Treatment resistant obesity among midlife women receiving care from a specialized weight management clinic

Midlife obesity is a major risk factor for vascular cognitive impairment (VCI) and dementia, but the cellular mechanisms linking obesity to brain microvascular dysfunction remain unclear. Here, we show that high-fat diet (HFD)-induced obesity accelerates cellular senescence within the neurovascular unit (NVU), resulting in structural and functional microcirculatory deficits. Combining multimodal in vivo longitudinal imaging with single-cell RNA sequencing, we identify a senescence-associated transcriptional program in endothelial cells and neurons, coinciding with reduced brain microvascular density, impaired neurovascular coupling (NVC), and disruption of blood-brain barrier (BBB) integrity. These vascular abnormalities associate with cognitive decline in behavioral assays. Transcriptomic profiling further revealed cell-type-specific senescence signatures, including dysregulation of angiogenic, mitochondrial, and inflammatory pathways, which were alleviated by senescent-cell clearance. Notably, clearing p16+ senescent cells partially restored BBB integrity, improved NVC responses, and reduced neuroinflammation. Together, these findings identify cellular senescence as a mechanistic driver of midlife obesity-induced cerebrovascular and cognitive dysfunction and provide proof-of-concept that senescence-targeted therapies may preserve brain health in individuals with midlife obesity who are at risk for dementia.

The parallel rise in obesity and neurological disorders suggests a potential mechanistic link between these two conditions. Midlife obesity is a well-established risk factor for cognitive decline and neurological disorders; however, the underlying mechanisms and cause-and-effect relationship remain poorly defined, in part owing to limited spatiotemporal resolution in existing studies and the absence of a unifying framework. Recent studies have begun to uncover pathways linking obesity to neurodegenerative vulnerability. First, we discuss how obesity induces brain-wide reprogramming across neural, metabolic and vascular systems including neurovascular coupling, blood-brain barrier integrity, cerebrospinal fluid dynamics and myelination. By systematically examining the disparate mechanisms for each condition, a more cohesive picture emerges, revealing progressive neurodegeneration driven by chronic metabolic overload. Lastly, we propose a framework that integrates these different mechanisms with both spatial and temporal specificity.

To determine population attributable fractions (PAFs) of modifiable dementia risk factors by income, and independent and interactive associations of race-ethnicity and income with each risk factor and cumulative number of midlife risk factors. This nationally representative cross-sectional study of the 1999-2008, 2011-2014, and primarily the 2015-2018 National Health and Nutrition Examination Surveys comprised of individuals aged 18-44, 45-64, and 65+ years for early-life, midlife, and late-life analyses, respectively. Income was operationalized using the poverty-income ratio. The primary outcomes were PAFs and prevalence ratios (PR) of the 13 individual-level dementia risk factors and cumulative number of midlife risk factors. There were 13,145 individuals with risk factor data between 2015 and 2018 (51.1% aged 18-44, 31.0% aged 45-64, and 17.9% aged ≥65 years; 51.5% female after survey-weighting). Higher income was associated with lower prevalence of each dementia risk factor except obesity, high LDL, and TBI. The highest PAF for those with incomes <100% of the federal poverty level was late-life vision loss (20.9%, 95% CI 16.8%-25.2%). Higher income was associated with lower number of midlife risk factors (PR: 0.91, 95% CI 0.89-0.94). Race-ethnicity categories historically-underrepresented in dementia studies were associated with midlife diabetes, obesity, physical inactivity, and late-life vision loss. Lower income and historically underrepresented race-ethnicity categories are associated with many dementia risk factors. Dementia prevention efforts may be more successful by targeting modifiable risk factors in these higher-risk populations.

Midlife obesity is a known risk factor for cognitive impairment, whereas its association in late life is complex, giving rise to the concept of the 'obesity paradox.' The weight-adjusted waist index (WWI), an indicator reflecting central obesity, has recently emerged. However, evidence regarding the association between WWI and cognitive impairment in Chinese older adults remains scarce. This study explores WWI's association with cognitive decline in older adults, addressing gaps in central obesity's role in neurocognitive health. A total of 5001 older adults aged ≥65 years with normal cognition from the Chinese Longitudinal Healthy Longevity Survey were included in this longitudinal analysis, with a median follow-up duration of 4 years. A time-varying Cox proportional hazards regression model was used to evaluate the association between WWI, waist circumference (WC), body mass index (BMI) and incident cognitive impairment. Nonlinear correlations were investigated using restricted-cubic-spline curves. Subgroup analyses and sensitivity analyses were conducted to enhance the robustness of findings. The incidence of cognitive impairment across the four WWI quartile groups (Q1-Q4) was 6.7%, 7.8%, 9.3% and 13.4%, respectively. WWI was positively associated with incident cognitive impairment, whether treated as a continuous variable (hazard ratio [HR] = 1.14, 95% confidence interval [95% CI] = 1.06-1.23) or a categorised variable (Q4 vs. Q1: HR = 1.70, 95% CI = 1.29-2.24; Q3 vs. Q1: HR = 1.43, 95% CI = 1.08-1.90) in models adjusted for multiple covariates. WC showed a similar trend, while BMI demonstrated no significant association. Associations persisted across subgroups and sensitivity analyses. Elevated WWI and WC, but not BMI, were significantly associated with an increased risk of incident cognitive impairment. The findings suggested that WWI may be a more precise indicator of the association between obesity and cognitive impairment.

BackgroundWhile there is considerable literature on individual risk factors for dementia, the combined effects of multiple risk factors remain poorly understood. We used data from the Whitehall II study to investigate whether obesity and short sleep duration in midlife were associated with cognitive decline and incident dementia in late life, and whether these associations were linked to, or mediated by inflammatory and metabolic proteins.MethodData on sleep duration and body mass index (BMI) were collected between 1997 and1999. All potential Participants were aged less than 65 years at baseline and followed for dementia onset until 2023, with repeated assessments of cognition conducted throughout this period. Baseline immuno‐metabolic biomarkers included 4,953 plasma proteins measured using the SomaScan assay (SomaLogic, Boulder, CO, USA). We compared the incidence of dementia in participants with short sleep (≤6 hours), obesity (BMI³30), or both to those with neither (reference group) after adjusted all analyses for age, sex, and ethnicity.ResultA total of 4,769 were enrolled in the study, with baseline mean age of 54 (standard deviation 5.4) and the mean follow‐up time of 23 years. Of the 2,381 participants with normal sleep and non‐obese weight, 8.7% (n =206) developed dementia during follow‐up. The corresponding incidence was 8.6% in those with short sleep but no obesity (N ‐cases=145/N‐total=1,694; adjusted hazard ratio [HR] 1.14, 95% confidence intervals [CI] 0.92‐1.42), 9.7% in participants with obesity but normal sleep (34/349; HR,1.36; 95%CI, 0.95‐1.97), and 11.6% in those with both short sleep and obesity (40/345, HR,1.61; 95%CI, 1.14‐2.27). YKL‐40 and CRP inflammatory markers were associated with short sleep and obesity, but they did not mediate the relationship between obesity, short sleep and dementia or cognitive decline.ConclusionWe found that short sleep combined with obesity was associated with inflammatory and metabolic biomarkers, as well as a higher risk for cognitive decline and incident dementia in late life. While the effects of individual risk factors have traditionally informed health choices and policy, our findings suggest that these factors may interact. Therefore, it is important to also consider combinations of risk factors in both research and prevention strategies.

Short sleep and obesity in midlife and the risk of cognitive decline and incident dementia in late life: the Whitehall II cohort study

The global rise in dementia, including early-onset cases, imposes a growing burden on patients and caregivers. While midlife obesity is a recognized risk factor, the role of body weight fluctuation in dementia and cognitive decline remains uncertain. This systematic review and meta-analysis examined the association between weight variability and the risk of dementia, including Alzheimer's disease, vascular dementia, and cognitive decline. We systematically searched PubMed, Scopus, Web of Science, and PsycINFO, supplemented by manual searches, up to July 2024. Pooled hazard ratios (HRs) were estimated through pairwise meta-analysis, with subgroup analyses conducted to explore heterogeneity. Additionally, the quality of the included studies and the certainty of the evidence were assessed using the "Risk of Bias in Non-randomized Studies of Interventions" (ROBINS-I) tool and the GRADE Tool, respectively. Sixteen studies met the inclusion criteria. Compared with the lowest levels of weight fluctuation, the highest levels were associated with an increased risk of all-cause dementia (HR 1.40, 95% CI 1.29-1.52), Alzheimer's disease (HR 1.33, 95% CI 1.21-1.45), and vascular dementia (HR 1.39, 95% CI 1.16-1.67). No significant association was observed with cognitive decline. No clear source of heterogeneity was identified. High body weight fluctuation is associated with an elevated risk of dementia, particularly Alzheimer's disease and vascular dementia. These findings highlight weight stability as a potential target for dementia prevention strategies. Further high-quality studies are warranted to clarify underlying mechanisms and long-term implications.

Short sleep duraiton is a putative risk for dementia, whereas midlife obesity is an well-known risk factor. Midlife short sleep and obesity share some biological changes such as inflammations or metabolic changes, but their combined impact is not yet fully understood. Our aim is to investigate the associations of short leep obesity with cognitive decline and dementia risk, and to investigate whether these associations are mediated by blood markers. This is an analysis of prospective cohort study of adults who were free of dementia, had data on sleep duration and BMI at baseline in 1997-1999, and were tracked for dementia diagnoses until 2023 via linkage to electronic health records. Participants will be divided into four groups: (1) the reference group (2) short sleep (2) short sleep (≤6 hours) and non-obese weight; (3) normal sleep and obesity (≥30kg/m 2); (4) short sleep and obesity, the main exposure group. Baseline blood-based biomarkers include chitinase-3-like protein (YKL-40), triggering receptor expressed on myeloid cells 2 (TREM2), neurofilament-light chain (NfL), and brain-derived neurotrophic factor (BDNF), interleukin (IL)-1(, IL-6, C-reactive protein (CRP), transforming growth factor (TGF)-(3, adiponectin, insulin, ghrelin, and leptin. Cognitive status, measured using tests of executive function, memory, phonemic fluency and semantic fluency, was repeatedly assessed. We will use linear mixed-effects models and Cox proportional hazard models to examine the associations of short sleep and obesity with change in cognitive functioning and risk of dementia, respectively. To examine whether blood-based biomarkers partially mediate these associations, formal mediation analyses will be performed, estimating the proportion of excess dementia risk mediated by the biomarkers individually and in combination. The results of this study may provide an additional insight whether co-occurring short sleep and obesity is a risk factor for dementia and the biological changes associated with these factors..

BackgroundThough mid-life obesity is a known risk factor for dementia, how obesity in late life impacts brain health is not well understood, especially in the presence of comorbid risk factors like hypertension (HTN) and impaired glucose tolerance (IGT).ObjectiveWe investigated associations between obesity, neuroimaging measures, and cognition in middle aged and older adults, specifically testing whether higher body mass index (BMI), waist circumference (WC), and waist-to-hip ratio are associated with brain health independent of HTN and IGT.MethodsA total of 599 participants with brain MRI, cognitive testing, and anthropometric measurements were examined. Chi square and one-way ANOVA tests were performed to compare participant characteristics across BMI categories. Linear regression models assessed relationships between anthropometric, neuroimaging, and cognitive outcomes with and without adjustment for relevant covariates. We also explored interactions between anthropometric measures and APOE ε4 status and cognitive status.ResultsHigher BMI was associated with higher cerebral blood flow (CBF) in both white matter (β = 0.2294 ± 0.0431, p < 0.001) and gray matter (β = 0.0872 ± 0.0405, p = 0.032), higher free water (β = 0.0906 ± 0.0425, p = 0.034), lower fractional anisotropy (β = -0.0891 ± 0.0433, p = 0.040), and better global cognition (β = 0.022 ± 0.007, p = 0.002) and cognitive composite scores (ps < 0.01), independent of IGT and HTN. Similar associations were observed for waist circumference. Evidence of effect modification by APOE ε4 carrier status and cognitive status were found for white matter CBF, white matter hyperintensities, fractional anisotropy, and cognition.ConclusionsObesity measures are positively associated with better brain structure, function, and cognition in aging adults, highlighting the importance of managing body weight in older age to maintain optimal brain health.

Mid-life obesity is a major risk factor for neurodegenerative diseases, with mitochondrial and cerebrovascular dysfunction considered key mediators. Lysine acetylation is a reversible post-translational modification that regulates several mitochondrial metabolic and biochemical processes. The present study investigatedthe sex-dependent effects of brain lysine acetylation and cerebrovascular and cognitive health in a high fat diet (HFD)-induced obesity mouse model. We hypothesize that a HFD will cause an increase in acetylation, dysregulating mitochondrial respiration, potentially due to the decline in overall cerebrovascular health. Six-month-old C57/Bl6 mice (M/F) were placed on a 60% HFD or normal chow (CON) for 4months. Changes in cerebral blood flux (CBF), behavioural testing, glucose tolerance testing and body composition were tested. Brain lysates were probed for various substrate utilizations, bioenergetics proteins and lysine acetylation. A HFD resulted in global metabolic dysregulation, with a substantial increase in weight and fat mass, with a greater increase in female mice; however, no cognitive changes were noted. Additionally, unlike female mice, males demonstrated a decrease in CBF after a HFD. Brain lysine acetylation was decreased in male HFD mice but increased in female HFD mice. Similarly, acetylation levels of fatty acid oxidation protein (long-chain acyl-CoA dehydrogenase), glucose oxidation proteins (pyruvate dehydrogenase, pyruvate carboxylase) and electron transport chain complex I (NDUFB8) and IV (MTCO1) proteins were decreased in male and increased in female brains after a HFD. In summary, our findings propose lysine acetylation as a novel and potential regulatory mechanism that impacts vascular and metabolic function in the brain mitochondria in a sex-dependent manner.

BackgroundAlmost half of all dementia cases could theoretically be delayed or prevented by addressing risk factors at the population level. However, dementia risk reduction requires awareness of, and action on, modifiable risk factors. This study aimed to explore public awareness of brain health, and the facilitators for, and barriers to, engaging in preventative action to reduce dementia risk, across the UK and Ireland.MethodsThe Brain Health and Lifestyle Survey (BHLS) was a co-developed and evidence-informed online survey, underpinned by behaviour change frameworks. The BHLS was distributed via convenience sampling to individuals aged ≥ 40 years living in the UK and Ireland. It comprised 31 main questions on awareness, beliefs and behaviour change surrounding brain health and took approximately 20–25 min to complete. Ethical approval was obtained from Queen’s University Belfast [Ref: MHLS20_162].ResultsA total of 6816 respondents (75% UK; 25% Ireland) completed the BHLS between February and June 2021. Most respondents were aged 50–74 years (78%), female (79%), white (99%), overweight (59%) and highly educated (64%). The majority of respondents rated their brain health as good (79%) and there was high awareness of protective factors, including cognitively stimulating activities (91%) and physical exercise (88%). However, awareness of risk factors such as hypertension (62%), midlife obesity (61%), air pollution (50%) and hearing loss (35%) was lower. Awareness differed according to demographic factors, with lower awareness among respondents aged 40–49 years, and those with lower educational attainment. The identified barriers to adopting a brain-healthy lifestyle were implementing changes which were not enjoyable (44%), lack of self-motivation (33%), and a lack of trusted information (27%). Facilitators for adopting a brain-healthy lifestyle included: noticing problems with brain health (70%) and receiving personalised advice (51%).ConclusionUnderstanding of brain health and dementia risk reduction was variable in this large sample of UK and Irish citizens. There were identified gaps in awareness of risk factors relating to cardiometabolic health, hearing loss, and air pollution. These findings highlight the need for credible sources of accessible and relevant information to improve awareness and behaviours surrounding brain health.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12889-025-24175-0.

To examine the prospective associations of metal mixtures during pregnancy with midlife adiposity and explore metal-folate interactions. In 500 participants from Project Viva, we measured six non-essential metals (arsenic, barium, cadmium, cesium, mercury, and lead) and five essential metals (copper, magnesium, manganese, selenium, and zinc) in red blood cells and folate in plasma collected during early pregnancy (mean gestational age: 10.0 weeks; mean age: 32.9 years). We assessed midlife (mean age: 51.2 years) adiposity using BMI and dual-energy X-ray absorptiometry (DXA) measures. We used multivariable-adjusted linear and multinomial logistic regression models to analyze individual exposures and Bayesian kernel machine regression to examine exposure mixtures. Higher arsenic, cesium, and mercury levels were associated with lower midlife DXA percentage fat, total fat mass index, and/or trunk fat mass index, even after adjustments for diet in pregnancy. We observed an antagonistic interaction between folate and arsenic: arsenic was associated with higher obesity risk at lower folate levels but lower obesity risk at higher folate levels. The essential metal mixture tended to be associated with lower midlife BMI and obesity risk. Higher pregnancy levels of arsenic, cesium, mercury, and the mixture of essential metals were associated with lower midlife adiposity.

Midlife obesity and high adiposity are recognized as risk factors for Alzheimer's disease (AD), with visceral adipose tissue (VAT) playing a central role due to its endocrine and metabolic activity. Disturbances in VAT metabolism and adipokine secretion exacerbate AD pathology. Andrographolide (Andro), known for its anti-diabetic properties, enhances neuronal glucose uptake and alleviates AD pathology. However, its effects on VAT metabolism in AD remain unexplored. This study aimed to investigate the impact of Andro on glucose metabolism in VAT using a high-fat diet (HFD)-induced obesity model in AD mice (APP/PS1). APP/PS1 mice were fed an HFD and received Andro injections (2 mg/kg, three times a week for 16 weeks). VAT samples were analyzed for glucose uptake, glycolytic rate, pentose phosphate flux, ADP-ATP levels, gene expression, and enzymatic activity of glucose metabolic regulators. In APP/PS1 mice, HFD significantly increased glucose uptake and reduced GLUT4 expression in VAT, effects counteracted by Andro (p < 0.05). Andro-treated HFD-fed mice exhibited reduced glucose oxidation through glycolysis (p < 0.05), leading to decreased ATP production (p < 0.05). Andro administration restored the activity of key glycolytic enzymes and mitigated several HFD-induced metabolic alterations (p < 0.05). The study reveals significant metabolic changes in the VAT of obese APP/PS1 mice and highlights Andro's potential as a therapeutic agent for addressing VAT impairment induced by obesity in AD.

Association of birth weight, midlife obesity, and transition patterns with mild cognitive impairment and brain MRI indices: A prospective population-based study.

Midlife obesity is a risk factor of dementia, but late-life obesity has been associated with lower dementia risk. We investigated this paradox by exploring the relationship between late-life body mass index (BMI) category and dementia, with and without considering midlife to late-life BMI change. This observational cohort study included participants of the community-based Atherosclerosis Risk in Communities (ARIC) study who were dementia-free at visit 5 (2011-2013). Dementia was ascertained by expert-adjudicated, algorithmic classification from an in-person neuropsychological battery, as well as telephone interviews and International Classification of Diseases codes from medical records. We first assessed the association of incident dementia with visit 5 BMI categories (normal weight, overweight, obese). Next, we used a cross-classification of visit 5 BMI categories with visit 4-visit 5 BMI change (decrease [loss of ≥2 kg/m2], increase [gain of ≥2 kg/m2], or stable [loss or gain of <2 kg/m2]) occurring during the 15 years before baseline. Cox regression was used. A total of 5,129 participants were included in the study (59% female; 22% identified as Black; mean (standard deviation) age at visit 5 of 75 (5) years). Over 8 years of follow-up, 20% of the sample developed dementia (n = 1,026). After covariate adjustment, participants with high late-life BMI had a lower risk of dementia; the hazard ratio (95% CI) was 0.86 (0.73-1.00) for overweight and 0.81 (0.68-0.96) for obesity. In stratified models, elevated dementia risk was observed only for participants of each late-life BMI category whose BMI had decreased from midlife to late life. Compared with normal-weight individuals who had maintained BMI from midlife to late life, the hazard ratio (95% CI) for those with BMI loss was 2.08 (1.62-2.67) for normal-weight individuals, 1.62 (1.25-2.10) for those with overweight, and 1.36 (1.00-1.85) for those with obesity. Our results provide insight into the dementia obesity paradox at older ages, tempering a causal interpretation of high late-life BMI as protective against dementia. Instead, they highlight the importance of considering weight loss from midlife to late life in conjunction with late-life BMI in dementia risk stratification.

While midlife obesity is consistently associated with cognitive decline in later life, there is limited understanding of how weight variations from early life to midlife affect cognitive decline. We investigated the association between early- to midlife weight trajectories and mid- to late-life cognitive decline. This is a longitudinal cohort study that used data from 3 waves (2008-2019) of the Brazilian Longitudinal Study of Adult Health, a multicenter cohort study that enrolled active and retired public servants aged 35+ years from public universities in Brazil. Participants with a history of stroke, missing cognitive data at baseline, and with incomplete body shape data were excluded from the analyses. Self-reported body shapes from ages 5 to 40 using the Stunkard Figure Rating Scale were categorized as underweight, normal, overweight, and obese. Sequence analysis and hierarchical clustering identified weight trajectories. Global cognition Z-scores were derived from memory (immediate recall, delayed recall, and recognition of a word list), phonemic and semantic verbal fluency, and Trail Making Test part B (TMT-B). Linear mixed models adjusted for sociodemographic, clinical, and lifestyle covariates investigated associations between clusters of weight trajectories and global cognition Z-scores. Inverse probability of attrition weighting was used to account for attrition bias. Among 11,361 participants (mean age: 51.5 ± 8.6, 55% women, 42.4% Black/mixed race), "normal to overweight," "underweight to normal," and "stable overweight" trajectories exhibited faster global cognitive decline than "stable normal" trajectory (β = -0.024; 95% CI -0.043 to -0.005; p = 0.015; β = -0.026; 95% CI -0.040 to -0.012; p < 0.001; β = -0.034; 95% CI -0.066 to -0.001; p = 0.043, respectively), representing 4.6-6.5 excess years of cognitive aging over a median follow-up of 8 years. Cognitive decline associated with weight trajectories was driven mainly by declines in memory and TMT-B performance. Associations were observed only in Black/mixed races and women when stratified. Weight gain and stable overweight trajectories from early life to midlife were associated with faster cognitive decline than stable normal weight trajectories. Weight management during early life may mitigate cognitive decline. Study limitations include reliance on self-reported body shape data, potential recall bias, and residual confounding from unmeasured early-life factors.

Rates of metabolic stress (obesity, prediabetes, metabolic syndrome, and diabetes) continue to grow worldwide. In parallel, the aging population is also growing. Aging itself is the number one risk factor for cognitive impairment, including dementias such as Alzheimer’s Disease and Alzheimer’s Disease Related Dementias. However, metabolic stress, particularly in midlife, also raises the risk of cognitive impairment later in life. While inflammation and immune system dysregulation are common etiologies of both aging and metabolic stress, precise underlying mechanisms remain unclear. Given its clear role in metabolic stress in the periphery, we hypothesized that midlife metabolic stress also triggers central nervous system over-activation of the innate inflammatory cGAS/STING pathway and contributes to cognitive impairment with age. To test our hypothesis, we used a high fat diet (HFD) fed murine model of obesity and prediabetes. Male and female wild-type (WT) C57BL6 and global cGAS knock out (KO) mice were fed either HFD or standard diet (SD) control chow (8 experimental groups, n=12 mice/group) starting at midlife (1-yr of age) until older age (2-yr of age). We performed longitudinal and terminal metabolic (body weights and glucose tolerance testing) and cognitive (puzzle box) phenotyping, with additional terminal transcriptomic (hippocampal singe cell RNAseq) analyses. We found that cGAS KO had minor effects on HFD-induced weight gain and glucose intolerance, specifically preventing age-associated weight loss and moderately reducing glucose intolerance dependent on time point. While overall HFD negatively impacted cognition in both sexes, females (particularly cGAS KO females) had a more pronounced deficit compared to males. In parallel, single cell transcriptomic analyses showed that HFD impacted gene expression profiles in both sexes and both genotypes (WT and KO). However, in response to HFD feeding, WT males had a gene expression profile that indicated a neurodegenerative and pro-inflammatory environment that was blunted in the male KO animals in response to diet. In contrast, KO females’ gene expression profiles indicated a pro-inflammatory environment in response to HFD feeding that was absent in the WT females. Together, these data highlight that in midlife obesity and prediabetes, cGAS KO has sexually dimorphic effects of on metabolic, cognitive and transcriptomic outcomes with age, potentially suggesting beneficial effects in males but detrimental effects in females. Funding for this work was provided by the NeuroNetwork for Emerging Therapies and from the NIA (K99/R00; 1K99AG071667-01A1). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

We examined associations between body mass index (BMI), waist circumference (WC), and dementia risk, and differences in BMI and WC trajectories before dementia diagnosis. We included 9,739 participants (54% women) aged 70+ from the Trøndelag Health Study (HUNT4 70+). BMI was measured four times (1984-2019) and WC three times (1995-2019). Dementia diagnoses were clinically assessed at HUNT4 70+ . Women and men with dementia had higher midlife BMI and WC than those without dementia. These differences diminished closer to diagnosis, especially in women. Midlife obesity in both sexes and midlife overweight, high WC, and overweight/obesity with high WC in men were linked to higher dementia risk. Lower dementia risk was observed with late-life overweight for both sexes, late-life high WC in women, late-life overweight/obesity with normal WC in men or high WC in women. Adiposity measures and their changes influence dementia risk differently in women and men.

While midlife obesity is linked to cognitive decline, this association is inconsistent in older adults, possibly due to the limitations of body mass index (BMI) in accurately assessing adiposity at older ages. Most studies focused on White or Asian populations, did not include other adiposity measures besides BMI, adjusted the analyses for mediators, and did not investigate potential subgroup-specific associations. We compared the associations of adiposity measured by anthropometrical and bioelectrical impedance analysis (BIA) with cognitive performance in a diverse population, examining modifications by age, sex, and race, and investigating the mediating effects of obesity-related comorbidities. Cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) cohort (n = 12,636). Adiposity was evaluated using BMI, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), and body fat percentage (BFP). A composite global cognition score was derived from immediate, delayed recall, and word recognition word list, phonemic and semantic verbal fluency, and trail-making tests. Adjusted linear regression models were used to investigate associations. We included an interaction term in the regression models to verify if age, sex, and race were modifiers of these associations and used causal mediation methods to assess the mediating role of obesity-related comorbidities. Among 10,725 participants [mean age (SD): 58.9 (8.6) years; 55.8% women, 54.4% White], larger WHR and WHtR were associated with worse global cognitive performance. These associations were not modified by age, sex, or race. An association of BFP with cognition was observed only in younger adults. Mediation analysis identified only indirect effects of these adiposity measures on cognitive performance and no direct effects. WHR and WHtR were more consistently associated with cognitive performance than BMI. BIA measures of adiposity were associated with cognition only in younger adults. Obesity-related comorbidities fully mediated the associations of adiposity with cognition.