Sedentary behavior and lifespan brain health.

Higher levels of physical activity are known to benefit aspects of brain health across the lifespan. However, the role of sedentary behavior (SB) is less well understood. In this review we summarize and discuss evidence on the role of SB on brain health (including cognitive performance, structural or functional brain measures, and dementia risk) for different age groups, critically compare assessment approaches to capture SB, and offer insights into emerging opportunities to assess SB via digital technologies. Across the lifespan, specific characteristics of SB (particularly whether they are cognitively active or cognitively passive) potentially act as moderators influencing the associations between SB and specific brain health outcomes. We outline challenges and opportunities for future research aiming to provide more robust empirical evidence on these observations.

Mendelian Randomization of Blood Metabolites Suggests Circulating Glutamine Protects Against Late-Onset Alzheimer's Disease.

Background: Late-onset Alzheimer's disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD. Objective: We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk. Methods: We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n = 115,082) and GWAS of LOAD (ncase = 21,982, ncontrol = 41,944). Results: MR analysis of metabolites as exposures revealed a negative association of genetically-predicted glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional. Conclusions: Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD.

Impact of age and apolipoprotein E ε4 status on regional white matter hyperintensity volume and cognition in healthy aging.

OBJECTIVE: White matter hyperintensity (WMH) volume is a neuroimaging marker of lesion load related to small vessel disease that has been associated with cognitive aging and Alzheimer's disease (AD) risk. METHOD: The present study sought to examine whether regional WMH volume mediates the relationship between APOE ε4 status, a strong genetic risk factor for AD, and cognition and if this association is moderated by age group differences within a sample of 187 healthy older adults (APOE ε4 status [carrier/non-carrier] = 56/131). RESULTS: After we controlled for sex, education, and vascular risk factors, ANCOVA analyses revealed significant age group by APOE ε4 status interactions for right parietal and left temporal WMH volumes. Within the young-old group (50-69 years), ε4 carriers had greater right parietal and left temporal WMH volumes than non-carriers. However, in the old-old group (70-89 years), right parietal and left temporal WMH volumes were comparable across APOE ε4 groups. Further, within ε4 non-carriers, old-old adults had greater right parietal and left temporal WMH volumes than young-old adults, but there were no significant differences across age groups in ε4 carriers. Follow-up moderated mediation analyses revealed that, in the young-old, but not the old-old group, there were significant indirect effects of ε4 status on memory and executive functions through left temporal WMH volume. CONCLUSIONS: These findings suggest that, among healthy young-old adults, increased left temporal WMH volume, in the context of the ε4 allele, may represent an early marker of cognitive aging with the potential to lead to greater risk for AD.

Regional covariance of white matter hyperintensity volume patterns associated with hippocampal volume in healthy aging.

Hippocampal volume is particularly sensitive to the accumulation of total brain white matter hyperintensity volume (WMH) in aging, but how the regional distribution of WMH volume differentially impacts the hippocampus has been less studied. In a cohort of 194 healthy older adults ages 50-89, we used a multivariate statistical method, the Scaled Subprofile Model (SSM), to (1) identify patterns of regional WMH differences related to left and right hippocampal volumes, (2) examine associations between the multimodal neuroimaging covariance patterns and demographic characteristics, and (3) investigate the relation of the patterns to subjective and objective memory in healthy aging. We established network covariance patterns of regional WMH volume differences associated with greater left and right hippocampal volumes, which were characterized by reductions in left temporal and right parietal WMH volumes and relative increases in bilateral occipital WMH volumes. Additionally, we observed lower expression of these hippocampal-related regional WMH patterns were significantly associated with increasing age and greater subjective memory complaints, but not objective memory performance in this healthy older adult cohort. Our findings indicate that, in cognitively healthy older adults, left and right hippocampal volume reductions were associated with differences in the regional distribution of WMH volumes, which were exacerbated by advancing age and related to greater subjective memory complaints. Multivariate network analyses, like SSM, may help elucidate important early effects of regional WMH volume on brain and cognitive aging in healthy older adults.

Associations between physical exercise type, fluid intelligence, executive function, and processing speed in the oldest-old (85 +).

BACKGROUND: While much is known about the effects of physical exercise in adult humans, literature on the oldest-old (≥ 85 years old) is sparse. The present study explored the relationship between self-reported engagement in physical exercise and cognition in the oldest-old. METHODS: The sample included 184 cognitively healthy participants (98 females, MoCA mean score = 24.81) aged 85 to 99 years old (mean = 88.49 years). Participants completed the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire and a cognitive battery including NIH-TB, Coding, Symbol Search, Letter Fluency, and Stroop task. Three groups of participants - sedentary (n = 58; MoCA mean score = 24; 36 females; mean age = 89.03), cardio (n = 60; MoCA mean score = 25.08; 29 females; mean age = 88.62), and cardio + strength training (n = 66; MoCA mean score = 25.28; 33 females; mean age = 87.91) - were derived from responses on CHAMPS. RESULTS: Analyses controlled for years of education, NIH-TB Crystallized Composite, and metabolic equivalent of tasks. The cardio + strength training group had the highest cognitive performances overall and scored significantly better on Coding (p < 0.001) and Symbol Search (p < 0.05) compared to the sedentary group. The cardio + strength training group scored significantly better on Symbol Search, Letter Fluency, and Stroop Color-Word compared to the cardio group (p < 0.05). CONCLUSIONS: Our findings suggest self-reported exercise in the oldest-old is linked to better performance on cognitive measures of processing speed and executive functioning, and that there may be a synergistic effect of combining aerobic and resistance training on cognition.

Lifestyle and patterns of physical activity in Hadza foragers.

OBJECTIVES: Physically active lifestyles are associated with several health benefits. Physical activity (PA) levels are low in post-industrial populations, but generally high throughout life in subsistence populations. The Hadza are a subsistence-oriented foraging population in Tanzania known for being physically active, but it is unknown how recent increases in market integration may have altered their PA patterns. In this study, we examine PA patterns for Hadza women and men who engage in different amounts of traditional foraging. MATERIALS AND METHODS: One hundred and seventy seven Hadza participants (51% female, 19-87 years) wore an Axivity accelerometer (dominant wrist) for ~6 days during dry season months. We evaluated the effects of age, sex, and lifestyle measures on four PA measures that capture different aspects of the PA profile. RESULTS: Participants engaged in high levels of both moderate-intensity PA and inactivity. Although PA levels were negatively associated with age, older participants were still highly active. We found no differences in PA between participants living in more traditional "bush" camps and those living in more settled "village" camps. Mobility was positively associated with step counts for female participants, and schooling was positively associated with inactive time for male participants. CONCLUSIONS: The similarity in PA patterns between Hadza participants in different camp types suggests that high PA levels characterize subsistence lifestyles generally. The sex-based difference in the effects of mobility and schooling on PA could be a reflection of the Hadza's gender-based division of labor, or indicate that changes to subsistence-oriented lifestyles impact women and men in different ways.

Sedentary Behavior and Incident Dementia Among Older Adults.

Importance: Sedentary behavior is associated with cardiometabolic disease and mortality, but its association with dementia is unclear. Objective: To investigate whether accelerometer-assessed sedentary behavior is associated with incident dementia. Design, Setting, and Participants: A retrospective study of prospectively collected data from the UK Biobank including 49 841 adults aged 60 years or older without a diagnosis of dementia at the time of wearing the wrist accelerometer and living in England, Scotland, or Wales. Follow-up began at the time of wearing the accelerometer (February 2013 to December 2015) and continued until September 2021 in England, July 2021 in Scotland, and February 2018 in Wales. Exposures: Mean daily sedentary behavior time (included in the primary analysis) and mean daily sedentary bout length, maximum daily sedentary bout length, and mean number of daily sedentary bouts (included in the secondary analyses) were derived from a machine learning-based analysis of 1 week of wrist-worn accelerometer data. Main Outcome and Measures: Incident all-cause dementia diagnosis from inpatient hospital records and death registry data. Cox proportional hazard models with linear and cubic spline terms were used to assess associations. Results: A total of 49 841 older adults (mean age, 67.19 [SD, 4.29] years; 54.7% were female) were followed up for a mean of 6.72 years (SD, 0.95 years). During this time, 414 individuals were diagnosed with incident all-cause dementia. In the fully adjusted models, there was a significant nonlinear association between time spent in sedentary behavior and incident dementia. Relative to a median of 9.27 hours/d for sedentary behavior, the hazard ratios (HRs) for dementia were 1.08 (95% CI, 1.04-1.12, P < .001) for 10 hours/d, 1.63 (95% CI, 1.35-1.97, P < .001) for 12 hours/d, and 3.21 (95% CI, 2.05-5.04, P < .001) for 15 hours/d. The adjusted incidence rate of dementia per 1000 person-years was 7.49 (95% CI, 7.48-7.49) for 9.27 hours/d of sedentary behavior, 8.06 (95% CI, 7.76-8.36) for 10 hours/d, 12.00 (95% CI, 10.00-14.36) for 12 hours/d, and 22.74 (95% CI, 14.92-34.11) for 15 hours/d. Mean daily sedentary bout length (HR, 1.53 [95% CI, 1.03-2.27], P = .04 and 0.65 [95% CI, 0.04-1.57] more dementia cases per 1000 person-years for a 1-hour increase from the mean of 0.48 hours) and maximum daily sedentary bout length (HR, 1.15 [95% CI, 1.02-1.31], P = .02 and 0.19 [95% CI, 0.02-0.38] more dementia cases per 1000 person-years for a 1-hour increase from the mean of 1.95 hours) were significantly associated with higher risk of incident dementia. The number of sedentary bouts per day was not associated with higher risk of incident dementia (HR, 1.00 [95% CI, 0.99-1.01], P = .89). In the sensitivity analyses, after adjustment for time spent in sedentary behavior, the mean daily sedentary bout length and the maximum daily sedentary bout length were no longer significantly associated with incident dementia. Conclusions and Relevance: Among older adults, more time spent in sedentary behaviors was significantly associated with higher incidence of all-cause dementia. Future research is needed to determine whether the association between sedentary behavior and risk of dementia is causal.

Genetic insights into the causal relationship between physical activity and cognitive functioning.

Physical activity and cognitive functioning are strongly intertwined. However, the causal relationships underlying this association are still unclear. Physical activity can enhance brain functions, but healthy cognition may also promote engagement in physical activity. Here, we assessed the bidirectional relationships between physical activity and general cognitive functioning using Latent Heritable Confounder Mendelian Randomization (LHC-MR). Association data were drawn from two large-scale genome-wide association studies (UK Biobank and COGENT) on accelerometer-measured moderate, vigorous, and average physical activity (N = 91,084) and cognitive functioning (N = 257,841). After Bonferroni correction, we observed significant LHC-MR associations suggesting that increased fraction of both moderate (b = 0.32, CI95% = [0.17,0.47], P = 2.89e - 05) and vigorous physical activity (b = 0.22, CI95% = [0.06,0.37], P = 0.007) lead to increased cognitive functioning. In contrast, we found no evidence of a causal effect of average physical activity on cognitive functioning, and no evidence of a reverse causal effect (cognitive functioning on any physical activity measures). These findings provide new evidence supporting a beneficial role of moderate and vigorous physical activity (MVPA) on cognitive functioning.

Validity of the NIH toolbox cognitive battery in a healthy oldest-old 85+ sample.

OBJECTIVE: To evaluate the construct validity of the NIH Toolbox Cognitive Battery (NIH TB-CB) in the healthy oldest-old (85+ years old). METHOD: Our sample from the McKnight Brain Aging Registry consists of 179 individuals, 85 to 99 years of age, screened for memory, neurological, and psychiatric disorders. Using previous research methods on a sample of 85 + y/o adults, we conducted confirmatory factor analyses on models of NIH TB-CB and same domain standard neuropsychological measures. We hypothesized the five-factor model (Reading, Vocabulary, Memory, Working Memory, and Executive/Speed) would have the best fit, consistent with younger populations. We assessed confirmatory and discriminant validity. We also evaluated demographic and computer use predictors of NIH TB-CB composite scores. RESULTS: Findings suggest the six-factor model (Vocabulary, Reading, Memory, Working Memory, Executive, and Speed) had a better fit than alternative models. NIH TB-CB tests had good convergent and discriminant validity, though tests in the executive functioning domain had high inter-correlations with other cognitive domains. Computer use was strongly associated with higher NIH TB-CB overall and fluid cognition composite scores. CONCLUSION: The NIH TB-CB is a valid assessment for the oldest-old samples, with relatively weak validity in the domain of executive functioning. Computer use's impact on composite scores could be due to the executive demands of learning to use a tablet. Strong relationships of executive function with other cognitive domains could be due to cognitive dedifferentiation. Overall, the NIH TB-CB could be useful for testing cognition in the oldest-old and the impact of aging on cognition in older populations.

Association of homocysteine-related subcortical brain atrophy with white matter lesion volume and cognition in healthy aging.

Homocysteine (Hcy) is a vascular risk factor associated with cognitive impairment and cerebrovascular disease but has also been implicated in Alzheimer's disease (AD). Using multivariate Scaled Subprofile Model (SSM) analysis, we sought to identify a network pattern in structural neuroimaging reflecting the regionally distributed association of plasma Hcy with subcortical gray matter (SGM) volumes and its relation to other health risk factors and cognition in 160 healthy older adults, ages 50-89. We identified an SSM Hcy-SGM pattern that was characterized by bilateral hippocampal and nucleus accumbens volume reductions with relative volume increases in bilateral caudate, pallidum, and putamen. Greater Hcy-SGM pattern expression was associated with greater white matter hyperintensity (WMH) volume, older age, and male sex, but not with other vascular and AD-related risk factors. Mediation analyses revealed that age predicted WMH volume, which predicted Hcy-SGM pattern expression, which, in turn, predicted cognitive processing speed performance. These findings suggest that the multivariate SSM Hcy-SGM pattern may be indicative of cognitive aging, reflecting a potential link between vascular health and cognitive dysfunction in healthy older adults.

Associations between physical activity and cognitive dysfunction in older companion dogs: results from the Dog Aging Project.

Canine cognitive dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimer's disease. Given that physical activity is believed to reduce risk of Alzheimer's disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6-18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity-with several important covariates-as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = - 0.10, 95% CI: - 0.11 to - 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate = - 0.07, 95% CI: - 0.09 to - 0.05, p < 0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p < 0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimer's disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical activity interventions.

The evolution of human step counts and its association with the risk of chronic disease.

Walking - humans' most fundamental form of moderate intensity physical activity - is associated with reduced risks of morbidity and mortality. Evolutionary perspectives have contributed much to understanding the effects of walking and other physical activities on health; however, we know comparatively little about how step counts (steps taken per day) changed over the course of human evolution, potentially affecting how selection operated on physiological responses to moderate intensity physical activity that influence morbidity and mortality. Here, we compare step counts across humans and our closest living relatives, the great apes. Compiling data from epidemiology and comparative physiology, we show how step counts more than tripled during human evolution, potentially linking higher levels of moderate intensity physical activity with reduced morbidity and mortality, and we highlight how recent decreases in step counts are an evolutionary mismatch. We raise the hypothesis that the dose-response relationship between moderate intensity physical activity and health was shifted in humans to require more steps per day to promote extended healthspan and lifespan.

Association of sedentary and physical activity behaviours with body composition: a genome-wide association and Mendelian randomisation study.

Objectives: Studies suggest that body composition can be independently improved through physical activity (PA). We performed a Mendelian randomisation (MR) study to test the incremental benefits of sedentary behaviour and various PA exposures on body composition outcomes as assessed by anthropometric indices, lean body mass (kg), body fat (%) and visceral adipose tissue (VAT) (kg). Methods: Genetic instruments were identified for both self-reported and accelerometer-measured sedentary behaviour and PA. Outcomes included anthropometric and dual-energy X-ray absorptiometry measures of adiposity, extracted from the UK Biobank and the largest available consortia. Multivariable MR (MVMR) included educational attainment as a covariate to address potential confounding. Sensitivity analyses were evaluated for weak instrument bias and pleiotropic effects. Results: We did not identify consistent associations between genetically predicted self-reported and accelerometer-measured sedentary behaviour and body composition outcomes. All analyses for self-reported moderate PA were null for body composition outcomes. Genetically predicted PA at higher intensities was protective against VAT in MR and MVMR analyses of both accelerometer-measured vigorous PA (MVMR ß=-0.15, 95% CI: -0.24 to -0.07, p<0.001) and self-reported participation in strenuous sports or other exercises (MVMR ß=-0.27, 95% CI: -0.52 to -0.01, p=0.034) was robust across several sensitivity analyses. Conclusions: We did not identify evidence of a causal relationship between genetically predicted PA and body composition, with the exception of a putatively protective effect of higher-intensity PA on VAT. Protective effects of PA against VAT may support prior evidence of biological pathways through which PA decreases risk of downstream cardiometabolic diseases.

Leisure-time sedentary behaviors are differentially associated with all-cause dementia regardless of engagement in physical activity.

Sedentary behavior (SB) is associated with cardiometabolic disease and mortality, but its association with dementia is currently unclear. This study investigates whether SB is associated with incident dementia regardless of engagement in physical activity (PA). A total of 146,651 participants from the UK Biobank who were 60 years or older and did not have a diagnosis of dementia (mean [SD] age: 64.59 [2.84] years) were included. Self-reported leisure-time SBs were divided into two domains: time spent watching television (TV) or time spent using a computer. A total of 3,507 individuals were diagnosed with all-cause dementia over a mean follow-up of 11.87 (±1.17) years. In models adjusted for a wide range of covariates, including time spent in PA, time spent watching TV was associated with increased risk of incident dementia (HR [95% CI] = 1.24 [1.15 to 1.32]) and time spent using a computer was associated with decreased risk of incident dementia (HR [95% CI] = 0.85 [0.81 to 0.90]). In joint associations with PA, TV time and computer time remained significantly associated with dementia risk at all PA levels. Reducing time spent in cognitively passive SB (i.e., TV time) and increasing time spent in cognitively active SB (i.e., computer time) may be effective behavioral modification targets for reducing risk of dementia regardless of engagement in PA.

Association of Physical Activity with Incidence of Dementia Is Attenuated by Air Pollution.

INTRODUCTION: Physical activity (PA) is recognized as one of the key lifestyle behaviors that reduces risk of developing dementia late in life. However, PA also leads to increased respiration, and in areas with high levels of air pollution, PA may increase exposure to pollutants linked with higher risk of developing dementia. Here, we investigate whether air pollution attenuates the association between PA and dementia risk. METHODS: This prospective cohort study included 35,562 adults 60 yrs and older from the UK Biobank. Average acceleration magnitude (ACCave) from wrist-worn accelerometers was used to assess PA levels. Air pollution levels (NO, NO2, PM10, PM2.5, PM2.5-10, and PM2.5 absorbance) were estimated with land use regression methods. Incident all-cause dementia was derived from inpatient hospital records and death registry data. RESULTS: In adjusted models, ACCave was associated with reduced risk of developing dementia (HR = 0.71, 95% confidence interval [CI] = 0.60-0.83), whereas air pollution variables were not associated with dementia risk. There were significant interactions between ACCave and PM2.5 (HRinteraction = 1.33, 95% CI = 1.13-1.57) and PM2.5 absorbance (HRinteraction = 1.24, 95% CI = 1.07-1.45) on incident dementia. At the lowest tertiles of pollution, ACCave was associated with reduced risk of incident dementia (HRPM 2.5 = 0.66, 95% CI = 0.49-0.91; HRPM 2.5 absorbance = 0.60, 95% CI = 0.44-0.81). At the highest tertiles of these pollutants, there was no significant association of ACCave with incident dementia (HRPM 2.5 = 0.88, 95% CI = 0.68-1.14; HRPM 2.5 absorbance = 0.79, 95% CI = 0.60-1.04). CONCLUSIONS: PA is associated with reduced risk of developing all-cause dementia. However, exposure to even moderate levels of air pollution attenuates the benefits of PA on risk of dementia.

Genome-wide Association Study of Liking for Several Types of Physical Activity in the UK Biobank and Two Replication Cohorts.

INTRODUCTION: A lack of physical activity (PA) is one of the most pressing health issues today. Our individual propensity for PA is influenced by genetic factors. Stated liking of different PA types may help capture additional and informative dimensions of PA behavior genetics. METHODS: In over 157,000 individuals from the UK Biobank, we performed genome-wide association studies of five items assessing the liking of different PA types, plus an additional derived trait of overall PA-liking. We attempted to replicate significant associations in the Netherlands Twin Register (NTR) and TwinsUK. Additionally, polygenic scores (PGS) were trained in the UK Biobank for each PA-liking item and for self-reported PA behavior, and tested for association with PA in the NTR. RESULTS: We identified a total of 19 unique significant loci across all five PA-liking items and the overall PA-liking trait, and these showed strong directional consistency in the replication cohorts. Four of these loci were previously identified for PA behavior, including CADM2 , which was associated with three PA-liking items. The PA-liking items were genetically correlated with self-reported ( rg = 0.38-0.80) and accelerometer ( rg = 0.26-0.49) PA measures, and with a wide range of health-related traits. Each PA-liking PGS significantly predicted the same PA-liking item in NTR. The PGS of liking for going to the gym predicted PA behavior in the NTR ( r2 = 0.40%) nearly as well as a PGS based on self-reported PA behavior ( r2 = 0.42%). Combining the two PGS into a single model increased the r2 to 0.59%, suggesting that PA-liking captures distinct and relevant dimensions of PA behavior. CONCLUSIONS: We have identified the first loci associated with PA-liking and extended our understanding of the genetic basis of PA behavior.

Exposure to air pollution and risk of incident dementia in the UK Biobank.

BACKGROUND: Air pollution may cause inflammatory and oxidative stress damage to the brain, leading to neurodegenerative disease. The association between air pollution and dementia, and modification by apolipoprotein E genotype 4 (APOE-ε4) has yet to be fully investigated. OBJECTIVES: To examine associations of air pollution with three types of incident dementias (Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VAD)), and their potential modification by APOE-ε4 genotype. METHODS: The UK Biobank enrolled >500,000 participants (2006-2010) with ongoing follow-up. We used annual averages of air pollution (PM2.5, PM10, PM2.5-10, PM2.5absorbance, NO2, NOX) for 2010 scaled to interquartile ranges (IQR). We included individuals aged ≥60 years, with no dementia diagnosis prior to January 1, 2010. Time to incident dementia and follow-up time were reported from baseline (January 01, 2010) to last censor event (death, last hospitalization, or loss to follow-up). Cox proportional hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated to estimate the association of air pollutants and incident dementia, and modification of these associations by APOE-ε4. RESULTS: Our sample included 187,194 individuals (including N = 680 AD, N = 377 VAD, N = 63 FTD) with a mean follow-up of 7.04 years. We observed consistent associations of PM2.5 with greater risk of all-cause dementia (HR = 1.17, 95% CI: 1.10, 1.24) and AD (HR = 1.17, 95% CI: 1.06, 1.29). NO2 was also associated with greater risk of any incident dementia (HR = 1.18, 95% CI: 1.10, 1.25), AD (HR = 1.15, 95% CI: 1.04, 1.28) and VAD (HR = 1.18, 95% CI: 1.03, 1.35). APOE-ε4 did not modify the association between any air pollutants and dementia. DISCUSSION: PM2.5 and NO2 levels were associated with several types of dementia, and these associations were not modified by APOE-ε4. Findings from the UK Biobank support and extend to other epidemiological evidence for the potential association of air pollutants with detrimental brain health during aging.

Association of Air Pollution and Physical Activity With Brain Volumes.

OBJECTIVE: In high pollution areas, physical activity may have a paradoxical effect on brain health by increasing particulate deposition in the lungs. We examined whether physical activity modifies associations of air pollution with brain volumes in an epidemiological framework. METHODS: The UK Biobank (UKB) enrolled >500,000 adult participants from 2006-2010. Wrist accelerometers, multimodal MRI with T1 images and T2 FLAIR data, and land use regression, were used to estimate vigorous physical activity (VigPA), structural brain volumes, and air pollution (AP) respectively in subsets of the full sample. We evaluated associations between AP interquartile ranges, VigPA, and brain structure volumes, and assessed interactions between AP and VigPA. RESULTS: 8,600 participants were included, with an average age of 55.55 (sd=7.46). After correcting for multiple testing, in overall models VigPA was positively associated with grey matter (GMV) and negatively associated with white matter hyperintensity volumes (WMHV), while NO2, PM2.5absorbance, and PM2.5 were negatively associated with GMV. NO2 and PM2.5absorbance interacted with VigPA on WMHV (FDR-corrected interaction p-values=0.037). Associations between these air pollutants and WMHVs were stronger among participants with high VigPA. Similarly, VigPA was negatively associated with WMHV for those in areas of low NO2 and PM2.5absorbance, but was null among those living in areas of high NO2 and PM2.5absorbance. CONCLUSIONS: Physical activity is associated with beneficial brain outcomes, while AP is associated with detrimental brain outcomes. Vigorous physical activity may exacerbate associations of AP with white matter hyperintensity lesions, and AP may attenuate the beneficial associations of physical activity with these lesions.

The energetics of uniquely human subsistence strategies.

The suite of derived human traits, including enlarged brains, elevated fertility rates, and long developmental periods and life spans, imposes extraordinarily high energetic costs relative to other great apes. How do human subsistence strategies accommodate our expanded energy budgets? We found that relative to other great apes, human hunter-gatherers and subsistence farmers spend more energy but less time on subsistence, acquire substantially more energy per hour, and achieve similar energy efficiencies. These findings revise our understanding of human energetic evolution by indicating that humans afford expanded energy budgets primarily by increasing rates of energy acquisition, not through energy-saving adaptations such as economical bipedalism or sophisticated tool use that decrease subsistence costs and improve the energetic efficiency of subsistence. We argue that the time saved by human subsistence strategies provides more leisure time for social interaction and social learning in central-place locations and would have been critical for cumulative cultural evolution.