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IntroductionWe evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle.MethodsParticipants 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.ResultsTsimane 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.DiscussionThe 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.

Brain atrophy is correlated with risk of cognitive impairment, functional decline, and dementia. Despite a high infectious disease burden, Tsimane forager-horticulturists of Bolivia have the lowest prevalence of coronary atherosclerosis of any studied population and present few cardiovascular disease (CVD) risk factors despite a high burden of infections and therefore inflammation. This study (a) examines the statistical association between brain volume (BV) and age for Tsimane and (b) compares this association to that of 3 industrialized populations in the United States and Europe. This cohort-based panel study enrolled 746 participants aged 40-94 (396 males), from whom computed tomography (CT) head scans were acquired. BV and intracranial volume (ICV) were calculated from automatic head CT segmentations. The linear regression coefficient estimate β^T of the Tsimane (T), describing the relationship between age (predictor) and BV (response, as a percentage of ICV), was calculated for the pooled sample (including both sexes) and for each sex. β^T was compared to the corresponding regression coefficient estimate β^R of samples from the industrialized reference (R) countries. For all comparisons, the null hypothesis β T = β R was rejected both for the combined samples of males and females, as well as separately for each sex. Our results indicate that the Tsimane exhibit a significantly slower decrease in BV with age than populations in the United States and Europe. Such reduced rates of BV decrease, together with a subsistence lifestyle and low CVD risk, may protect brain health despite considerable chronic inflammation related to infectious burden.

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.

In high-income countries, one's relative socio-economic position and economic inequality may affect health and well-being, arguably via psychosocial stress. We tested this in a small-scale subsistence society, the Tsimane, by associating relative household wealth (n = 871) and community-level wealth inequality (n = 40, Gini = 0.15-0.53) with a range of psychological variables, stressors, and health outcomes (depressive symptoms [n = 670], social conflicts [n = 401], non-social problems [n = 398], social support [n = 399], cortisol [n = 811], body mass index [n = 9,926], blood pressure [n = 3,195], self-rated health [n = 2523], morbidities [n = 1542]) controlling for community-average wealth, age, sex, household size, community size, and distance to markets. Wealthier people largely had better outcomes while inequality associated with more respiratory disease, a leading cause of mortality. Greater inequality and lower wealth were associated with higher blood pressure. Psychosocial factors did not mediate wealth-health associations. Thus, relative socio-economic position and inequality may affect health across diverse societies, though this is likely exacerbated in high-income countries.

Humans have the longest post-reproductive lifespans and lowest rates of actuarial ageing among primates. Understanding the links between slow actuarial ageing and physiological change is critical for improving the human 'healthspan'. Physiological dysregulation may be a key feature of ageing in industrialized populations with high burdens of chronic 'diseases of civilization', but little is known about age trajectories of physiological condition in subsistence populations with limited access to public health infrastructure. To better characterize human physiological dysregulation, we examined age trajectories of 40 biomarkers spanning the immune (n = 13 biomarkers), cardiometabolic (n = 14), musculoskeletal (n = 6) and other (n = 7) systems among Tsimane forager-horticulturalists of the Bolivian Amazon using mixed cross-sectional and longitudinal data (n = 22 115 observations). We characterized age-related changes using a multi-system statistical index of physiological dysregulation (Mahalanobis distance; Dm) that increases with age in both humans and other primates. Although individual biomarkers showed varied age profiles, we found a robust increase in age-related dysregulation for Tsimane (β = 0.17-0.18) that was marginally faster than that reported for an industrialized Western sample (β = 0.14-0.16), but slower than that of other non-human primates. We found minimal sex differences in the pace or average level of dysregulation for Tsimane. Our findings highlight some conserved patterns of physiological dysregulation in humans, consistent with the notion that somatic ageing exhibits species-typical patterns, despite cross-cultural variation in environmental exposures, lifestyles and mortality. This article is part of the theme issue 'Evolution of the primate ageing process'.

BackgroundIn an energy-limited environment, caloric investments in one characteristic should trade-off with investments in other characteristics. In high pathogen ecologies, biasing energy allocation towards immune function over growth would be predicted, given strong selective pressures against early-life mortality.MethodologyIn the present study, we use flow cytometry to examine trade-offs between adaptive immune function (T cell subsets, B cells), innate immune function (natural killer cells), adaptive to innate ratio and height-for-age z scores (HAZ) among young children (N = 344; aged 2 months-8 years) in the Bolivian Amazon, using maternal BMI and child weight-for-height z scores (WHZ) as proxies for energetic status.ResultsMarkers of adaptive immune function negatively associate with child HAZ, a pattern most significant in preadolescents (3+ years). In children under three, maternal BMI appears to buffer immune and HAZ associations, while child energetic status (WHZ) moderates relationships in an unexpected direction: HAZ and immune associations are greater in preadolescents with higher WHZ. Children with low WHZ maintain similar levels of adaptive immune function, but are shorter compared to high WHZ peers.ConclusionsReduced investment in growth in favor of immunity may be necessary for survival in high pathogen contexts, even under energetic constraints. Further, genetic and environmental factors are important considerations for understanding variation in height within this population. These findings prompt consideration of whether there may be a threshold of investment into adaptive immunity required for survival in high pathogen environments, and thus question the universal relevance of height as a marker of health.Lay summaryAdaptive immune function is negatively associated with child height in this high pathogen environment. Further, low weight-for-height children are shorter but maintain similar immune levels. Findings question the relevance of height as a universal health marker, given that costs and benefits of height versus immunity may be calibrated to local ecology.

BackgroundConventional coronary artery disease risk factors might potentially explain at least 90% of the attributable risk of coronary artery disease. To better understand the association between the pre-industrial lifestyle and low prevalence of coronary artery disease risk factors, we examined the Tsimane, a Bolivian population living a subsistence lifestyle of hunting, gathering, fishing, and farming with few cardiovascular risk factors, but high infectious inflammatory burden.MethodsWe did a cross-sectional cohort study including all individuals who self-identified as Tsimane and who were aged 40 years or older. Coronary atherosclerosis was assessed by coronary artery calcium (CAC) scoring done with non-contrast CT in Tsimane adults. We assessed the difference between the Tsimane and 6814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). CAC scores higher than 100 were considered representative of significant atherosclerotic disease. Tsimane blood lipid and inflammatory biomarkers were obtained at the time of scanning, and in some patients, longitudinally.FindingsBetween July 2, 2014, and Sept 10, 2015, 705 individuals, who had data available for analysis, were included in this study. 596 (85%) of 705 Tsimane had no CAC, 89 (13%) had CAC scores of 1-100, and 20 (3%) had CAC scores higher than 100. For individuals older than age 75 years, 31 (65%) Tsimane presented with a CAC score of 0, and only four (8%) had CAC scores of 100 or more, a five-fold lower prevalence than industrialised populations (p≤0·0001 for all age categories of MESA). Mean LDL and HDL cholesterol concentrations were 2·35 mmol/L (91 mg/dL) and 1·0 mmol/L (39·5 mg/dL), respectively; obesity, hypertension, high blood sugar, and regular cigarette smoking were rare. High-sensitivity C-reactive protein was elevated beyond the clinical cutoff of 3·0 mg/dL in 360 (51%) Tsimane participants.InterpretationDespite a high infectious inflammatory burden, the Tsimane, a forager-horticulturalist population of the Bolivian Amazon with few coronary artery disease risk factors, have the lowest reported levels of coronary artery disease of any population recorded to date. These findings suggest that coronary atherosclerosis can be avoided in most people by achieving a lifetime with very low LDL, low blood pressure, low glucose, normal body-mass index, no smoking, and plenty of physical activity. The relative contributions of each are still to be determined.FundingNational Institute on Aging, National Institutes of Health; St Luke's Hospital of Kansas City; and Paleocardiology Foundation.

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, and 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 who 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The study reveals that the apolipoprotein-ε4 (APOE-ε4) allele, often associated with increased risk of diseases like dementia and cardiovascular issues, is linked to higher fertility rates in a natural fertility population. Among Tsimane women, carriers of APOE-ε4 had more children, starting reproduction earlier and having shorter interbirth intervals, shedding light on potential evolutionary advantages of this allele in ancestral environments.