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Objective: Subclinical vascular brain injury is an increasingly recognized risk factor for stroke and dementia. Despite well-established sex differences in vascular risk and disease prevalence, the impact of sex on drivers of subclinical vascular brain injury remains unclear, presenting a barrier to developing sex-specific prevention guidelines. We aimed to establish the extent to which sex moderates associations between vascular risk factors and magnetic resonance imaging (MRI) measures of subclinical brain injury in stroke-free older adults., Methods: We leveraged cross-sectional data from 1,579 stroke- and dementia-free Framingham Heart Study Offspring participants at exam 8 (age 65.7 ± 8.8 years, 53% women). Vascular risks were assessed using components of the Framingham Stroke Risk Profile (FSRP) and diastolic blood pressure (DBP). White matter hyperintensity volume (WMH), total cerebral brain volume (TBV), and covert brain infarcts were quantified using MRI. We examined whether vascular risk factors were associated with MRI measures across the combined cohort, and then determined whether sex modified these associations., Results: Higher FSRP and specifically systolic blood pressure (SBP) were associated with greater WMH. These associations were stronger in women and remained after adjusting for menopause age and hormone therapy use. By contrast, diabetes and lower DBP were associated with smaller TBV primarily in men. The DBP-atrophy relationship was only observed in men with declining DBP or prior hypertension., Interpretation: Our findings highlight differential vulnerability to the impact of vascular risk factors on white matter health in women and global atrophy in men, supporting the development of sex-specific guidelines to better preserve vascular brain health in aging. ANN NEUROL 2025;97:460-469., (© 2024 American Neurological Association.)

Background: Ultra-processed food consumption is emerging as a risk factor for various cardiometabolic diseases, however its association with dementia and Alzheimer's disease has rarely been explored., Objectives: We sought to examine whether ultra-processed food consumption is associated with risk of all-cause dementia and Alzheimer's disease among middle-age and older adults., Design: A prospective cohort study., Setting: The Framingham Heart Study, a single-site, community-based cohort study., Participants: Offspring cohort participants who attended examination cycles 5 (1991-1995) and 7 (1998-2001) at age ≥60 years and who were dementia-free at baseline., Measurements: Nutritional information was retrieved from food frequency questionnaires, and ultra-processed food was categorized based on the NOVA system. Participants were followed-up for all-cause dementia and Alzheimer's disease. Cox regression models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) adjusting for potential confounders., Results: The study sample included 1,375 participants free of dementia and stroke at baseline (mean age 68 ± 6y, 54 % females). During a mean follow-up of 12.7 ± 6.0 years, 224 and 172 individuals were diagnosed with all-cause dementia and Alzheimer's disease, respectively. An interaction of ultra-processed food consumption with age was observed with regard to dementia and Alzheimer's disease (p for interaction = 0.02 and 0.007, respectively). Therefore, all analyses were stratified by the median age of 68 years. Among participants who were <68 years of age at baseline, each serving per day of ultra-processed food was associated with 13 % increased risk for Alzheimer's disease (HR = 1.13, 95 % CI:1.03-1.25), and consumption of ≥10 servings/day vs. <10 servings/day of ultra-processed food was associated with a 2.7-fold increase in Alzheimer's disease risk (HR = 2.71, 95 % CI:1.18-6.24), after adjustment for age, sex, education, total energy, metabolic factors and diet quality. The associations with all-cause dementia were less robust, and no significant findings were observed when age at baseline was 68 years or above., Conclusions: Our findings suggest that consumption of ultra-processed food in middle-age may be linked with an increased risk for Alzheimer's disease. Future clinical studies are warranted to assess whether reduction of ultra-processed food consumption improves brain health., Competing Interests: Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2024. Published by Elsevier Masson SAS.)

Aim: The current study aims to investigate the association of serum brain-derived neurotrophic factor (BDNF) levels with symptoms of depression in adults with and without prevalent cardiovascular disease (CVD), an often burdensome comorbidity., Methods: This cross-sectional study included participants from FHS (Framingham Heart Study) who had available serum BDNF levels. Depressive symptoms were assessed using the Center for Epidemiological Studies-Depression Scale (CES-D) with a score ≥16 indicating mild to moderate and ≥21 severe depression. Participants taking antidepressant medications were excluded from the study., Results: Altogether 3716 FHS participants were included in the final analysis (mean age, 64.3 ± 11.5 years; 55% women). After adjusting for potential confounders, greater BDNF levels were associated with reduced severe depression risk (odds ratio [OR], 0.78 [95% CI, 0.64-0.96]; P = 0.016). Among participants with CVD, greater BDNF levels were related to lower risk of depressive symptoms (CES-D ≥ 16 OR, 0.63 [95% CI, 0.45-0.89], P = 0.008; CES-D ≥ 21 OR, 0.49 [95% CI, 0.31-0.76], P = 0.002). The inverse relationship between BDNF and depressive symptom risk was present in women with CVD (CES-D ≥ 16 OR, 0.63 [95% CI, 0.40-0.99], P = 0.047; CES-D ≥ 21 OR, 0.38 [95% CI, 0.21-0.70], P = 0.002) but not in men., Conclusion: Lower serum BDNF levels are associated with a higher risk of depressive symptoms in CVD, particularly among women. These findings implicate BDNF in the complex biological mechanisms that underlie prior associations observed between CVD and depression. To reduce the burden of depression in the large proportion of midlife and older adults with CVD, a better understanding of how BDNF may modify these pathways is merited., (© 2024 The Authors. Psychiatry and Clinical Neurosciences © 2024 Japanese Society of Psychiatry and Neurology.)

Importance: Human brain development and maintenance is under both genetic and environmental influences that likely affect later-life dementia risk., Objective: To examine environmental influences by testing whether time-dependent secular differences occurred in cranial and brain volumes and cortical thickness over birth decades spanning 1930 to 1970., Design, Setting, and Participants: This cross-sectional study used data from the community-based Framingham Heart Study cohort for participants born in the decades 1930 to 1970. Participants did not have dementia or history of stroke and had magnetic resonance imaging (MRI) obtained from March 18, 1999, to November 15, 2019. The final analysis dataset was created in October 2023., Exposure: Years of birth ranging from 1925 to 1968., Main Measures: Cross-sectional analysis of intracranial, cortical gray matter, white matter, and hippocampal volumes as well as cortical surface area and cortical thickness. The secular measure was the decade in which the participant was born. Covariates included age at MRI and sex., Results: The main study cohort consisted of 3226 participants with a mean (SD) age of 57.7 (7.8) years at the time of their MRI. A total of 1706 participants were female (53%) and 1520 (47%) were male. The birth decades ranged from the 1930s to 1970s. Significant trends for larger intracranial, hippocampal, and white matter volumes and cortical surface area were associated with progressive birth decades. Comparing the 1930s birth decade to the 1970s accounted for a 6.6% greater volume (1234 mL; 95% CI, 1220-1248, vs 1321 mL; 95% CI, 1301-1341) for ICV, 7.7% greater volume (441.9 mL; 95% CI, 435.2-448.5, vs 476.3 mL; 95% CI, 467.0-485.7) for white matter, 5.7% greater value (6.51 mL; 95% CI, 6.42-6.60, vs 6.89 mL; 95% CI, 6.77-7.02) for hippocampal volume, and a 14.9% greater value (1933 cm2; 95% CI, 1908-1959, vs 2222 cm2; 95% CI, 2186-2259) for cortical surface area. Repeat analysis applied to a subgroup of 1145 individuals of similar age range born in the 1940s (mean [SD] age, 60.0 [2.8] years) and 1950s (mean [SD] age, 59.0 [2.8] years) resulted in similar findings., Conclusion and Relevance: In this study, secular trends for larger brain volumes suggested improved brain development among individuals born between 1930 and 1970. Early life environmental influences may explain these results and contribute to the declining dementia incidence previously reported in the Framingham Heart Study cohort.

Background: Higher midlife physical activity engagement has been associated with lower dementia risk in late life. However, the underlying mechanisms contributing to the protective effect remain unclear., Objective: The goal of the current study was to evaluate the associations of physical activity with cerebral amyloid-β (Aβ) and tau in a predominately middle-aged community-based cohort, as well as to explore whether the associations differ by sex or age., Methods: Participants from the Framingham Heart Study underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Total physical activity levels were evaluated by self-report using the Physical Activity Index (PAI). Cross-sectional associations between total PAI with regional Aβ and tau PET retention were evaluated using linear regression models adjusted for demographic and cardiovascular risk factors. Interactions with sex and age group were examined and stratified analyses were performed when significant. FDR-correction for multiple comparisons was applied., Results: The sample included 354 participants (mean age 53±8 years, 51% female). Higher total PAI scores were associated with lower entorhinal cortex tau PET binding (β (SE) = -0.021(0.008), p = 0.049). There were significant interactions with sex. In men alone, total PAI inversely associated with entorhinal cortex (β (SE) = -0.035(0.009), p = 0.001), inferior temporal (β (SE) = -0.029(0.010), p = 0.012), and rhinal cortex tau(β (SE) = -0.033(0.010), p = 0.002)., Conclusions: The results suggest that higher midlife physical activity engagement may confer resistance to tau pathology. However, the effects may vary based on sex, highlighting the importance of better understanding and tailoring lifestyle interventions to address sex disparities.

Background Recent data suggest that dementia incidence is declining. We investigated whether similar secular trends consisting of increasing size of brain structures and improving memory performance could be simultaneously occurring as a possible explanation. Method The Framingham Heart Study is a 3 generation, longitudinal study that includes cognitive assessment and medical surveillance. This study cohort consisted of 4,506 unique, non-demented, stroke free, individuals with brain MRI, cognitive assessment, and demographic information spanning dates of birth from 1902 to 1985. Outcomes consisted of height, MRI, and memory measures. Covariates included age at MRI, sex, decade of birth, and all interactions. Models with neuropsychological outcomes also included educational achievement as a covariate. Results Height and intracranial (TCV), hippocampus and cortical gray matter volumes were significantly larger, and memory performance significantly better, with advancing decades of birth after adjusting for age, sex, and interactions. Sensitivity analysis using progressively restricted age-ranges to reduce the association between age and decade of birth, confirmed the findings. Mediation analysis showed that hippocampal volume mediated approximately 5-7% of the effect of decade of birth on logical memory performance. Discussion These findings indicate improvement in brain health and memory performance with advancing decades of birth. Although brain structures are under substantial genetic influence, we conclude that improved early life environmental influences over ensuing decades likely explain these results. We hypothesize that these secular improvements are consistent with declining dementia incidence in this cohort potentially through a mechanism of increased brain reserve.