Poor oral health is associated with inflammation, aortic valve calcification, and brain volume among forager-farmers.

Poor oral health is associated with cardiovascular disease and dementia. Potential pathways include sepsis from oral bacteria, systemic inflammation, and nutritional deficiencies. However, in post-industrialized populations, links between oral health and chronic disease may be confounded because the lower socioeconomic exposome (poor diet, pollution, low physical activity) often entails insufficient dental care. We assessed tooth loss, caries, and damaged teeth, in relation to cardiovascular and brain aging among the Tsimane, a subsistence population living a relatively traditional forager-horticulturalist lifestyle with poor dental health, but minimal cardiovascular disease and dementia. Dental health was assessed by a physician in 739 participants aged 40-92 years with cardiac and brain health measured by chest computed tomography (CT) (n=728) and brain CT (n=605). A subset of 356 individuals aged 60+ were also assessed for dementia and mild cognitive impairment (n=33 impaired). Tooth loss was highly prevalent, with 2.2 teeth lost per decade and a 2-fold greater loss in women. The number of teeth with exposed pulp was associated with higher inflammation, as measured by cytokine levels and white blood cell counts, and lower body mass index. Coronary artery calcium and thoracic aortic calcium were not associated with tooth loss or damaged teeth. However, aortic valve calcification and brain tissue loss were higher in those that had more teeth with exposed pulp. Overall, these results suggest that dental health is associated with indicators of chronic diseases in the absence of typical confounds, even in a population with low cardiovascular and dementia risk factors.

Testosterone is positively associated with coronary artery calcium in a low cardiovascular disease risk population.

Background: In industrialized populations, low male testosterone is associated with higher rates of cardiovascular mortality. However, coronary risk factors like obesity impact both testosterone and cardiovascular outcomes. Here, we assess the role of endogenous testosterone on coronary artery calcium in an active subsistence population with relatively low testosterone levels, low cardiovascular risk and low coronary artery calcium scores. Methodology: In this cross-sectional community-based study, 719 Tsimane forager-horticulturalists in the Bolivian Amazon aged 40+ years underwent computed tomography (49.8% male, mean age 57.6 years). Results: Coronary artery calcium levels were low; 84.5% had no coronary artery calcium. Zero-inflated negative binomial models found testosterone was positively associated with coronary artery calcium for the full sample (Incidence Rate Ratio [IRR] = 1.477, 95% Confidence Interval [CI] 1.001-2.170, P = 0.031), and in a male-only subset (IRR = 1.532, 95% CI 0.993-2.360, P = 0.053). Testosterone was also positively associated with clinically relevant coronary atherosclerosis (calcium >100 Agatston units) in the full sample (Odds Ratio [OR] = 1.984, 95% CI 1.202-3.275, P = 0.007) and when limited to male-only sample (OR = 2.032, 95% CI 1.118-4.816, P = 0.024). Individuals with coronary artery calcium >100 had 20% higher levels of testosterone than those with calcium <100 (t = -3.201, P = 0.007). Conclusions and Implications: Among Tsimane, testosterone is positively associated with coronary artery calcium despite generally low normal testosterone levels, minimal atherosclerosis and rare cardiovascular disease (CVD) events. Associations between low testosterone and CVD events in industrialized populations are likely confounded by obesity and other lifestyle factors.

Sustainable Production Insight Through LCA and LCC Analysis of Injection Overmolded Structural Electronics Manufactured through Roll-to-Roll Processes.

Printed electronics (PE) have provided new material and application opportunities for devices and systems as well as new manufacturing routes that all need to be considered for commercialization. This paper introduces a case study with universally relevant manufacturing processes and applications in the PE area, focusing on the Life Cycle Assessment (LCA) and Life Cycle Costing (LCC) of the Personal Activity Monitor (PAM) device. In the study, the PAM device's most important costs and environmental impacts during the prototype pilot production and device use phases are identified and assessed. Additionally, the potential environmental impacts of post-consumption scenarios are considered. The LCA results indicate that the roll-to-roll (R2R) assembly of electronics and the R2R injection over-molding are generally the most prominent production process steps affecting the results. From the LCC perspective, the capitial expenditure (CAPEX) contributor is the R2R assembly pilot line, due to its high investment cost and long operating time compare to other production assets. The traditional electronic components are the major operating expenditures (OPEX), especially the microcontroller units (MCUs) and accelerometers, in contrast to the low impact from the printed electronics. There are several advantages to applying LCA and LCC since they provide explanations of the relationships between cost, environmental, design, and manufacturing characteristics.

Applying an evolutionary mismatch framework to understand disease susceptibility.

Noncommunicable diseases (NCDs) are on the rise worldwide. Obesity, cardiovascular disease, and type 2 diabetes are among a long list of "lifestyle" diseases that were rare throughout human history but are now common. The evolutionary mismatch hypothesis posits that humans evolved in environments that radically differ from those we currently experience; consequently, traits that were once advantageous may now be "mismatched" and disease causing. At the genetic level, this hypothesis predicts that loci with a history of selection will exhibit "genotype by environment" (GxE) interactions, with different health effects in "ancestral" versus "modern" environments. To identify such loci, we advocate for combining genomic tools in partnership with subsistence-level groups experiencing rapid lifestyle change. In these populations, comparisons of individuals falling on opposite extremes of the "matched" to "mismatched" spectrum are uniquely possible. More broadly, the work we propose will inform our understanding of environmental and genetic risk factors for NCDs across diverse ancestries and cultures.

Metapopulation dynamics of SARS-CoV-2 transmission in a small-scale Amazonian society.

The severity of infectious disease outbreaks is governed by patterns of human contact, which vary by geography, social organization, mobility, access to technology and healthcare, economic development, and culture. Whereas globalized societies and urban centers exhibit characteristics that can heighten vulnerability to pandemics, small-scale subsistence societies occupying remote, rural areas may be buffered. Accordingly, voluntary collective isolation has been proposed as one strategy to mitigate the impacts of COVID-19 and other pandemics on small-scale Indigenous populations with minimal access to healthcare infrastructure. To assess the vulnerability of such populations and the viability of interventions such as voluntary collective isolation, we simulate and analyze the dynamics of SARS-CoV-2 infection among Amazonian forager-horticulturalists in Bolivia using a stochastic network metapopulation model parameterized with high-resolution empirical data on population structure, mobility, and contact networks. Our model suggests that relative isolation offers little protection at the population level (expected approximately 80% cumulative incidence), and more remote communities are not conferred protection via greater distance from outside sources of infection, due to common features of small-scale societies that promote rapid disease transmission such as high rates of travel and dense social networks. Neighborhood density, central household location in villages, and household size greatly increase the individual risk of infection. Simulated interventions further demonstrate that without implausibly high levels of centralized control, collective isolation is unlikely to be effective, especially if it is difficult to restrict visitation between communities as well as travel to outside areas. Finally, comparison of model results to empirical COVID-19 outcomes measured via seroassay suggest that our theoretical model is successful at predicting outbreak severity at both the population and community levels. Taken together, these findings suggest that the social organization and relative isolation from urban centers of many rural Indigenous communities offer little protection from pandemics and that standard control measures, including vaccination, are required to counteract effects of tight-knit social structures characteristic of small-scale populations.

Evolutionary mismatch and the role of GxE interactions in human disease.

Globally, we are witnessing the rise of complex, non-communicable diseases (NCDs) related to changes in our daily environments. Obesity, asthma, cardiovascular disease, and type 2 diabetes are part of a long list of "lifestyle" diseases that were rare throughout human history but are now common. A key idea from anthropology and evolutionary biology-the evolutionary mismatch hypothesis-seeks to explain this phenomenon. It posits that humans evolved in environments that radically differ from the ones experienced by most people today, and thus traits that were advantageous in past environments may now be "mismatched" and disease-causing. This hypothesis is, at its core, a genetic one: it predicts that loci with a history of selection will exhibit "genotype by environment" (GxE) interactions and have differential health effects in ancestral versus modern environments. Here, we discuss how this concept could be leveraged to uncover the genetic architecture of NCDs in a principled way. Specifically, we advocate for partnering with small-scale, subsistence-level groups that are currently transitioning from environments that are arguably more "matched" with their recent evolutionary history to those that are more "mismatched". These populations provide diverse genetic backgrounds as well as the needed levels and types of environmental variation necessary for mapping GxE interactions in an explicit mismatch framework. Such work would make important contributions to our understanding of environmental and genetic risk factors for NCDs across diverse ancestries and sociocultural contexts.

Prevalence of dementia and mild cognitive impairment in indigenous Bolivian forager-horticulturalists.

INTRODUCTION: We evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle. METHODS: Participants from population-based samples ≥ 60 years of age (n = 623) were assessed using adapted versions of the Modified Mini-Mental State Examination, informant interview, longitudinal cognitive testing and brain computed tomography (CT) scans. RESULTS: Tsimane exhibited five cases of dementia (among n = 435; crude prevalence = 1.2%, 95% confidence interval [CI]: 0.4, 2.7); Moseten exhibited one case (among n = 169; crude prevalence = 0.6%, 95% CI: 0.0, 3.2), all age ≥ 80 years. Age-standardized MCI prevalence was 7.7% (95% CI: 5.2, 10.3) in Tsimane and 9.8% (95% CI: 4.9, 14.6) in Moseten. Cognitive impairment was associated with visuospatial impairments, parkinsonian symptoms, and vascular calcification in the basal ganglia. DISCUSSION: The prevalence of dementia in this cohort is among the lowest in the world. Widespread intracranial medial arterial calcifications suggest a previously unrecognized, non-Alzheimer's disease (AD) dementia phenotype.

Female cooperative labour networks in hunter-gatherers and horticulturalists.

Cooperation in food acquisition is a hallmark of the human species. Given that costs and benefits of cooperation vary among production regimes and work activities, the transition from hunting-and-gathering to agriculture is likely to have reshaped the structure of cooperative subsistence networks. Hunter-gatherers often forage in groups and are generally more interdependent and experience higher short-term food acquisition risk than horticulturalists, suggesting that cooperative labour should be more widespread and frequent for hunter-gatherers. Here we compare female cooperative labour networks of Batek hunter-gatherers of Peninsular Malaysia and Tsimane forager-horticulturalists of Bolivia. We find that Batek foraging results in high daily variation in labour partnerships, facilitating frequent cooperation in diffuse networks comprised of kin and non-kin. By contrast, Tsimane horticulture involves more restricted giving and receiving of labour, confined mostly to spouses and primary or distant kin. Tsimane women also interact with few individuals in the context of hunting/fishing activities and forage mainly with spouses and primary kin. These differences give rise to camp- or village-level networks that are more modular (have more substructure when partitioned) among Tsimane horticulturalists. Our findings suggest that subsistence activities shape the formation and extent of female social networks, particularly with respect to connections with other women and non-kin. We discuss the implications of restricted female labour networks in the context of gender relations, power dynamics and the adoption of farming in humans. This article is part of the theme issue 'Cooperation among women: evolutionary and cross-cultural perspectives'.

Repercussions of patrilocal residence on mothers' social support networks among Tsimane forager-farmers.

While it is commonly thought that patrilocality is associated with worse outcomes for women and their children due to lower social support, few studies have examined whether the structure of female social networks covaries with post-marital residence. Here, we analyse scan sample data collected among Tsimane forager-farmers. We compare the social groups and activity partners of 181 women residing in the same community as their parents, their husband's parents, both or neither. Relative to women living closer to their in-laws, women living closer to their parents are less likely to be alone or solely in the company of their nuclear family (odds ratio (OR): 0.6, 95% CI: 0.3-0.9), and more likely to be observed with others when engaging in food processing and manufacturing of market or household goods, but not other activities. Women are slightly more likely to receive childcare support from outside the nuclear family when they live closer to their parents (OR = 1.8, 95% CI 0.8-3.9). Their social group size and their children's probability of receiving allocare decrease significantly with distance from their parents, but not their in-laws. Our findings highlight the importance of women's proximity to kin, but also indicate that patrilocality per se is not costly to Tsimane women. This article is part of the theme issue 'Cooperation among women: evolutionary and cross-cultural perspectives'.

Natural selection of immune and metabolic genes associated with health in two lowland Bolivian populations.

A growing body of work has addressed human adaptations to diverse environments using genomic data, but few studies have connected putatively selected alleles to phenotypes, much less among underrepresented populations such as Amerindians. Studies of natural selection and genotype-phenotype relationships in underrepresented populations hold potential to uncover previously undescribed loci underlying evolutionarily and biomedically relevant traits. Here, we worked with the Tsimane and the Moseten, two Amerindian populations inhabiting the Bolivian lowlands. We focused most intensively on the Tsimane, because long-term anthropological work with this group has shown that they have a high burden of both macro and microparasites, as well as minimal cardiometabolic disease or dementia. We therefore generated genome-wide genotype data for Tsimane individuals to study natural selection, and paired this with blood mRNA-seq as well as cardiometabolic and immune biomarker data generated from a larger sample that included both populations. In the Tsimane, we identified 21 regions that are candidates for selective sweeps, as well as 5 immune traits that show evidence for polygenic selection (e.g., C-reactive protein levels and the response to coronaviruses). Genes overlapping candidate regions were strongly enriched for known involvement in immune-related traits, such as abundance of lymphocytes and eosinophils. Importantly, we were also able to draw on extensive phenotype information for the Tsimane and Moseten and link five regions (containing PSD4, MUC21 and MUC22, TOX2, ANXA6, and ABCA1) with biomarkers of immune and metabolic function. Together, our work highlights the utility of pairing evolutionary analyses with anthropological and biomedical data to gain insight into the genetic basis of health-related traits.

Cultural variation in running techniques among non-industrial societies.

Research among non-industrial societies suggests that body kinematics adopted during running vary between groups according to the cultural importance of running. Among groups in which running is common and an important part of cultural identity, runners tend to adopt what exercise scientists and coaches consider to be good technique for avoiding injury and maximising performance. In contrast, among groups in which running is not particularly culturally important, people tend to adopt suboptimal technique. This paper begins by describing key elements of good running technique, including landing with a forefoot or midfoot strike pattern and leg oriented roughly vertically. Next, we review evidence from non-industrial societies that cultural attitudes about running associate with variation in running techniques. Then, we present new data from Tsimane forager-horticulturalists in Bolivia. Our findings suggest that running is neither a common activity among the Tsimane nor is it considered an important part of cultural identity. We also demonstrate that when Tsimane do run, they tend to use suboptimal technique, specifically landing with a rearfoot strike pattern and leg protracted ahead of the knee (called overstriding). Finally, we discuss processes by which culture might influence variation in running techniques among non-industrial societies, including self-optimisation and social learning.

Enhanced immunogenic potential of cancer immunotherapy antibodies in human IgG1 transgenic mice.

ABBREVIATIONS: ADA Anti-Drug Antibodies; BCR B Cell Receptor; BId Idiotype-specific B Cell; BiTE Bispecific T cell Engager; BMC Bone Marrow Chimeric Mice; BSA Bovine Serum Albumin; CDR Complementary Determining Region; CEA Carcinoembryonic Antigen; CIT Cancer Immunotherapy; CitAbs Cancer Immunotherapy Antibodies; DC Dendritic Cell; ELISA Enzyme-Linked Immunosorbent Assay; FcRn Neonatal Fc Receptor; FcyR Fc gamma Receptor; GM-CSF Granulocyte-Macrophage Colony Stimulating Factor; gMFI Geometric Mean Fluorescence Intensity; H Heavy Chain; IC Immune Complex; Id Idiotype; IgA Immunoglobulin alpha; IgG1 Immunoglobulin gamma 1; IL-2 Interleukin 2; IL-2R Interleukin 2 Receptor; IL2v Interleukin 2 Variant; IVIG1 Intravenous Immunoglobulin 1; KLH Keyhole Limpet Hemocyanin; L Light Chain; MAPPs MHC-associated Peptide Proteomics; MHC Major Histocompatibility Complex; PBMC Peripheral Blood Mononuclear Cells; PBS Phosphate Buffered Saline; SHM Somatic Hypermutation; scFv Single-chain Variable Fragment; TCR T cell Receptor; TFc Fc-specific T cell; TId Id-specific T cell; UV Ultraviolet; V Variable.

Investigating brain uptake of a non-targeting monoclonal antibody after intravenous and intracerebroventricular administration.

Monoclonal antibodies play an important role in the treatment of various diseases. However, the development of these drugs against neurological disorders where the drug target is located in the brain is challenging and requires a good understanding of the local drug concentration in the brain. In this original research, we investigated the systemic and local pharmacokinetics in the brain of healthy rats after either intravenous (IV) or intracerebroventricular (ICV) administration of EGFRvIII-T-Cell bispecific (TCB), a bispecific monoclonal antibody. We established an experimental protocol that allows serial sampling in serum, cerebrospinal fluid (CSF) and interstitial fluid (ISF) of the prefrontal cortex in freely moving rats. For detection of drug concentration in ISF, a push-pull microdialysis technique with large pore membranes was applied. Brain uptake into CSF and ISF was characterized and quantified with a reduced brain physiologically-based pharmacokinetic model. The model allowed us to interpret the pharmacokinetic processes of brain uptake after different routes of administration. The proposed model capturing the pharmacokinetics in serum, CSF and ISF of the prefrontal cortex suggests a barrier function between the CSF and ISF that impedes free antibody transfer. This finding suggests that ICV administration may not be better suited to reach higher local drug exposure as compared to IV administration. The model enabled us to quantify the relative contribution of the blood-brain barrier (BBB) and Blood-CSF-Barrier to the uptake into the interstitial fluid of the brain. In addition, we compared the brain uptake of three monoclonal antibodies after IV dosing. In summary, the presented approach can be applied to profile compounds based on their relative uptake in the brain and provides quantitative insights into which pathways are contributing to the net exposure in the brain.

Orang Asli Health and Lifeways Project (OA HeLP): a cross-sectional cohort study protocol.

INTRODUCTION: Non-communicable disease (NCD) risk is influenced by environmental factors that are highly variable worldwide, yet prior research has focused mainly on high-income countries where most people are exposed to relatively homogeneous and static environments. Understanding the scope and complexity of environmental influences on NCD risk around the globe requires more data from people living in diverse and changing environments. Our project will investigate the prevalence and environmental causes of NCDs among the indigenous peoples of Peninsular Malaysia, known collectively as the Orang Asli, who are currently undergoing varying degrees of lifestyle and sociocultural changes that are predicted to increase vulnerability to NCDs, particularly metabolic disorders and musculoskeletal degenerative diseases. METHODS AND ANALYSIS: Biospecimen sampling and screening for a suite of NCDs (eg, cardiovascular disease, type II diabetes, osteoarthritis and osteoporosis), combined with detailed ethnographic work to assess key lifestyle and sociocultural variables (eg, diet, physical activity and wealth), will take place in Orang Asli communities spanning a gradient from remote, traditional villages to acculturated, market-integrated urban areas. Analyses will first test for relationships between environmental variables, NCD risk factors and NCD occurrence to investigate how environmental changes are affecting NCD susceptibility among the Orang Asli. Second, we will examine potential molecular and physiological mechanisms (eg, epigenetics and systemic inflammation) that mediate environmental effects on health. Third, we will identify intrinsic (eg, age and sex) and extrinsic (eg, early-life experiences) factors that predispose certain people to NCDs in the face of environmental change to better understand which Orang Asli are at greatest risk of NCDs. ETHICS AND DISSEMINATION: Approval was obtained from multiple ethical review boards including the Malaysian Ministry of Health. This study follows established principles for ethical biomedical research among vulnerable indigenous communities, including fostering collaboration, building cultural competency, enhancing transparency, supporting capacity building and disseminating research findings.

Forest terrains influence walking kinematics among indigenous Tsimane of the Bolivian Amazon.

Laboratory-based studies indicate that a major evolutionary advantage of bipedalism is enabling humans to walk with relatively low energy expenditure. However, such studies typically record subjects walking on even surfaces or treadmills that do not represent the irregular terrains our species encounters in natural environments. To date, few studies have quantified walking kinematics on natural terrains. Here we used high-speed video to record marker-based kinematics of 21 individuals from a Tsimane forager-horticulturalist community in the Bolivian Amazon walking on three different terrains: a dirt field, a forest trail and an unbroken forest transect. Compared with the field, in the unbroken forest participants contacted the ground with more protracted legs and flatter foot postures, had more inclined trunks, more flexed hips and knees, and raised their feet higher during leg swing. In contrast, kinematics were generally similar between trail and field walking. These results provide preliminary support for the idea that irregular natural surfaces like those in forests cause humans to alter their walking kinematics, such that travel in these environments could be more energetically expensive than would be assumed from laboratory-based data. These findings have important implications for the evolutionary energetics of human foraging in environments with challenging terrains.

Helminth infection is associated with dampened cytokine responses to viral and bacterial stimulations in Tsimane forager-horticulturalists.

BACKGROUND: Soil-transmitted helminths (STHs) and humans share long co-evolutionary histories over which STHs have evolved strategies to permit their persistence by downregulating host immunity. Understanding the interactions between STHs and other pathogens can inform our understanding of human evolution and contemporary disease patterns. METHODOLOGY: We worked with Tsimane forager-horticulturalists in the Bolivian Amazon, where STHs are prevalent. We tested whether STHs and eosinophil levels-likely indicative of infection in this population-are associated with dampened immune responses to in vitro stimulation with H1N1 and lipopolysaccharide (LPS) antigens. Whole blood samples (n = 179) were treated with H1N1 vaccine and LPS and assayed for 13 cytokines (INF-γ, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, GM-CSF and TNF-ɑ). We evaluated how STHs and eosinophil levels affected cytokine responses and T helper (Th) 1 and Th2-cytokine suite responses to stimulation. RESULTS: Infection with Ascaris lumbricoides was significantly (P ≤ 0.05) associated with lower response of some cytokines to H1N1 and LPS in women. Eosinophils were significantly negatively associated with some cytokine responses to H1N1 and LPS, with the strongest effects in women, and associated with a reduced Th1- and Th2-cytokine response to H1N1 and LPS in women and men. CONCLUSIONS AND IMPLICATIONS: Consistent with the 'old friends' and hygiene hypotheses, we find that STHs were associated with dampened cytokine responses to certain viral and bacterial antigens. This suggests that STH infections may play an essential role in immune response regulation and that the lack of STH immune priming in industrialized populations may increase the risk of over-reactive immunity. Lay Summary: Indicators of helminth infection were associated with dampened cytokine immune responses to in vitro stimulation with viral and bacterial antigens in Tsimane forager-horticulturalists in the Bolivian Amazon, consistent with the 'old friends' and hygiene hypotheses.

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.

Polymer-Assisted Single-Step Slot-Die Coating of Flexible Perovskite Solar Cells at Mild Temperature from Dimethyl Sulfoxide.

The industrialization of perovskite solar cells relies on solving intrinsic-to-material issues. To reach record efficiencies perovskite deposition needs to be finely adjusted by multi-step processes, in a humidity free glove-box environment and by means of hardly scalable techniques often associated with toxic solvents and anti-solvent dripping/bath. Herein, the use of polymeric material is proposed to deposit perovskite layers with easy processability. To the scope, a starch-polymer/perovskite composite is developed to suit slot-die coating technique requirement, allowing the deposition of hybrid halide perovskite material in a single straightforward step without the use of toxic solvents, and in uncontrolled humid environment (RH up to 70 %). The starch-polymer increases the viscosity of the perovskite precursor solutions and delays the perovskite crystallization that results in the formation of perovskite films at mild temperature (60 °C) with good morphology. These innovative inks enables the fabrication of flexible solar cells with p-i-n configuration featured by a power conversion efficiency higher than 3 %. . Overall, this approach can be exploited in the future to massively reduce perovskite manufacturing costs related to keeping the entire fabrication line at high-temperature and under nitrogen or dry conditions.

APOE4 is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population.

In post-industrial settings, apolipoprotein E4 (APOE4) is associated with increased cardiovascular and neurological disease risk. However, the majority of human evolutionary history occurred in environments with higher pathogenic diversity and low cardiovascular risk. We hypothesize that in high-pathogen and energy-limited contexts, the APOE4 allele confers benefits by reducing innate inflammation when uninfected, while maintaining higher lipid levels that buffer costs of immune activation during infection. Among Tsimane forager-farmers of Bolivia (N = 1266, 50% female), APOE4 is associated with 30% lower C-reactive protein, and higher total cholesterol and oxidized LDL. Blood lipids were either not associated, or negatively associated with inflammatory biomarkers, except for associations of oxidized LDL and inflammation which were limited to obese adults. Further, APOE4 carriers maintain higher levels of total and LDL cholesterol at low body mass indices (BMIs). These results suggest that the relationship between APOE4 and lipids may be beneficial for pathogen-driven immune responses and unlikely to increase cardiovascular risk in an active subsistence population.

Genes contain the instructions needed for a cell to make molecules called proteins, which perform various roles in the body. Different variants of a gene can affect how the protein works, and in some cases, can increase a person's risk to develop certain diseases. For example, people who carry a version of the apolipoprotein E gene called APOE4 have a greater risk of developing Alzheimer's disease or heart disease. Individuals with two copies of this genetic variant have a 45% higher risk of heart disease and 12 times higher risk of Alzheimer's disease. Studies in industrialized countries suggest this increased risk may be the result of higher cholesterol and inflammation in people with APOE4. But if APOE4 is harmful, why does it continue to be so common worldwide? One potential explanation is that APOE4, which has been around since before modern humans, may be beneficial in some contexts. Cholesterol is essential for many vital tasks in the body. In physically demanding environments where parasitic infections are common ­ conditions similar to those experienced by early humans ­ APOE4 might be beneficial. Under those circumstances, having more cholesterol might help fuel metabolic activities, fight infections, or reduce inflammation caused by infections. Garcia et al. investigated the link between the APOE4 genetic variant, cholesterol and inflammation in 1,266 Indigenous Tsimane people from 80 villages in Bolivia. Tsimane people live an active lifestyle foraging and farming for food. Parasite infections are a common problem in their communities, but obesity rates are very low. Garcia et al. found that Tsimane people with at least one copy of the APOE4 have lower levels of inflammation and higher levels of cholesterol than those who have two copies of the APOE3 version of the gene. Very lean people with APOE4 had especially high levels of the so called "bad" low density lipoprotein (LDL) cholesterol compared to people with APOE3 only. However, in this situation, storing a little extra cholesterol may not be so bad. The findings contradict other studies that have linked obesity to higher LDL levels and APOE4 to higher levels of inflammation. For the majority of human history, humans lived in more physically strenuous and calorically restrictive environments, with less access to clean water. Garcia et al. suggest that the harmful effects of APOE4 seen in studies in more industrialized societies ­ where people tend to be more sedentary and have less exposure to pathogens ­ may reflect a mismatch between a person's environment and their genes. More studies that capture the diversity of environmental conditions under which people live will help clarify the role of APOE4 health and disease.