Browsing by Autor "Daniel Eid Rodriguez"

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APOE4 is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population
(eLife Sciences Publications Ltd, 2021) Angela R. García; Caleb E. Finch; Margaret Gatz; Thomas S. Kraft; Daniel Eid Rodriguez; Daniel K. Cummings; Mia Charifson; Kenneth H. Buetow; Bret Beheim; Hooman Allayee
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.
Author response: APOE4 is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population
(2021) Angela R. García; Caleb E. Finch; Margaret Gatz; Thomas S. Kraft; Daniel Eid Rodriguez; Daniel K. Cummings; Mia Charifson; Kenneth H. Buetow; Bret Beheim; Hooman Allayee
Article Figures and data Abstract eLife digest Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract 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. eLife digest 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. Introduction The apolipoprotein E4 (APOE4) allele is considered a major shared risk factor for both cardiovascular disease (CVD) (Hansson and Libby, 2006) and Alzheimer’s disease (AD) (Belloy et al., 2019; Smith et al., 2019), in part due to its role in lipid metabolism and related inflammation (Huebbe and Rimbach, 2017). APOE4+ carriers consistently show higher levels of total cholesterol, low-density lipoprotein (LDL), and oxidized LDL (Safieh et al., 2019; Yassine and Finch, 2020). While some studies suggest APOE4+ carriers have higher inflammatory responses (Gale et al., 2014; Olgiati et al., 2010), the APOE4 allele is also associated with downregulation of aspects of innate immune function, including acute phase proteins (Lumsden et al., 2020; Martiskainen et al., 2018; Vasunilashorn et al., 2011), and toll-like receptor (TLR) signaling molecules (Dose et al., 2018). APOE, lipids, and immune function may interact differently in contemporary obesogenic post-industrial contexts compared to environments where infections are prevalent. For instance, a prospective U.S.-based cohort study (Framingham Heart Study) found that individuals with APOE4 and low-grade chronic obesity-related inflammation had higher risk of developing AD, with earlier onset than APOE3/3 and APOE4+ carriers without inflammation (Tao et al., 2018). By contrast, APOE4 may protect against cognitive loss among those infected with parasites (Oriá et al., 2005; Trumble et al., 2017) and accelerate recovery from viral infection (Mueller et al., 2016). These findings suggest that interactive influences of APOE4, lipids, and immune function on disease risks may be environmentally moderated. However, this is difficult to test because most biomedical research is conducted in controlled laboratory settings using animal models, or in post-industrial populations with low-pathogen burden and high obesity prevalence (Gurven and Lieberman, 2020). Here, we begin to fill this gap by evaluating both immune and lipid profiles of individuals with APOE3/3 and APOE4+ genotypes living in a pathogenically diverse, energy-limited environment. APOE, cholesterols, and immune function APOE has three functionally polymorphic allelic variants: E4, E3, and E2 (Demarchi et al., 2005; Safieh et al., 2019). The most prevalent, APOE3, arose ~200K years ago from a single nucleotide polymorphism (SNP) (C → T) at locus 19q13 from the ancestral APOE4 (Fullerton et al., 2000). The evolutionary success of APOE3 has been attributed to its greater plasticity in response to environmental changes compared to the ancestral APOE4 allele (Huebbe and Rimbach, 2017). However, APOE4 is maintained at frequencies up to 40%, such as those in some central African populations. Maintenance and distribution of APOE variants may in part be due to the distinct functional capabilities of allelic variants (Trotter et al., 2010). Eisenberg and colleagues have suggested that the benefits of APOE4 may be most appreciable in environments where cholesterol requirements are increased to meet higher metabolic demands, such as at high and low latitudes where there are climatic extremes (e.g. northern Europe and South America) (Eisenberg et al., 2010). Another leading explanation for APOE4 persistence is based on the theory of antagonistic pleiotropy (Williams, 1957), which posits that the APOE4 allele may persist due to the fitness benefits of lipid buffering in early life relative to APOE3, outweighing any harmful health effects that manifest in a post-reproductive life stage (i.e. ‘selection’s shadow’) (Smith et al., 2019). Consistent with the notion of early life fitness advantage, the APOE4 variant is associated with lower infant mortality and higher fertility among rural Ghanaians experiencing high-pathogen burden (van Exel et al., 2017). Innate immune responses with fever and systemic inflammation are also energetically expensive (Muehlenbein et al., 2010), and cholesterol and other lipids are necessary for fueling these responses (Tall and Yvan-Charvet, 2014). Helminths and some protozoal parasites also require lipids to fuel their own metabolic activities, either pulling them from the host bloodstream, or modulating host metabolic activities like LDL endocytosis or lipid remodeling to gain access to lipids (Bansal et al., 2005). Thus, in high-pathogen and energy-limited environments, where there may be persistent pathogen-driven immune activation, the ability to maintain peripheral cholesterol levels would presumably be a benefit throughout life (Finch and Martin, 2016; Gurven et al., 2016). Despite APOE4 being associated with neuroinflammation among those with AD (Kloske and Wilcock, 2020), in ‘healthy’ individuals the APOE4 allele is associated with downregulated innate immunity. Specifically, blood levels of C-reactive protein (CRP) in APOE4+ carriers are lower in several post-industrial populations (Lumsden et al., 2020; Martiskainen et al., 2018), as well as the Tsimane, an Amerindian population in rural Bolivia (and focus of the present study) (Vasunilashorn et al., 2011). Moreover, among the Tsimane, APOE4+ carriers had lower levels of blood eosinophils (Trumble et al., 2017; Vasunilashorn et al., 2011). Other studies have documented lower levels of certain proinflammatory cytokines (e.g. IL-6, TNF-alpha) in APOE4+ carriers (Olgiati et al., 2010), and downregulated expression of biomarkers mediating innate immune sensing (TLR-signaling molecules) (Dose et al., 2018). Experimental studies also showed the associations of APOE4 with heightened innate and complement inflammatory responses to lipopolysaccharide stimulation in Gale et al., 2014; Tzioras et al., 2019. Maintaining lower levels of baseline innate immunity may minimize the accumulative damage caused by low-grade innate inflammation over the long term, while still enabling strong targeted immune responses to pathogens following exposure (Franceschi et al., 2000; Trumble and Finch, 2019), particularly in environments with a diversity of species of pathogens. Further, pathogens like helminthic parasites, may moderate inflammation by triggering Th2-mediated (anti-inflammatory) immunological pathways (Maizels and McSorley, 2016; Motran et al., 2018), which may be important for counterbalancing a strong proinflammatory response. In energy-limited, pathogenically diverse environments, APOE4+ carriers may thus be better able to tolerate energetic costs imposed by infection by having higher concentrations of circulating lipids to fuel immune responses, while also minimizing damage from exposure to generalized systemic inflammation through downregulation of innate immune function. By contrast, in post-industrialized contexts, without the moderating influences of parasites on both cholesterol and immune functions, non-pathogenic stimuli (e.g. obesity) may be more likely to trigger systemic low-grade inflammatory pathways and, in the absence of a brake, lead to arterial and vascular damage and disease. Thus, the link between APOE4 and inflammatory diseases in post-industrialized contexts may in part be due to an environmental mismatch. Hypothesis and aims In pathogenically diverse environments, innate immune defenses are likely to be activated owing to more frequent encounters with novel pathogens. This more diverse pathogenic setting may increase selective pressure to favor stronger immune regulation. We hypothesize that in such a context, an APOE4 variant is less harmful because it (a) minimizes damage caused by chronic innate inflammation and (b) maintains higher circulating cholesterol levels, which buffer energetic costs of pathogen-driven innate immune activation. In post-industrial contexts, where there is a relative absence of diverse pathogens and thus reduced pathogen-mediated lipid regulation, coupled with an overabundance of calories, the effect of APOE4 on circulating lipids may instead incur a cost. Lifestyle factors that promote obesity and excessive circulating lipids may lead to sterile endogenous inflammation (Trumble and Finch, 2019) that overshadows any potentially positive effects of APOE4 on immune function. Thus, the APOE4 variant has greater potential to lead to hyperlipidemia and coincide with related inflammatory diseases in high-calorie, low-pathogen, environments (Figure 1). Figure 1 Download asset Open asset Hypothetical pathways through which the apolipoprotein E4 (APOE4) allele influences lipid processing, immune regulation and disease risk in post-industrialized and non-industrialized contexts. In both contexts, the APOE4 allele leads to increased levels of circulating lipids; however, in post-industrialized contexts (a), lipid levels can reach dangerously high levels due to obesogenic diets, and an absence of moderation by parasites and pathogen-driven immune activation. Immune activation by non-pathogenic elements triggers damage-associated molecular pattern pathways, which generates a proinflammatory ‘sterile’ immune response. Obesity and hyperlipidemia can simultaneously fuel sterile inflammation and promote oxidization of cholesterols, which, due to their lack of function, cause further tissue damage associated with cardiovascular and neurodegenerative disease risk. In energetically limited, pathogenically diverse contexts (b), the pathway between APOE4 and disease risk is considerably more complex. Briefly, immune responses to parasites and microbes require cholesterol, and there are both direct and indirect effects of different species of parasites which further regulate cholesterol production and utilization. In addition, anti-inflammatory immune responses are generated by ox-LDL (e.g. in response to bacteria and protozoal infections), and helminthic parasites, which balance the immune system’s overall response. It is possible that in contexts where there is higher pathogen diversity, an APOE4 phenotype may be less harmful because it minimizes the damage caused by upregulated innate immune function, while also maintaining higher cholesterol levels which would buffer the cost of innate immune activation due to infection. Whereas in high-calorie, low-pathogen environments, the utility of having an APOE4 allele may be muted, and the costs more severe. Image created with BioRender.com. This study describes the immunophenotypes and lipid profiles of individuals with APOE3/3 and APOE4+ genotypes living in a pathogenically diverse, energy-limited environment. For the purpose of hypothesis testing, we focus on testing genotype-related differences in components of innate immunity (CRP, neutrophils, eosinophils, and erythrocyte sedimentation rate [ESR]) and blood lipids linked to inflammation (total cholesterol, LDL, and oxidized LDL [ox-LDL]). We evaluate the extent to which body mass index (BMI) moderates the association between lipids and innate inflammation (CRP, neutrophils, ESR). Finally, we test whether the APOE4 allele has a moderating effect on the relationship between BMI and lipids to evaluate the role of APOE4 in the maintenance of stable lipid levels under energetic restriction. This research focused on the Tsimane, an Amerindian population in the Bolivian tropics that faces high exposure to a diverse suite of pathogens, and endemic helminthic infections. Tsimane have high rates of infection across all ages, with 70% helminth prevalence and >50% of adults with co-infections from multiple species of parasite or protozoan (Blackwell et al., 2015; Garcia et al., 2020). Compared to U.S. and European reference populations, the Tsimane have also been found to have upregulated immune function across the life course (Blackwell et al., 2016). In most villages, there is little or no access to running water or infrastructure for sanitation (Dinkel et al., 2020). The Tsimane are primarily reliant on foods acquired through slash-and-burn horticulture, fishing, hunting, gathering, and small animal domestication, supplemented with market goods (e.g. salt, sugar, cooking oil) (Kraft et al., 2018). Tsimane are rarely sedentary, instead engaging in sustained low and moderate physical activity over much of their life course (Gurven et al., 2013), and have minimal atherosclerosis (Kaplan et al., 2017). However, with greater globalization and improvements in technology, the Tsimane are experiencing ongoing lifestyle changes; there is variation in participation in the market economy, and related variation in diet (e.g. access and uptake of processed foods) and activity level. Despite increasing access to markets and towns, infections remain the largest source of morbidity (Gurven et al., 2020). Results Data include APOE genotype and multiple measurements of BMI, lipids, and immune markers in 1266 Tsimane adults. Mixed effects multiple regression models were used to accommodate for multiple measurements per individual for some biomarkers, as well as community-level differences in pathogen exposures. Leveraging multiple observations per individual over time should better capture individuals’ average levels, and minimize the potential of single or few outliers driving results. Models also include covariates which adjust for age, sex, seasonality, and current infection (WBC >12 × 109/L) (see Materials and methods for details). The sample is 50% female and includes individuals from 80 villages. The mean ± SD age of the sample is 54 ± 11 years (range: 21–93). Mean ± SD BMI is 24 ± 3 for both sexes; Tsimane adults are relatively short (women: 150.5 ± 4.8 cm; men: 161.7 ± 5.3 cm) with low body fat (median body fat percentage for men and women is 18% and 26%, respectively). Prevalence of obesity is relatively low (10%). In general, blood immune biomarkers vary significantly across adult ages (Supplementary file 1; Figure 2). Table 1 provides a full description of lipid and immune levels of individuals by APOE genotype. Table 1 Description of immune and lipid measures for homozygous APOE3/3 and APOE4+ carriers for whom age and sex are available. Values are reported as mean (standard deviation). Linear mixed effects models fit by REML were used to test for differences between groups, controlling for age, sex, current immune activation, and seasonality, with random effects for community and individual ID. Model to test age differences includes only a random effect for individual ID. Multiple test correction was conducted for models used for hypothesis-testing; False Discovery Rate (FDR) adjusted p-values are reported for these models. No. of observations is reported as: total number of observations for the main biomarker (number of unique individuals) in each model. T-statistics use Satterthwaite's method. Due to skewness of biomarkers, statistical models use transformed and scaled data for normalization, as such, estimates are reported as standardized betas (b) with standard errors (SE). Full models with covariates and 95% confidence intervals can be found in Tables 2-3 in the Supplement. See methods for transformations for each marker. VariablesAPOE 3/3Apoe4+No. observations per modelβSEt-valuep-valueFDR adj p-valueN998268––––––% female51%48%––––––Age (in years)54 (11.5)54 (11.2)6615 (1268)0.0070.070.1060.915–BMI (kg/m2)23.9 (3.4)24.6 (3.7)6224 (1263)0.150.062.4210.016*–C-reactive protein (mg/L)3.7 (3.3)2.9 (2.6)1032 (907)-0.290.08-3.731<0.001***<0.001***Eosinophil (mm3)1617 (1060)1375 (910)6129 (1259)-0.160.04-3.871<0.001***<0.001***Neutrophil (mm3)5044 (1803)4816 (1697)6144 (1259)-0.030.03-0.8160.4150.435Sed Rate (mm/hr)29.4 (19.5)29.7 (19.2)5987 (1253)0.060.041.3340.1820.217Eosin : Lymph ratio0.36 (0.14)0.33 (0.14)6121 (1260)-0.140.04-3.1970.001**–---Leukocytes (1000/mm3)9.3 (2.5)8.8 (2.4)6229 (1266)-0.080.03-2.2810.023*–Lymphocytes (mm3)2590 (832)2565 (852)6136 (1260)00.040.1040.917–Hemoglobin (g/dL)13.2 (1.5)13.2 (1.4)6195 (1263)-0.040.05-0.8050.421–Triglycerides (mg/dL)107 (51)114 (61)2633 (1174)0.070.061.1570.248–Total cholesterol (mg/dL)144 (32)148 (33)2581 (1168)0.150.062.5940.010**0.021HDL cholesterol (mg/dL)38 (9)38 (9)2477 (1167)0.050.060.830.407–LDL cholesterol LDL is as: Figure Download asset Open asset in immune markers across age, by apolipoprotein E4 genotype. were from mixed effects regression models and estimates of the interactive effects of APOE genotype and age on each immune marker. Models adjust for sex, and current (Supplementary file 1). sedimentation rate is as In have at least one APOE4 individuals are and are homozygous The = are homozygous for of the APOE4 allele is The allele was the of the APOE genotype is individuals as homozygous APOE3 or as APOE4+ carriers had at least one copy of the APOE4 and APOE4 were due to the small number of of total and thus small of a for statistical of lipid and immune profiles by APOE genotype to APOE3/3 APOE4 carriers have higher BMI = = total cholesterol = = and oxidized LDL = = lower levels of innate immune blood = eosinophils = Figure in models that all individuals with and APOE4 carriers maintained lower levels of relative to APOE3/3 = = = respectively). for multiple testing, and eosinophils remain significantly different between APOE APOE4 is also associated with a lower to = = and lower total = = but not with LDL, lipoprotein or (Figure 1). Full models in file Figure 3 with 1 all Download asset Open asset show of biomarker data by APOE genotype APOE those that have at least one copy of the E4 include and standard errors per from mixed effects regression models that adjust for age, sex, and current For full models with file and sedimentation rate is as See Figure 1 for of biomarkers by APOE genotype. is as: BMI moderate the association between lipids and For Tsimane with higher BMI, total cholesterol and LDL not with however, for individuals with BMI or low BMI, higher total cholesterol and LDL with lower (Figure considered as a BMI significantly moderates these associations (total = = BMI also with ox-LDL = in however, this relationship is distinct from the other lipids For Tsimane with high BMI, ox-LDL with while for those with low BMI the is (Figure For total cholesterol = = and LDL = = with only among Tsimane with higher for multiple testing, between and all remain as does the relationship between total cholesterol and = Figure with 1 all Download asset Open asset of on C-reactive protein based on three levels of body mass index (BMI) ± 1 standard deviation). show effects between BMI and total cholesterol, LDL, and oxidized LDL. For total and LDL cholesterol, among those with low and mean BMI, cholesterol is negatively associated with LDL is only associated with higher among individuals with high BMI are from mixed effects that adjust for age, sex, seasonality, with random effects for individual and community (Supplementary file Data are based on BMI level. are transformed and See Figure 1 for associations between BMI and with markers of inflammation. there are no direct relationship between ox-LDL and higher total cholesterol and LDL are associated with lower (total = = = (Figure 1). cholesterol is also negatively associated with = = are no or interactive between BMI, cholesterols, and For full models, file APOE genotype moderate the association between BMI and Finally, we whether APOE genotypes moderate associations between cholesterol and BMI for lean and high BMI evaluate the effects of the APOE4 allele on lipid levels across the of BMI, we an between BMI and APOE genotype to the mixed effects regression models between BMI and lipids 2). These show that APOE4 carriers maintain similar levels of total cholesterol and LDL across = = = = APOE3/3 show higher cholesterol with Specifically, APOE4 carriers maintain higher levels of total and LDL cholesterol at lower but have lower levels of both at higher relative to individuals that are homozygous APOE3/3 (Figure However, of these associations are and not vary by APOE across For full models, file Table Models evaluating the moderating effects of APOE genotype on associations between BMI and Results are effects estimates from mixed effects which include random effects for and community In to age, sex, and a was used as a for current 12 Results are reported as standardized is the 95% confidence were transformed and to APOE genotype is as a as individuals that are homozygous those that have at least one copy of the E4 allele Figure Download asset Open asset moderating effects of APOE genotype on associations between body mass index (BMI) and (see Table in the for for low and high For the during an immune response to pathogens – total cholesterol and LDL – individuals with an E4 allele maintain higher levels of those at low compared to homozygous are from mixed effects that include age, sex, and current infection as as well as random effects for individual and community Data are by APOE genotype. Discussion We that the effect of the APOE4 polymorphism on disease risk may be environmentally and that in an energy-limited and pathogenically diverse context, an APOE4 allele may some benefit if it with downregulated innate immune function and higher circulating In of this we that Tsimane with an APOE4 allele have higher levels of lipids, lower levels of and eosinophils, compared to individuals that have a homozygous
P3‐134: APOE GENOTYPE AND COGNITIVE PERFORMANCE IN TSIMANE AND MOSETEN OF BOLIVIA
(Wiley, 2019) Margaret Gatz; Hillard Kaplan; Ben C. Trumble; Randall C. Thompson; Juan J. Copajira Adrian; M. Linda Sutherland; James D. Sutherland; Helena C. Chui; Daniel Eid Rodriguez; Raúl Quispe Gutierrez
The ε4 allele of the apolipoprotein gene (APOE) is an established risk factor for Alzheimer's disease (AD), with evidence predominantly from Caucasian populations. Results are mixed whether non-demented older adult ε4 carriers perform more poorly on cognitive tests. Some evidence indicates that APOE influences AD risk through episodic memory. We therefore hypothesized ε4 carriers would show lower episodic memory scores. Participants were indigenous lowland Bolivians practicing subsistence level horticulture (469 Tsimane; 86 Moseten) aged ≥55 (mean 66, range 55-96), with data from both cognitive testing and APOE genotyping from PCR. Culturally/linguistically adapted cognitive tests included episodic memory, digit span forward, semantic fluency, visual scan, and visuoconstructional ability. Episodic memory included immediate memory (average of 3 learning trials for an 8-word list), and delayed recall assessed after 10 minutes. General linear modelling evaluated whether memory scores were associated with carrying the ε4 allele. Distribution of APOE genotypes was not significantly different between Tsimane and Moseten populations: unadjusted 21% ε3/ε4 heterozygotes; 1% ε4/ε4 homozygotes. Controlling for population, age, gender, and education, there was a significant effect for delayed recall: those carrying an ε4 allele scored significantly lower, b = −0.705, SE = 0.203, p = .0006, ηP2 = 0.024. Neither immediate memory nor any other cognitive test showed a significant ε4 effect. There were no significant interactions between APOE and population, age, gender, or education. Within each population, controlling for age, gender, and education, the ε4 main effect was significant on delayed recall for both Tsimane, b = −0.527, SE = 0.212, p = .0131, ηP2 = 0.0132, and Moseten, b = −0.935, SE = 0.427, p = .0316, ηP2 = 0.0558, with a trend for Moseten on immediate memory, b = −0.589, SE = 0.240, p = .0163, ηP2 = 0.0692.
Pathway‐based genome analysis of cognitive impairment in a forager‐horticulturalist South American population
(Wiley, 2022) Angela R. García; Yih‐Kuang Lu; Margaret Gatz; Daniel Eid Rodriguez; Raúl Quispe Gutierrez; Juan J Copajira Adrian; Jesus Bani Cuata; M Linda Sutherland; James D. Sutherland; Daniel K. Cummings
Abstract Background The genetic etiology of Cognitive Impairment (CI) is poorly understood. This is due, in part, to the complexity of diverse genetic and environmental risk factors in large, heterogeneous study populations. To overcome this obstacle, we examined a population with low genetic heterogeneity and fewer risk factors commonly found in industrialized populations ‐ the Tsimane of Bolivia (N = 353; mean age = 69 years [60–93 years]). The Tsimane are a geographically isolated forager‐horticulturalist population with high levels of physical activity and low prevalence of coronary artery disease, hypertension, and diabetes, even at advanced ages. The absence of these typical Alzheimer’s Disease (AD)‐related comorbidities provides a novel opportunity to isolate aspects of CI that are often intertwined with cardiometabolic and other non‐communicable chronic diseases. Method CI was determined from field evaluations using a locally translated and adapted cognitive battery, mental status examination, informant interview, and neurological evaluation (CI = 31, AD = 1). Genome‐wide variation was characterized using the Infinum Multi‐Ethnic Global Array (1,754,170 SNPs) and evaluated with a novel analytic tool that uses biologic processes as the unit of analysis — Pathways of Distinction Analysis (PoDA). PoDA captures interactions across the multiple genes within a network and assesses significance via empiric resampling. A catalog of 1167 curated networks representing the diversity of biologic function was evaluated. Result The pathway that most significantly distinguishes individuals with CI from those without impairment is the KEGG Alzheimer’s Disease Pathway (Distance Score [DS] = 3.23; FDR‐adjusted pDS<0.001). This pathway is composed of 169 genes that capture the major processes associated with AD. Refined analysis identified a subset of 35 genes that is associated with a 6‐fold difference (OR = 6.26; pOR = 1.21×10 −12 ) in relative risk for prevalent CI vs. no impairment. Those genes are involved in insulin signaling, calcium signaling, and mitochondrial oxidative phosphorylation subcomponents of the AD Pathway. It also includes variation within the AD risk loci APBB1 and MAPT (Figure 1). Conclusion In a population with minimal cardiometabolic disease, pathway‐based genome analysis objectively identifies subcomponents within the AD pathway tied to cellular energy metabolism as important in CI. Following validation in larger, heterogenous populations, these components may provide targets for prevention and intervention.
Prevalence of dementia and mild cognitive impairment in indigenous Bolivian forager‐horticulturalists
(Wiley, 2022) Margaret Gatz; Wendy J. Mack; Helena C. Chui; Emma Law; Giuseppe Barisano; M. Linda Sutherland; James D. Sutherland; Daniel Eid Rodriguez; Raúl Quispe Gutierrez; Juan Copajira Adrian
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.