletal muscle response to exercise from multiple perspectives, including the genetic, physiological, and environmental factors leading to metabolic dysfunction, has advanced our understanding of disease risk and helped identify avenues for the prevention and treatment of metabolic disorders and chronic diseases. The National Institutes of Health-funded Boston Area Nutrition Obesity Research Center, in partnership with the Harvard Medical School Division of Nutrition, hosted its 26th Annual Symposium, Muscle Movement and Metabolism: Exercise and Skeletal Muscle as Mediators of Health," in June of 2025. Speakers presented novel research and unique perspectives on exercise and skeletal muscle as key determinants of health. This manuscript synthesizes the symposium's major themes: 1) physiological and molecular mechanisms of exercise, 2) clinical implications of physical inactivity and reduced muscle function, and 3) individual variability and personalized medicine. By bridging mechanistic and clinical insights with principles of personalized medicine, the symposium provided key insights into the current landscape of treatments for metabolic diseases and evidence-based strategies for disease prevention.

Chronic psychological stress has been implicated as a risk factor for Alzheimer’s disease (AD), potentially through cortisol-mediated acceleration of disease progression. However, the molecular pathways underlying this relationship remain poorly understood. Epigenetic regulation of the glucocorticoid and mineralocorticoid receptor genes (NR3C1 and NR3C2), which encode receptors for cortisol, may play an important role, but has not been examined in relation to AD progression. Therefore, this study investigated associations between DNA methylation of NR3C1/NR3C2 and AD-related phenotypes, including cognition, brain amyloid-β (Aβ) burden, and regional brain volumes. These associations were examined in two independent cohorts of cognitively unimpaired individuals with accumulating brain Aβ (n = 89–298 across outcomes) using linear regression and meta-analyses. The study also explored whether DNA methylation within NR3C1 and NR3C2 interacted with depression symptoms to influence relationships with AD-related phenotypes. While only nominal associations were observed in direct analyses, stronger associations emerged in interaction with depressive symptoms. Interaction analyses showed that relationships between DNA methylation and AD-related phenotypes (cognition, hippocampal volume and ventricular expansion) differed depending on the presence of depression symptoms. Consistent patterns across cohorts were observed, with associations primarily evident among individuals with clinically relevant depressive symptoms. One site (NR3C1 cg24052866) was associated with cognitive decline, one (NR3C1 cg08845721) with cross-sectional hippocampal volume, and eight (NR3C1 cg21979215, cg16594263; NR3C2 cg27460943, cg17253842, cg04867484, cg10993059, cg25672354, cg27234800) with ventricular expansion. These exploratory findings suggest epigenetic variation within cortisol receptor genes may influence AD-related neurodegeneration in a depression-dependent manner.

Introduction and Objective: T2D is a risk factor for CI. However, the role of glycemia changes over time in CI risk remains unclear. We investigated longitudinal glycemia trajectories in relation to CI among people living with pre-diabetes or T2D in DPPOS. Methods: Among 1,682 middle-aged adults with pre-diabetes at enrollment (median [IQR]; age 49 [43,53]) we investigated the association of HbA1c trajectory over 20 years of follow-up with prevalent CI assessed via the National Alzheimer’s Coordinating Center Uniform Data Set (v3) 25 years after enrollment. HbA1c trajectories were characterized from a random effects model as intercept (mean HbA1c over time) and slope (rate of HbA1c change over time). CI categories were dementia (n=48), amnestic mild cognitive impairment (aMCI; n=137), non-amnestic MCI (naMCI; n=136), CI-not-MCI (n=189), and no CI (reference; n=973). Multinomial logistic models sequentially added a priori covariates for demographics (DPP randomization group, age, sex, education, income, race and ethnicity), cardiovascular risk factors (smoking status, HDL, LDL, systolic blood pressure[SBP]), and APOE genotype. Results: Independent of demographics, higher mean HbA1c was associated with higher risk for aMCI (OR=1.77 [95% CL: 1.06, 2.97; p=0.03]). However, in sequentially adjusted models, HbA1c parameters were not associated with risk for CI. In the fully adjusted model, older age, male sex, Black race and Hispanic ethnicity, higher SBP, and APOE copy number were associated with higher risk for CI (p<0.05, for all). Conclusion: In the context of pre-diabetes and T2D, glycemia trajectory may not confer risk for CI that is independent of established demographic, genetic, and cardiovascular risk factors. The findings emphasize the importance of managing of multi-faceted cardiometabolic risks for CI and understanding high-CI-risk groups in the setting of pre-diabetes and T2D. Disclosure A. Shapiro: None. R. Shu: None. M. Temprosa: None. D. Dabelea: None. S. Kahn: Advisory Panel; Current; AltPep, Amgen Inc., Congruence Therapeutics, Eli Lilly and Company, General Medicines, Kayothera, Merck & Co., Inc., Neurimmune, Novo Nordisk, Roche Pharmaceuticals. V. Shah: None. W. Knowler: None. B. Laferrère: Consultant; Ended; Azurity. J.A. Luchsinger: Consultant; Current; Merck KGaA, Novo Nordisk. Other - Merck KGaA provides investigational product including matching placebo free of charge for an NIH funded clinical trial.; Current; Merck KGaA. S. Aleksic: Stock/Shareholder; Current; Novo Nordisk, Lilly. S. Kuo: None. W. Hsueh: None. O. Carmichael: Research Support; Current; Eli Lilly and Company. D. Research Group: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) (U01 DK048489), National Institute on Aging of the NIH (5 U19 AG078558)

White matter microstructural changes play a crucial role in cognitive decline in aging and neurodegenerative disorders including Alzheimer’s disease (AD). However, the processes underlying white matter microstructural changes and the molecular pathways leading to these changes in AD remain largely unknown. AD involves cortical and juxtacortical microstructural changes, with free water fraction (FWF) as a potential imaging marker. We measured FWF using diffusion magnetic resonance imaging in 68 juxtacortical regions of 153 cognitively normal controls and 194 patients with AD as evidenced by elevated amyloid PET. We estimated the expression of 15,633 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. The biological processes and cell types associated with the linked genes were evaluated. Mediation analysis was used to examine whether FWF mediates the association between APOE ε4 status and cognitive performance. Gene ontological analyses revealed that these genes were enriched for biological processes relating to lipid metabolic process, ensheathment of neurons, and synaptic signaling and were predominantly expressed in oligodendrocytes, GABAergic neurons, and pyramidal neurons from the hippocampus CA region. These ontological enrichment results were replicated in two additional datasets. Furthermore, mediation analyses revealed a domain-specific role of FWF in the association between APOE ε4 status and cognitive performance. Our findings provide mechanistic insights into regional juxtacortical microstructural changes in AD, particularly the processes involving lipid metabolism, offering potential therapeutic targets.

Although mounting evidence supports that neighborhood greenspaces (e.g., trees and parks) may benefit cognitive health in older age, fewer studies have investigated benefits to brain health measured via magnetic resonance imaging (MRI). We used data on 892 older adults without dementia from three Alzheimer's Disease Research Centers, examining whether neighborhood greenspace (i.e., greenness and percentage park space) is associated with white matter hyperintensity (WMH) and hippocampal volumes from MRI. We also examined whether associations varied by sex, racial group, urbanicity, or apolipoprotein E genotype (genetic risk factor for Alzheimer's disease). Linear regression models that accounted for neighborhood clustering controlled for demographics, research center, cognitive function, neighborhood deprivation, and comorbidities (e.g., hypertension, diabetes, obesity). Interaction terms (e.g., greenness×sex) were added to the models to evaluate potential effect modification. Living in greener neighborhoods was associated with fewer WMH and greater hippocampal volume in the overall sample. In stratified analyses, the beneficial greenness-WMH association was restricted to Black (not White) participants (i.e., significant interaction). In contrast, an adverse association between park space and lower hippocampal volumes was detected among Black (not White) participants (i.e., significant interaction). Overall, this study suggests associations between living in neighborhoods with more greenspace and MRI biomarkers of lower cerebrovascular and dementia risk, although results were mixed for Black individuals. Our findings need replication in other cohorts that are ethnoracially diverse and that represent different geographic regions, and future studies are needed explain the counterintuitive associations between park space and hippocampal volume among Black older adults.

Context: Obesity is a driver of cardiometabolic (CM) disease and previous studies have suggested a relationship between obesity measures and structural brain health and cognition. However, most studies focused solely on BMI. Here we evaluate 2023 Lancet Commission obesity classifications, which include abnormal CM physiology, and MRI markers of brain integrity. Objective: To examine associations between obesity status across early-to-mid adulthood, using Lancet Commission obesity classifications, and midlife MRI markers of brain integrity in the Bogalusa Heart Study (BHS). Design, Setting, and Participants: The BHS is a longitudinal study which began in childhood and followed black and white boys and girls in Bogalusa, Louisiana, for >50 years into midlife. Participants underwent repeated CM phenotyping between 1985–2010. Six examinations during young adulthood to midlife had all information necessary for the analysis. Brain MRI was obtained on n=283 participants between 2016–2024 to quantify white matter hyperintensity (WMH) and gray to total matter volume (GMV/TV). Longitudinal analyses included 283 participants. Analyses on specific examinations included 144 to 212 participants. Main Outcomes and Measures: Participants were classified as Non-Obese, Preclinically Obese, or Clinically Obese at each examination, per LancetCommission obesity guidelines. WMH and GMV/TV were compared across groups. Using Kruskal–Wallis tests followed by Dunn’s post hoc comparisons (Bonferroni adjusted), Hodges–Lehmann estimators, RT-ANCOVA followed by Holms post hoc test (to adjust for covariates), Results: Mean (SD) age at initial young adult examinations was 23.3 (2.2) years and 42.7 (4.3) during the last exam prior to MRI . Mean (SD) age at MRI was 57.4 (4.6) yrs. Participants who were clinically obese (n=184) at any time in their young adult years had significantly higher WMH volume in midlife compared to participants who were non-obese (n = 92) during the entirety of that same period (Bonferroni adjusted p = 0.0022; HL difference = 0.076 mL, 95% CI: 0.027–0.14, Holmes p= 0.0415). Conclusions: Having clinical obesity, as defined by the 2023 Lancet Commission, at any point in in young adulthood was significantly associated with greater WMH burden in midlife compared with non-obese individuals. These findings suggest that excess adiposity when paired with abnormal CM physiology may have long-term consequences for brain health and cognition.

Importance Blood-based biomarkers (BBMs) are clinically available to aid in the diagnosis of Alzheimer disease (AD) and AD-related dementias (ADRD), but their association with cognition among older adults with specific chronic conditions has not been examined. Objective To longitudinally examine associations between baseline AD and ADRD BBMs and change in BBMs with cognition among participants with type 2 diabetes (T2D) and overweight or obesity. Design, Setting, and Participants The Look AHEAD (Action for Health in Diabetes) study was a clinical trial of older adults with T2D and overweight or obesity randomized to a 10-year intensive lifestyle intervention for weight loss or a diabetes support and education condition. Participants were recruited and followed up at 16 clinical sites across the US. Enrollment occurred from January 1, 2001, to December 31, 2004. The primary intervention spanned the first 4 years after participants’ enrollment (January 1, 2008, to December 31, 2011). The clinical trial was stopped in September 2012 and was converted to an observational study. Blood samples were drawn at baseline and 8 to 12 years later. Cognitive assessments were performed from January 1, 2013, to December 31, 2014, and from January 1, 2018, to December 31, 2020. Data for the present cohort study were analyzed between January and August 2024. Exposures Baseline and 8- to 12-year change in plasma levels of amyloid-β (Aβ) 40 , Aβ 42 , Aβ 42/40 ratio, phosphorylated tau 181 (pTau-181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Main Outcomes and Measures Cognitive composite z score and adjudicated mild cognitive impairment or probable dementia. Results The mean (SD) baseline age of 758 participants was 61.5 (6.1) years, and 424 participants [55.9%] were female. Mean (SD) body mass index was 34.8 (5.3). Of the participants, 373 were randomized to diabetes support and education and 385 to intensive lifestyle intervention. Increasing baseline BBM levels were not associated with any cognitive composite z score. Increasing levels of NfL (β = −0.032 [SE, 0.013]; P = .01) and GFAP (β = −0.087 [SE, 0.025]; P < .001), but not the Aβ 42/40 ratio (β = 0.006 [SE, 0.040]; P = .88) or pTau-181 (β = 0.026 [SE, 0.025]; P = .31), were associated with worsening cognitive function and incident mild cognitive impairment or probable dementia. The intervention had no association with 8- to 12-year change in BBM levels. Conclusions and Relevance In this study of participants with T2D and overweight or obesity, increasing plasma NfL and GFAP levels over time, but not Aβ 42/40 or pTau-181 levels, were associated with cognitive decline and incident cognitive impairment. These results suggest that plasma NfL and GFAP may be important biomarkers of cognitive change among this patient population.

Introduction: The excess childhood burden of cardiovascular risk factors (CVRFs) is linked to poorer midlife cognitive performance, independent of adult exposure. Despite the importance of life-course approaches to dementia prevention, childhood data remains limited in cognitive studies. Moreover, the impact of childhood CVRFs on metabolomics profiles is unclear. Hypothesis: This study aimed to identify metabolomics signatures of cumulative childhood CVRF burden and examine their associations with midlife cognitive function. Methods: The study included 1,204 participants from the Bogalusa Heart Study with untargeted serum metabolomics profiled in midlife and data to estimate cumulative childhood (ages 4-17) burden of CVRFs, including BMI, systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), and glucose (calculated as the area under the curve, AUC). Metabolomics signatures for each childhood CVRF AUC were constructed using elastic net regression. Global cognition and three cognition domains (i.e., attention and processing speed, verbal memory, and working memory and language) were assessed. Education was approximated using a language index. Results: Among BHS participants with a mean age of 48.1 years at the time of cognitive testing, higher AUCs for childhood BMI and LDL-C were significantly or nominally associated with poorer attention and processing speed (BMI AUC: β = -0.01, p = 0.04; LDL-C AUC: β = -0.003, p = 0.05) and global cognition (LDL-C AUC: β = -0.001, p = 0.09), after adjusting for demographics, education and lifestyle factors, consistent with previous studies. Metabolomic signatures of childhood BMI, SBP, LDL-C, TGs, and glucose showed strong associations, explaining 15%, 1%, 12%, 23%, and 38% of the variance in AUCs in the testing dataset, respectively (p < 0.001, except for childhood SBP AUC signature: p = 0.04). Metabolomics signatures of higher childhood burdens of BMI and LDL-C predicted worse attention and processing (BMI: β = -0.06, p = 0.001; LDL-C: β = -0.007, p = 0.02) and global cognition (LDL-C: β = -0.007, p = 0.01). Markedly, the association between the BMI signature and attention remained significant (β = -0.07, p < 0.001) after adjusting for midlife CVRFs. Conclusion: Metabolomics signatures of childhood BMI and LDL-C burdens are associated with poorer midlife cognition, independent of traditional risk factors in midlife, and may serve as useful surrogates for childhood burdens of CVRFs.

Background: Plasma proteins associated with Alzheimer’s disease (AD) include β-amyloid-42 (Aβ 42 ), phosphorylated -tau at threonine-181 (p-tau 181 ), and neurofilament light chain (NfL). This study assessed the relationship between these biomarkers and digital neuropsychological test performance. Methods: Middle-aged participants in the DECADE study had blood drawn and completed the Rowan Digital Cancellation Test (RDCT) consisting of 64 targets embedded among foils. Within 90 seconds, participants circled as many targets as possible, alternating between letters and symbols. RDCT outcomes included correct targets; ‘think’ time between correct targets; ‘ink’ time to circle correct targets; total pen strokes; commission errors; and total pen stroke distance and were summarized using factor analysis. Their association with AD biomarkers was done using linear regression. Results: The first 77 participants (age=55.3±8.7; 81.6% female) were included, with serum Aβ 42 (mean±SD: 7.8 + 2.7 pg/ml), p-Tau 181 (17.2 + 11.1 pg/ml), and NfL (10.5 + 13.8 pg/ml) assessed. Factor analysis identified 2 factors (Table). Higher scores on Factor 1 (49.2% variance) correspond to fewer correct responses, more think time, commission errors, and pen strokes. Higher scores on Factor 2 (27.9% variance) correspond to more correct responses, fewer commission errors, ink time, and pen strokes. Adjusting for age, sex, education, and both RDCT factor scores, NfL was negatively associated with Factor 2 (R 2 = 0.176, β= -0.445[JW1] , SE=2.57; p< 0.01 ) suggesting worse RDCT test performance with increasing biomarker level. In contrast, Aβ42 was positively associated with Factor 1 (R 2 =0.268, β= 0.503, SE= p< 0.003. Analyses involving p-Tau 181 were not significant. Conclusion: In this community-dwelling, middle-aged sample, plasma levels of AD-related proteins are associated with digital measures of neurocognitive performance. Middle-age assessment of serum AD-related proteins and digital neuropsychological performance have the potential to help identify emergent neurodegenerative illness.

Introduction: Compartment model analysis of diffusion MRI data provides unique information on the microstructural properties of white matter. However, studies relating compartment model microstructural measures to longitudinal cardiometabolic health data are rare. Methods: 130 cognitively healthy participants in the Bogalusa Heart Study completed diffusion MRI scans. Compartment model analysis was performed, and summary metrics were measured in organized and diffuse white matter. Multiple linear regression models were used to relate the white matter microstructure metrics to demographics and cardiometabolic risk factors. Results: In both organized and diffuse white matter, age was associated with worse diffusion metrics, women had better diffusion metrics than men, and African American participants had worse diffusion metrics compared to White participants. Greater blood pressure in pre-adulthood was associated with worse diffusion metrics in midlife. Discussion: Summary metrics from compartment model analyses of diffusion MRI data were associated cardiometabolic risk factors from youth to midlife as well as demographic factors.