Midlife Obesity Research Articles

Endoplasmic reticulum stress contributes to the decline in doublecortin expression in the immature neurons of mice with long-term obesity

Adult hippocampal neurogenesis (AHN) plays an important role in hippocampus-dependent function. The number of doublecortin (Dcx)-positive immature neurons in the dentate gyrus decreases over time, especially in the early stages of Alzheimer’s disease (AD), and is further reduced in later stages of AD. Obesity in midlife is associated with dementia later in life; however, the underlying mechanisms by which obesity results in the development of dementia later in life remain unknown. Here, we show that endoplasmic reticulum (ER) stress was activated in the hippocampus and processes of Dcx-expressing immature neurons were shortened, coexpressing CHOP in APP23 AD model mice with high-fat diet-induced long-term obesity and in aged Leprdb/db (db/db) mice. Moreover, in cells differentiating from hippocampal neurospheres, Dcx mRNA was rapidly degraded via a microRNA (miRNA) pathway after thapsigargin treatment in vitro. These results indicate that loss of Dcx mRNA induced by ER stress during AHN may cause memory impairment in obese individuals later in life.

Late-Life Obesity Associated with Tau Pathology in Cognitively Normal Individuals: The CABLE Study.

Existed evidence suggests that midlife obesity increases the risk of Alzheimer's disease (AD), while there is an inverse association between AD and obesity in late life. However, the underlying metabolic changes of AD pathological proteins attributed to obesity in two life stages were not clear. To investigate the associations of obesity types and obesity indices with AD biomarkers in cerebrospinal fluid (CSF) in different life stages. We recruited 1,051 cognitively normal individuals (61.94±10.29 years, 59.66%male) from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study with CSF detections for amyloid-β 42 (Aβ42), total-tau (T-tau), and phosphorylated tau (P-tau). We utilized body mass index, waist circumference, waist-to-height ratio, and metabolic risk factors to determine human obesity types. Multiple linear models and interaction analyses were run to assess the impacts of obesity on AD biomarkers. The metabolically unhealthy obesity or healthy obesity might exert a reduced tau pathology burden (p < 0.05). Individuals with overweight, general obesity, and central obesity presented lower levels of tau-related proteins in CSF than normal controls (p < 0.05). Specially, for late-life individuals, higher levels of obesity indices were associated with a lower load of tau pathology as measured by CSF T-tau and T-tau/Aβ42 (p < 0.05). No similar significant associations were observed in midlife. Collectively, late-life general and central obesity seems to be associated with the reduced load of tau pathology, which further consolidates the favorable influence of obesity in specific life courses for AD prevention.

Evidence and consensus-based clinical practice guidelines for management of overweight and obesity in midlife women: An AIIMS-DST initiative.

Evidence and consensus-based clinical practice guidelines for management of overweight and obesity in midlife women: An AIIMS-DST initiative.

Obesity and Brain Health: The Impact of Metabolic Syndrome and Cardiorespiratory Fitness on Cognitive Performances in Middle-Aged Obese Women.

Mid-life obesity has been reported to be a significant risk factor for later-life dementia and Alzheimer's disease. Metabolic syndrome (MetS) has been suggested to have an adverse effect while cardiorespiratory fitness (CRF) has been suggested to have a protective effect on cognitive function of older adults. However, studies investigating such effects in middle-aged obese women are limited. To compare cognitive performances between obese and normal weight middle-aged women and examine the effects of MetS and CRF on cognitive performances when combined with obesity. Cross-sectional study with the data of 87 middle-aged women (58 obese and 29 normal weight, with age and education matched). The non-invasive screening method for metabolic syndrome (NIM-MetS) was used to detect MetS. CRF was determined by using maximal oxygen consumption (VO2 max) and was classified as high or low (VO2 max higher or lower than 50th percentile) based on the American College of Sports Medicine's guidelines. Neurocognitive tests including Montreal Cognitive Assessment (MoCA), digit span (DS), trail making test (TMT), hand reaction time (HRT), logical memory (LM), and semantic verbal fluency test (SVFT) were administered to all participants. The obese group demonstrated significantly lower score in MoCA, DS, TMT, HRT, and LM than the normal weight group (p < 0.05). The obese with MetS subgroup (n = 28) showed significantly lower score in LM than the obese non-MetS subgroup (n = 30) (p = 0.002). Normal weight with high CRF participants (NW-high CRF; n = 28) demonstrated significantly higher score in MoCA and HRT than obese with high CRF participants (OB-high CRF; n = 24) (p < 0.05), and demonstrated better score in MoCA, DS, TMT, HRT, and LM than obese with low CRF participants (OB-low CRF; n = 24) (p < 0.05). OB-high CRF showed significantly greater score in DS, TMT and LM than OB-low CRF (p < 0.05). Obesity shows negative impact on several cognitive functions, which memory appears to be further affected when combined with MetS in middle-aged women, whereas CRF is suggested to have benefit on certain aspects of cognitive domains. Maintaining a healthy body weight and improving CRF are beneficial for cognitive function of middle-aged women.

Gut Microbiome, Inflammation, and Cerebrovascular Function: Link Between Obesity and Cognition.

Obesity affects 13% of the adult population worldwide and this number is only expected to increase. Obesity is known to have a negative impact on cardiovascular and metabolic health, but it also impacts brain structure and function; it is associated with both gray and white matter integrity loss, as well as decreased cognitive function, including the domains of executive function, memory, inhibition, and language. Especially midlife obesity is associated with both cognitive impairment and an increased risk of developing dementia at later age. However, underlying mechanisms are not yet fully revealed. Here, we review recent literature (published between 2010 and March 2021) and discuss the effects of obesity on brain structure and cognition, with a main focus on the contributions of the gut microbiome, white adipose tissue (WAT), inflammation, and cerebrovascular function. Obesity-associated changes in gut microbiota composition may cause increased gut permeability and inflammation, therewith affecting cognitive function. Moreover, excess of WAT in obesity produces pro-inflammatory adipokines, leading to a low grade systemic peripheral inflammation, which is associated with decreased cognition. The blood-brain barrier also shows increased permeability, allowing among others, peripheral pro-inflammatory markers to access the brain, leading to neuroinflammation, especially in the hypothalamus, hippocampus and amygdala. Altogether, the interaction between the gut microbiota, WAT inflammation, and cerebrovascular integrity plays a significant role in the link between obesity and cognition. Future research should focus more on the interplay between gut microbiota, WAT, inflammation and cerebrovascular function to obtain a better understanding about the complex link between obesity and cognitive function in order to develop preventatives and personalized treatments.

Public health interventions to reduce Alzheimer’s risk: Need for tailored approaches

AbstractBackgroundWe have previously estimated that 30% of Alzheimer’s disease in the U.S. may be attributable to modifiable risk factors, and that the most important risk factors to target are physical inactivity, depression, and smoking. However, estimates in the U.S. population as a whole may not be ideal for guiding public health messaging about Alzheimer's risk reduction because they do not take into consideration the unique risk factor profiles of different regions. In this study, we estimate the proportion of Alzheimer’s disease cases that are potentially attributable to modifiable risk factors in California, which has the largest and most diverse population in the U.S.MethodWe calculated individual and combined population attributable risks (PARs) for Alzheimer’s disease in California for eight modifiable risk factors: physical inactivity, smoking, depression, low education, diabetes, midlife obesity, midlife hypertension, and hearing loss. Relative risks for each risk factor were extracted from recent meta‐analyses. Risk factor prevalence and communality were determined using data from the 2017 and 2018 California Behavioral Risk Factor Surveillance Survey, a population‐based survey weighted to provide representative estimates. To account for non‐independence of the risk factors, we estimated the communality and uniqueness of each risk factor via principal component analysis and applied them to Levin’s formula.ResultsIn California, the estimated PARs (95% confidence intervals) for modifiable risk factors were as follows: low education: 14.0% (13.3%, 14.8%), midlife obesity: 13.4% (12.9%, 13.9%), physical inactivity: 10.3% (9.8%, 10.8%), midlife hypertension: 7.4% (7.2%, 7.7%), depression: 7.4% (7.0%, 7.7%), diabetes: 6.7% (6.2%, 7.2%), smoking: 4.5% (4.2%, 4.8%), and hearing loss: 1.9% (1.7%, 2.1%). The combined PAR estimate was 29.4% (28.1%, 30.7%) incorporating the correlations between risk factors.ConclusionConsistent with our previous U.S. estimates, we found that about a third of Alzheimer’s disease cases in California might be attributable to modifiable risk factors. However, the most important risk factors differed, with low education, midlife obesity and physical inactivity contributing to the largest proportion of cases. Public health interventions to reduce dementia risk may be more effective if tailored to address the most important risk factors in the region.

INSPIRATION: Study design and preliminary results of a crosssectional risk AD‐profiling study

AbstractBackgroundEstimates suggest that between 30% and 40% of all AD cases are attributable to potentially modifiable risk factors such as hypertension, midlife obesity, diabetes mellitus, depression, social isolation, physical inactivity, smoking, low level of education, and hearing loss (Barnes and Yaffe 2011; Livingston et al. 2020; Luck and Riedel‐Heller 2016). In addition, other risk factors for AD such as stress and sleep disturbances have been identified in recent years (Escher et al. 2019; Sindi et al. 2018). The Individual risk profiling for Alzheimer's disease and dementia prevention (INSPIRATION) study aims to explore the frequency and distribution of risk factors for AD in the participants of an Alzheimer Prevention Registry in order to establish individualized risk profiles and aid the development of personalized prevention programs.MethodCross‐sectional assessment of healthy study participants aged 50 or older recruited through a local volunteer Alzheimer Prevention Registry is performed to determine the prevalence of key risk factors. This protocol includes established questionnaires and medical examination. Data is collected on demographics, medical history, family history, physical activity, diet, BMI, waist circumference, hearing loss, smoking and drinking habits, presence of depression, anxiety, stress, resilience, and loneliness. In addition, we perform neuropsychological testing and blood sampling for ApoE determination and AD‐biomarker testing. The aim is to enroll 200 individuals.ResultPreliminary results in 32 participants indicate that the three most frequent risk factors were non‐adherence to recommended diets (i.e. Mediterranean diet) in 84.4% of the subjects, obesity in 68.8% with a mean BMI of 27.6 kg/m2 (22.3‐41.6kg/m2, min./max.), and sleep problems in 50% of the subjects. The full set of assessed risk factor will be presentedConclusionThe INSPIRATION study aims to understand the prevalence of modifiable AD risk factors, in order develop a tool box of interventions for personalized strategies to prevent AD in a population, which is particularly interesting in dementia prevention.

Obesity modulates Alzheimer's disease through accelerated immune ageing.

Emerging studies in Alzheimer's disease (AD) have identified, among numerous risk factors, immune dysfunction and midlife obesity. Here, we hypothesized that these two elements might be linked. AD-prone 5xFAD mice at 2 months of age were switched to a high-fat diet (HFD, 60% calories from fat) for 28 weeks to induce obesity. As controls, we used 5xFAD mice fed a control diet (CD, 20% calories from fat). WT littermates for both diet groups were included in the study. We assessed cognition using the novel object recognition task until capturing divergence between the 5xFAD diet groups. Upon culling, the following tissues were harvested for analyses: brain (right hemisphere), for histopathological examination and ELISA; hippocampus (left hemisphere), for single-nucleus RNA sequencing (sNuc-seq); spleen, for flow cytometry and cytometry by time-of-flight (CyTOF); and plasma, for metabolic and non-targeted polar metabolite screening. HFD induced obesity accelerated cognitive deterioration, neuronal loss, and brain gliosis in 5xFAD mice, without altering amyloid β content. HFD had no effect on either cognition or brain phenotype in WT mice. sNuc-seq of the hippocampus revealed a diet-induced signature in oligodendrocytes, but did not detect changes beyond the AD-associated signatures in microglia and astrocytes. Obese 5xFAD mice displayed immune ageing-related signatures, including elevation of CD4+ FOXP3+ regulatory T cells (Tregs) and exhausted T cells expressing the inhibitory molecules PD-1 and LAG-3. Analysis of the plasma metabolome identified comorbidity-associated signatures. Our study highlights accelerated immune ageing as a diet-induced risk factor in AD.

Association of body mass index with brain structure and biomarkers of inflammation in cognitively unimpaired middle‐aged adults with and without evidence of β‐amyloid pathology

AbstractBackgroundObesity has been linked to brain atrophy and peripheral inflammation. However, the association between body mass index (BMI) and brain structure can be confounded by Alzheimer’s disease (AD) pathology‐related weight loss, and its association with neuroinflammation remains unknown. We explored associations of BMI with brain structure and biomarkers of peripheral and central nervous system inflammation in cognitively unimpaired middle‐aged adults with and without evidence of β‐amyloid (Aβ) pathology.MethodWe analyzed data from 385 ALFA+ study participants. We measured plasma C‐reactive protein (CRP), CSF p‐tau and t‐tau with the Elecsys® immunoassays and CSF Aβ42, Aβ40 and neuroinflammation biomarkers (sTREM2, GFAP, YKL40, S100 and IL6) with the exploratory Roche NeuroToolKit robust prototype assays. We used separated linear regression models to analyze associations of BMI with plasma CRP, CSF AD and neuroinflammation biomarkers, and mean cortical thickness (CTh) in a composite AD signature region. We explored voxelwise associations (p&lt;0.001, k=100) between BMI and gray matter volume (GMv) with SPM12. We stratified all analyses by Aβ status (defining positivity as Aβ42/40&lt;0.071) and adjusted by age, sex, systolic blood pressure, triglyceride, glycated hemoglobin and physical exercise levels.ResultBMI was positively associated with CRP levels in Aβ‐ and Aβ+ groups (p&lt;0.001). We found no significant associations between BMI and CSF AD or neuroinflammation biomarkers. BMI was negatively associated with mean CTh in the AD signature region in the Aβ‐ (p&lt;0.001), but not in the Aβ+ group (p=0.543). Voxel‐based morphometry analyses showed widespread negative associations between BMI and GMv in Aβ‐ participants involving bilateral prefrontal, medial temporal, parietal, occipital, thalamic and cerebellar regions (Figure 1), without positive associations. Among Aβ+ participants, we found positive associations with BMI in small clusters in the cerebellum, middle frontal and anterior cingulate gyri (Figure 2), without negative associations.ConclusionIn the absence of Aβ pathology, higher BMI is associated with brain atrophy involving AD‐related areas, suggesting that midlife obesity may increase dementia risk by mechanisms unrelated to AD pathology. Conversely, among individuals on the AD continuum, higher BMI appears to be associated with more preserved brain structure. We found no evidence of an association between higher BMI and neuroinflammation.

Regional abdominal adiposity is associated with BMI‐related brain regions in middle‐aged adults at high risk of Alzheimer’s dementia

AbstractBackgroundThere is evidence for the involvement of midlife obesity in mild cognitive impairment (MCI), dementia, and Alzheimer’s dementia (AD) risk in late life. Obesity is primarily measured by body mass index (BMI), which poorly reflects body fat distribution. Regional abdominal adiposity has been related to inflammation and metabolic syndrome, both consistently linked to the neuropathology of AD and related disorders (ADRD). We examined the relationship between regional abdominal adiposity and regional brain volume, among middle‐aged adults enriched for AD risk due to parental history of AD.MethodParticipants were from the Israel Registry for Alzheimer’s Prevention (IRAP), which follows middle‐aged offspring of AD patients (N=390). At this time, 44 participants (Table 1) were scanned, via magnetic resonance imaging (MRI), for regional abdominal adiposity, including hepatic, pancreatic, and abdominal adipose tissues (AAT, visceral (VAT), and subcutaneous (SAT)). T1‐weighted volumetric brain MRI focused on three regions implicated in obesity and cognitive impairment: para‐hippocampus, amygdala, and inferior frontal gyrus (IFG). Following logarithmic normalization, linear regression was used to examine the association of regional abdominal fat with brain volume adjusting for age, sex, education, and intracranial volume. An additional adjustment for BMI was done to examine whether the associations are above and beyond global adiposity.ResultSmaller amygdalar volume was associated with the percentage of VAT fat (r=‐0.324, p=0.044) and approached significance for pancreatic (r=‐0.283, p=0.08) and hepatic (r=‐0.307, p=0.057) fat. A smaller para‐hippocampal volume was associated with the percentage of pancreatic fat (r=‐0.317, p=0.05) and hepatic (r=‐0.447, p=0.004) fat, and approached significance for VAT fat (r=‐0.309, p=0.056). Fat percentage was not associated with IFG volume (Table 2; Figure 1).ConclusionGreater regional abdominal adiposity was associated with higher amygdalar and para‐hippocampal volumes, already in midlife, regardless of global body adiposity measured by BMI. Regional adiposity affects secreted factors relevant to brain function, suggesting an underlying mechanism. By AAIC 2021, we anticipate 100 IRAP participants will be assessed for regional abdominal adiposity, blood‐based related secreted factors, and brain MRI. These data may lead to the development of age‐specific interventions targeting specific adipose depots, which are expected to prevent or delay neuropathology, cognitive decline, and ultimately AD.

Regional abdominal adiposity and related factors are associated with brain volumes and cognitive functioning in middle‐aged adults at high AD‐risk

AbstractBackgroundAlzheimer’s dementia (AD) is one of the most challenging diseases, affecting individuals, their families, and society. There is evidence for the involvement of midlife obesity (measured by BMI) in mild cognitive impairment (MCI), dementia, and AD risk in late life. Regional abdominal adiposity has been related to metabolic syndrome and inflammation, both consistently linked to cognitive impairment and neuropathology of AD. The accelerating prevalence of obesity and dementia in our aging population further amplifies the potential public health impact of the proposed investigation.MethodThe Israel Registry for Alzheimer’s Prevention (IRAP) (N=500), which aims to examine the connection between longevity and dementia, was capitalized. Newly collected data ‐ regional abdominal adiposity (abdominal (AAT) visceral (VAT), subcutaneous (SAT), pancreatic, and hepatic adipose tissue) by MRI (N=92), and adiposity‐related factors of visceral fat (TNF‐α, Leptin), pancreases (PP, PYY), and liver (PAI‐1, Fetuin) via serum (N=26).ResultHigh pancreatic fat percentage was associated with lower hippocampal and IFG volumes, and lower executive memory function. High hepatic fat percentage was associated with lower hippocampal volume and lower executive memory function. High VAT percentage was associated with lower amygdalar and hippocampal volumes, while high VAT volume was associated with lower cognitive functioning (executive and working memory, language, and global cognition). Serum levels of PP, PAI‐1, and Fetuin were negatively associated with para‐hippocampal and IFG volumes. Serum levels of Leptin were associated with amygdala and hippocampal volumes. High levels of PYY, PAI‐1, and TNF‐α were associated with lower executive memory function.ConclusionGreater regional abdominal adiposity and related secreted factors are associated with poorer cognitive functions and lower volumes of cognition and BMI‐related brain regions, already in midlife in asymptomatic individuals enriched for AD risk, regardless of global body adiposity measured by BMI. These results strongly support our overall hypothesis that specific fat deposits in specific tissues and organs are differentially associated with cerebrovascular and AD‐related neuropathology and cognition, advancing the field to new potential mechanistic pathways underlying the adipose tissue‐brain link.

Modifiable Risk Factors for Dementia: The Role of Gut Microbiota.

Dementia is a syndrome resulting from chronic or progressive brain disease. Around 40% of worldwide dementia can be prevented or delayed by modifying 12 risk factors: low educational attainment in early life, mid-life hypertension, mid-life obesity, hearing loss, traumatic brain injury, excessive alcohol consumption, smoking, depression, physical inactivity, social isolation, diabetes mellitus, and air pollution. There is growing evidence that gastrointestinal tract microbiota may significantly contribute to dementia pathogenesis. In particular, gut dysbiosis can trigger metabolic diseases and the progression of low-grade systemic inflammation, being involved in much of the major modifiable risk factors. In this review, we focus on studies that have evaluated the association between modifiable risk factors for dementia and the role of gut microbiota. We also suggest clinical implications for researchers in dementia-gut microbiota related fields.

The Effect of Sex and Wealth on Population Attributable Risk Factors for Dementia in South Africa

Background and Aims: South Africa is a middle-income country with high levels of income inequality and a rapidly aging population and increasing dementia prevalence. Little is known about which risk factors for dementia are important and how they differ by social determinants of health as well as key demographic characteristics such as sex and wealth. We sought to calculate the population attributable risks (PARs) for established potentially modifiable risk factors for dementia among these different groups.Methods: We obtained risk factor prevalence from population-based surveys for established dementia risk factors (diabetes, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, low educational attainment, social isolation). We used relative risk estimates reported in previous meta-analyses and estimated PARs using Levin's formula and accounting for communality. We tested for one-way and two-way interactions by sex and wealth using Pearson's χ2. In stratified analyses, we performed tests for trend using logistic regression.Results: The prevalence of established risk factors for dementia ranged from 5% for depression to 64% for low education. After accounting for communality, the risk factors contributing the greatest PAR were low education (weighted PAR 12%, 95% CI 7% to 18%), physical inactivity (9, 5–14%), and midlife hypertension (6, 5–14%). Together, 45% of dementia cases may be attributable to modifiable risk factors (95% CI 25–59%). We found significant interactions (p < 0.005) between sex, wealth, or both (sex * wealth) and each risk factor except social isolation and physical activity. Low education was inversely associated with wealth in both male and female. The PAR for midlife hypertension, obesity, and diabetes was associated with increasing wealth, and was higher in female. In contrast, the PAR for smoking was higher in male (8% vs. 2%) and was associated with increasing wealth among female only. We found that either a strategy of large reductions in selected risk factors with the highest PAR (midlife hypertension, smoking, physical inactivity) or small reductions across all risk factors could potentially reduce dementia cases by as many as 250,000 by 2050.Discussions: The potential impact on dementia risk by decreasing exposure to established dementia risk factors is large and differs by sex and social determinants of health like wealth. Risk factor PAR should inform national and local health policy dementia initiatives in South Africa including which risk factors to target in the whole population and which to target in high-risk groups for maximum public health benefit.

Comparative Evaluation of Cognitive Function among Indian Obese and Non-Obese Middle-Aged Subjects

Background: Obesity has become one of the common problems encountered by people of the present day. This condition is often accompanied by cardiovascular problems like hypertension, hyperlipidemia, is chemic heart disease. Also, that the relationship between obesity and cognitive impairment plays an important role in the development of neurodegenerative disorders. But reports on the association between obesity and working memory lack scientific evidence. So, the present study planned to assess the influence of obesity on cognitive functions and compare among obese and non - obese individuals.&#x0D; Objective: This study evaluated the changes in cognitive functions comparative between samples of obese and non-obese individuals from India.&#x0D; Methods: Based on the Body Mass Index (BMI), the participants were classified into 2 groups. Cognitive screening was done using MINI MENTAL STATE EXAMINATION and the parameters like level of orientation, registration, recall, language, copy art skills were analyzed and scores were calculated. The data was statistically analyzed using SPSS version 23 and the independent sample t test was used to analyze the differences in cognitive functions.&#x0D; Results: The study reported that there was statistically significant decline in language, recall and copy art skills in obese individuals compared to non-obese group.&#x0D; Conclusion: The study concluded an innovative finding that obesity is associated with impaired cognitive performance pertaining to recall, language and copy art and overall decreased MMSE scores indicating that accelerated cognitive decline and neurodegenerative pathologies such as dementia in later life is influenced by changes in body weight. Interventions that target mid-life obesity may be helpful in reducing the cognitive risks associated with obesity.

Adiponectin, Leptin, and Resistin and the Risk of Dementia.

BackgroundAdipokines are hormones secreted by adipose tissue with roles in energy homeostasis and regulation of metabolism. Their dysregulation is suggested to contribute to the increased risk of dementia seen with midlife obesity, but longitudinal studies investigating this are scarce. We determined the association between plasma levels of adiponectin, leptin, and resistin with the risk of dementia.MethodsWe performed a case–cohort study embedded in the prospective, population-based Rotterdam Study. Plasma levels of the adiponectin, leptin, and resistin were measured at baseline (1997–1999) in a random subcohort of 945 participants without dementia, and additionally in 177 participants, who were diagnosed with dementia during follow-up (until January 1, 2018).ResultsHigher levels of leptin and resistin were associated with a decreased risk of dementia (adjusted hazard ratio [95% confidence interval] per SD increase of log-transformed values: 0.85 [0.72–1.00] for leptin; 0.82 [0.71–0.95] for resistin). The association of leptin with dementia was further modified by body mass index and by APOE ε4 carrier status. Adiponectin levels were not associated with the risk of dementia.ConclusionsThese findings support the hypothesis that adipokines have a role in the pathophysiology of dementia. Future studies are warranted to confirm the findings and to explore the underlying mechanisms.

Physical Activity From Adolescence Through Midlife and Associations With Body Mass Index and Endometrial Cancer Risk.

Physical activity is associated with lower risk for endometrial cancer, but the extent to which the association is mediated by body mass index (BMI) in midlife is unclear. This study describes the physical activity-endometrial cancer association and whether BMI mediates this relationship. Participants were 67 705 women in the National Institutes of Health-AARP Diet and Health Study (50-71 years) who recalled their physical activity patterns starting at age 15-18 years. We identified 5 long-term physical activity patterns between adolescence and cohort entry (ie, inactive, maintained low, maintained high, increasers, decreasers). We used Cox regression to assess the relationship between these patterns and midlife BMI and endometrial cancer, adjusting for covariates. Mediation analysis was used to estimate the proportion of the physical activity-endometrial cancer association that was mediated by midlife BMI. During an average 12.4 years of follow-up 1468 endometrial cancers occurred. Compared with long-term inactive women, women who maintained high or increased activity levels had a 19% to 26% lower risk for endometrial cancer (maintained high activity: hazard ratio = 0.81, 95% confidence interval [CI] = 0.67 to 0.98; increasers: hazard ratio = 0.74, 95% CI = 0.61 to 0.91). They also had a 50% to 77% lower risk for obesity in midlife (eg, maintained high activity: odds ratio for a BMI of 30-39.9 kg/m2 = 0.50, 95% CI = 0.46 to 0.55; and maintained high activity, odds ratio for a BMI of ≥40 kg/m2 = 0.32, 95% CI = 0.26 to 0.39). BMI was a statistically significant mediator accounting for 55.5% to 62.7% of the physical activity-endometrial cancer associations observed. Both maintaining physical activity throughout adulthood and adopting activity later in adulthood can play a role in preventing obesity and lowering the risk for endometrial cancer.

Major Neurocognitive Disorders

Major neurocognitive disorder is the most common neurodegenerative condition in the world and the leading cause of dependence and disability among older adults worldwide. There are numerous etiologies for major neurocognitive disorder, of which Alzheimer disease (AD) is the most common. Available evidence indicates that the risk factors for major neurocognitive disorder include older age, female sex, lower educational attainment, obesity, and vascular risk factors, including smoking, hypertension, diabetes mellitus, and hyperlipidemia. Certain etiologies for major neurocognitive disorder are heritable, especially those due to AD and frontotemporal lobar degeneration. The pathophysiologic changes associated with the various etiologies of major neurocognitive disorder include neuronal loss, senile plaques, neurofibrillary tangles, vascular pathology, and α-synuclein neuronal inclusions. Major neurocognitive disorder remains a clinical diagnosis with a thorough history, appropriate laboratory tests, and standardized rating scales assisting in determining the etiology and severity of the condition. In older adults, major neurocognitive disorder must be differentiated from depression and delirium as these three conditions may have similar clinical presentations or may coexist. Current data indicate that approximately a third of the cases of major neurocognitive disorder, especially those due to AD, may be prevented by controlling potentially modifiable risk factors, including diabetes, depression, smoking, physical inactivity, midlife hypertension, midlife obesity, and low educational attainment. Currently, the only Food and Drug Administration–approved medications are acetylcholinesterase inhibitors and memantine for use in major neurocognitive disorder due to AD and rivastigmine (an acetylcholinesterase inhibitor) for major neurocognitive disorder due to Parkinson disease. Key words: acetylcholinesterase inhibitors, Alzheimer disease, amyloid precursor protein, frontotemporal lobar degeneration, Lewy body disease, major neurocognitive disorder, memantine, Parkinson disease, tau proteins, vascular disease

Major Neurocognitive Disorders

Major neurocognitive disorder is the most common neurodegenerative condition in the world and the leading cause of dependence and disability among older adults worldwide. There are numerous etiologies for major neurocognitive disorder, of which Alzheimer disease (AD) is the most common. Available evidence indicates that the risk factors for major neurocognitive disorder include older age, female sex, lower educational attainment, obesity, and vascular risk factors, including smoking, hypertension, diabetes mellitus, and hyperlipidemia. Certain etiologies for major neurocognitive disorder are heritable, especially those due to AD and frontotemporal lobar degeneration. The pathophysiologic changes associated with the various etiologies of major neurocognitive disorder include neuronal loss, senile plaques, neurofibrillary tangles, vascular pathology, and α-synuclein neuronal inclusions. Major neurocognitive disorder remains a clinical diagnosis with a thorough history, appropriate laboratory tests, and standardized rating scales assisting in determining the etiology and severity of the condition. In older adults, major neurocognitive disorder must be differentiated from depression and delirium as these three conditions may have similar clinical presentations or may coexist. Current data indicate that approximately a third of the cases of major neurocognitive disorder, especially those due to AD, may be prevented by controlling potentially modifiable risk factors, including diabetes, depression, smoking, physical inactivity, midlife hypertension, midlife obesity, and low educational attainment. Currently, the only Food and Drug Administration–approved medications are acetylcholinesterase inhibitors and memantine for use in major neurocognitive disorder due to AD and rivastigmine (an acetylcholinesterase inhibitor) for major neurocognitive disorder due to Parkinson disease. Key words: acetylcholinesterase inhibitors, Alzheimer disease, amyloid precursor protein, frontotemporal lobar degeneration, Lewy body disease, major neurocognitive disorder, memantine, Parkinson disease, tau proteins, vascular disease

The distributional effect of education on body mass

We investigate the effect of education on mid-life obesity, with particular attention to potential heterogeneity across the Body Mass Index (BMI) distribution. Applying quantile regression methods to British men and women, we first find that childhood and parental BMI are critical determinants of obesity in middle age. We then establish that even when controlling for various weight-related factors in childhood and a potential endogeneity bias, a higher education level reduces the probability of being obese in middle age. We show that this education effect is obtained by a compression of the distribution of BMI (kg/m2) and a shifting of its center leftward toward a more healthy BMI range. We further show that income and physical activity are important channels of the education effect, and the significant effect of education at the upper quantile of the BMI distribution is neither a disguised income effect nor a healthy behavior effect.

Investigating the relationship between BMI across adulthood and late life brain pathologies

BackgroundIn view of reported associations between high adiposity, particularly in midlife and late-life dementia risk, we aimed to determine associations between body mass index (BMI), and BMI changes across adulthood and brain structure and pathology at age 69–71 years.MethodsFour hundred sixty-five dementia-free participants from Insight 46, a sub-study of the British 1946 birth cohort, who had cross-sectional T1/FLAIR volumetric MRI, and florbetapir amyloid-PET imaging at age 69–71 years, were included in analyses. We quantified white matter hyperintensity volume (WMHV) using T1 and FLAIR 3D-MRI; β-amyloid (Aβ) positivity/negativity using a SUVR approach; and whole brain (WBV) and hippocampal volumes (HV) using 3D T1-MRI. We investigated the influence of BMI, and BMI changes at and between 36, 43, 53, 60–64, 69 and 71 years, on late-life WMHV, Aβ-status, WBV and mean HV. Analyses were repeated using overweight and obese status.ResultsAt no time-point was BMI, change in BMI or overweight/obese status associated with WMHV or WBV at age 69–71 years. Decreasing BMI in the 1–2 years before imaging was associated with an increased odds of being β-amyloid positive (OR 1.45, 95% confidence interval 1.09, 1.92). There were associations between being overweight and larger mean HV at ages 60–64 (β = 0.073 ml, 95% CI 0.009, 0.137), 69 (β = 0.076 ml, 95% CI 0.012, 0.140) and 71 years (β = 0.101 ml, 95% CI 0.037, 0.165). A similar, albeit weaker, trend was seen with obese status.ConclusionsUsing WMHV, β-amyloid status and brain volumes as indicators of brain health, we do not find evidence to explain reported associations between midlife obesity and late-life dementia risk. Declining BMI in later life may reflect preclinical Alzheimer’s disease.