{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:21:35Z","timestamp":1788931295782,"version":"build-2803163510"},"reference-count":100,"publisher":"SAGE Publications","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2023,5,30]]},"abstract":"<jats:p>Until 300,000 years ago, ancestors of modern humans ubiquitously carried the apolipoprotein E (APOE) \u025b4\/\u025b4 genotype, when the \u025b3 allele mutated from the ancestral \u025b4, which elevates the risk of Alzheimer\u2019s disease. Modern humans living today predominantly carry the \u025b3 allele, which provides protection against heart disease and dementia in long-lived populations. The ancestral \u025b4 allele has been highly preserved in isolated populations in tropical and Arctic regions with high pathogen burdens, e.g., helminths. Early humans experienced serious enteric infections that exerted evolutionary selection pressure, and factors that mitigate infant and childhood mortality from enteric infections also exert selection pressure. Some bacteria can exploit the host\u2019s defensive inflammatory response to colonize and invade the host. Pathogen-induced inflammation associated with infant and childhood diarrhea can damage the gut wall long after the invading organisms are no longer present. Inflammation not only resides in the mucosal wall, but also induces systemic inflammation. Baseline systemic inflammation is lower in \u025b4 carriers, yet \u025b4 carriers display a stronger host inflammatory response that reduces pathogen burdens, increasing infant and early childhood survival. Evolutionary selection of the \u025b3 allele likely occurred after humans moved into temperate zones with lower pathogen burdens, unrelated to protection from Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.3233\/jad-221218","type":"journal-article","created":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T12:29:45Z","timestamp":1682684985000},"page":"907-918","source":"Crossref","is-referenced-by-count":27,"title":["Apolipoprotein \u025b4-Associated Protection Against Pediatric Enteric Infections Is a Survival Advantage in Pre-Industrial Populations"],"prefix":"10.1177","volume":"93","author":[{"given":"Carr J.","family":"Smith","sequence":"first","affiliation":[{"name":"Society for Brain Mapping and Therapeutics, Pacific Palisades, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Wesson","family":"Ashford","sequence":"additional","affiliation":[{"name":"Stanford University and VA Palo Alto Health Care System, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-221218_ref1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1001\/jamaneurol.2016.4899","article-title":"Association of docosahexaenoic acid supplementation with Alzheimer disease stage in apolipoprotein E epsilon4 carriers: A review","volume":"74","author":"Yassine","year":"2017","journal-title":"JAMA Neurol"},{"key":"10.3233\/JAD-221218_ref2","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1001\/jama.1997.03540340056033","article-title":"Apolipoprotein E epsilon4 and incidence ofAlzheimer disease in a community population of older persons","volume":"277","author":"Evans","year":"1997","journal-title":"JAMA"},{"key":"10.3233\/JAD-221218_ref3","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1086\/303070","article-title":"Apolipoprotein E variation at the sequence haplotype level: Implications for the origin and maintenance of a major human polymorphism","volume":"67","author":"Fullerton","year":"2000","journal-title":"Am J Hum Genet"},{"key":"10.3233\/JAD-221218_ref4","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1385\/JMN:23:3:157","article-title":"APOE genotype effects on Alzheimer\u2019s disease onset and epidemiology","volume":"23","author":"Ashford","year":"2004","journal-title":"J Mol Neurosci"},{"key":"10.3233\/JAD-221218_ref5","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.nlm.2017.10.008","article-title":"Possible positiveeffect of the APOE \u025b2 allele on cognition in early tomid-adult life","volume":"146","author":"Sinclair","year":"2017","journal-title":"Neurobiol Learn Mem"},{"key":"10.3233\/JAD-221218_ref6","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1002\/ana.24369","article-title":"APOEepsilon2 is associated with milder clinical and pathological Alzheimer disease","volume":"77","author":"Serrano-Pozo","year":"2015","journal-title":"Ann Neurol"},{"key":"10.3233\/JAD-221218_ref7","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.nlm.2017.10.008","article-title":"Possible positive effect of the APOE \u025b2 allele on cognition in early to mid-adult life","volume":"146","author":"Sinclair","year":"2017","journal-title":"Neurobiol Learn Mem"},{"key":"10.3233\/JAD-221218_ref8","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1023\/A:1024449603891","article-title":"Lipoprotein disorders and cardiovascular risk","volume":"26","author":"Genest","year":"2003","journal-title":"J Inherit Metab Dis"},{"key":"10.3233\/JAD-221218_ref9","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1093\/nutrit\/nuab063","article-title":"Immunoinflammatoryrole of apolipoprotein E4 in malnutrition and enteric infections andthe increased risk for chronic diseases under adverse environments","volume":"80","author":"Freitas","year":"2022","journal-title":"Nutr Rev"},{"key":"10.3233\/JAD-221218_ref10","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1126\/science.8346443","article-title":"Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families","volume":"261","author":"Corder","year":"1993","journal-title":"Science"},{"key":"10.3233\/JAD-221218_ref11","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.neurobiolaging.2003.12.023","article-title":"ApoE genotype accounts for the vast majority of AD risk and AD pathology","volume":"25","author":"Raber","year":"2004","journal-title":"Neurobiol Aging"},{"issue":"Suppl","key":"10.3233\/JAD-221218_ref12","doi-asserted-by":"crossref","first-page":"S183","DOI":"10.1194\/jlr.R800069-JLR200","article-title":"Apolipoprotein E: Structure determines function, from atherosclerosis to Alzheimer\u2019s disease to AIDS","volume":"50","author":"Mahley","year":"2009","journal-title":"J Lipid Res"},{"key":"10.3233\/JAD-221218_ref13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.nbd.2014.08.025","article-title":"Apolipoprotein E: Structure and functionin lipid metabolism, neurobiology, and Alzheimer\u2019s diseases","volume":"72","author":"Huang","year":"2014","journal-title":"Neurobiol Dis"},{"key":"10.3233\/JAD-221218_ref14","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.neuron.2019.01.056","article-title":"A quarter century of APOE and Alzheimer\u2019s disease: Progress to date and the path forward","volume":"101","author":"Belloy","year":"2019","journal-title":"Neuron"},{"key":"10.3233\/JAD-221218_ref15","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1007\/BF00225073","article-title":"High frequency of the apo allele in Khoi San from South Africa","volume":"95","author":"Sandholzer","year":"1995","journal-title":"Hum Genet"},{"key":"10.3233\/JAD-221218_ref16","first-page":"575","article-title":"High frequency of the apolipoprotein E *4 allelein African pygmies and most of the African populations insub-Saharan Africa","volume":"69","author":"Zekraoui","year":"1997","journal-title":"Hum Biol"},{"key":"10.3233\/JAD-221218_ref17","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/j.1399-0004.1991.tb02981.x","article-title":"Genetic studies of human apolipoproteins. ApoE polymorphism and cholesterol levels in the Mayans of the Yucatan peninsula, Mexico","volume":"39","author":"Kamboh","year":"1991","journal-title":"Clin Genet"},{"key":"10.3233\/JAD-221218_ref18","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1046\/j.1469-1809.1999.6340301.x","article-title":"Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a \u2018thrifty\u2019 allele?","volume":"63","author":"Corbo","year":"1999","journal-title":"Ann Hum Genet"},{"key":"10.3233\/JAD-221218_ref19","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1515\/CCLM.2003.094","article-title":"The common polymorphism of apolipoprotein E: Geographical aspects and new pathophysiological relations","volume":"41","author":"Gerdes","year":"2003","journal-title":"Clin Chem Lab Med"},{"key":"10.3233\/JAD-221218_ref20","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1093\/gerona\/59.1.B16","article-title":"The APOE gene and differences in life expectancy in Europe","volume":"59","author":"Ewbank","year":"2004","journal-title":"J Gerontol A"},{"key":"10.3233\/JAD-221218_ref21","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s11033-010-0132-0","article-title":"Does the geographical gradient of ApoE4 allele exist in China? A systemic comparison among multiple Chinese populations","volume":"38","author":"Hu","year":"2011","journal-title":"Mol Biol Rep"},{"key":"10.3233\/JAD-221218_ref22","doi-asserted-by":"crossref","first-page":"e1002355","DOI":"10.1371\/journal.pgen.1002355","article-title":"Correction: Signatures of environmental genetic adaptation pinpoint pathogens as the main selective pressure through human evolution","volume":"7","author":"Fumagalli","year":"2011","journal-title":"PLoS Genet"},{"key":"10.3233\/JAD-221218_ref23","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.ijpara.2016.05.008","article-title":"Out of Africa: Origins and evolution of the human malaria parasites Plasmodium falciparum and Plasmodium vivax","volume":"47","author":"Loy","year":"2017","journal-title":"Int J Parasitol"},{"key":"10.3233\/JAD-221218_ref24","doi-asserted-by":"crossref","first-page":"e0007154","DOI":"10.1371\/journal.pntd.0007154","article-title":"Etiology and severity of diarrheal diseases in infants at the semiarid region of Brazil: A case-control study","volume":"13","author":"Lima","year":"2019","journal-title":"PLoS Negl Trop Dis"},{"key":"10.3233\/JAD-221218_ref25","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/j.1461-0248.2007.01125.x","article-title":"Evolution of virulence: Triggering host inflammation allows invading pathogens to exclude competitors","volume":"11","author":"Brown","year":"2008","journal-title":"Ecol Lett"},{"key":"10.3233\/JAD-221218_ref26","first-page":"268","article-title":"Fish tapeworm in Eskimos in the Port Harrison area, Canada. }","volume":"51","author":"Arh","year":"1960","journal-title":"Health"},{"key":"10.3233\/JAD-221218_ref27","doi-asserted-by":"crossref","first-page":"185","DOI":"10.4269\/ajtmh.1961.10.185","article-title":"Intestinal parasites of man in Arctic Greenland","volume":"10","author":"Babbott","year":"1961","journal-title":"Am J Trop Med Hyg"},{"key":"10.3233\/JAD-221218_ref28","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1139\/z61-009","article-title":"Parasites from northern Canada. I. Entozoa of Chime Eskimos","volume":"39","author":"Laird","year":"1961","journal-title":"Canad J Zool"},{"key":"10.3233\/JAD-221218_ref29","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1017\/S0032247400055662","article-title":"Parasitological problems in high northern latitudes, with particular reference to Canada","volume":"11","author":"Cameron","year":"1963","journal-title":"Polar Record"},{"key":"10.3233\/JAD-221218_ref30","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0035-9203(67)90008-9","article-title":"Helminths in Eskimos in western Alaska, with particular reference to Diphyllobothrium infection and anaemia","volume":"61","author":"Rausch","year":"1967","journal-title":"Trans Roy Soc Trop Med Hyg"},{"key":"10.3233\/JAD-221218_ref31","first-page":"706","article-title":"Amebiasis in northern Saskatchewan: Epidemiological considerations","volume":"99","author":"Eaton","year":"1968","journal-title":"Canad Med Assoc J"},{"key":"10.3233\/JAD-221218_ref32","first-page":"306","volume-title":"Proceedings of the 3rdInternational Symposium on Circumpolar Health, Yellowknife, NWT","author":"Freeman","year":"1976"},{"key":"10.3233\/JAD-221218_ref33","unstructured":"Augustyn A. The Editors of Encyclopaedia Britannica (2019) Sami. https:\/\/www.britannica.com\/topic\/Sami, Date published January 9, 2020. Access date November 23, 2020."},{"key":"10.3233\/JAD-221218_ref34","first-page":"553","article-title":"Lifestyle, genetics, and disease in Sami","volume":"47","author":"Ross","year":"2006","journal-title":"Croat Med J"},{"key":"10.3233\/JAD-221218_ref35","unstructured":"Veen, Ellis. Sami Food: What to eat in Lapland. September 2022, https:\/\/www.backpackadventures.org\/sami-food-in-lapland\/."},{"issue":"Suppl","key":"10.3233\/JAD-221218_ref36","first-page":"741","article-title":"Nutrient intake among Saami people today compared with an old, traditional Saami diet","author":"H\u00e5glin","year":"1991","journal-title":"Arctic Med Res"},{"key":"10.3233\/JAD-221218_ref37","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1126\/science.1227721","article-title":"Genomic variation in seven Khoe-San groups reveals adaptation and complex African history","volume":"338","author":"Schlebusch","year":"2012","journal-title":"Science"},{"key":"10.3233\/JAD-221218_ref38","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1093\/molbev\/msr212","article-title":"An early divergence of KhoeSan ancestors from those of other modern humans is supported by an ABC-based analysis of autosomal resequencing data","volume":"29","author":"Veeramah","year":"2012","journal-title":"Mol Biol Evol"},{"key":"10.3233\/JAD-221218_ref39","doi-asserted-by":"crossref","first-page":"e80031","DOI":"10.1371\/journal.pone.0080031","article-title":"The first modern human dispersals across Africa","volume":"8","author":"Rito","year":"2013","journal-title":"PLoS One"},{"key":"10.3233\/JAD-221218_ref40","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.cell.2017.08.049","article-title":"Reconstructing prehistoric African populationstructure","volume":"171","author":"Skoglund","year":"2017","journal-title":"Cell"},{"key":"10.3233\/JAD-221218_ref42","doi-asserted-by":"crossref","first-page":"5692","DOI":"10.1038\/ncomms6692","article-title":"Khoisan hunter-gatherers have been the largest population throughout most of modern-human demographic history","volume":"5","author":"Kim","year":"2014","journal-title":"Nat Commun"},{"key":"10.3233\/JAD-221218_ref43","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/j.1728-4457.2007.00171.x","article-title":"Longevity among hunter-gatherers: A cross-cultural examination","volume":"33","author":"Gurven","year":"2007","journal-title":"Popul Dev Rev"},{"key":"10.3233\/JAD-221218_ref44","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1203\/01.PDR.0000148719.82468.CA","article-title":"APOE4 protects thecognitive development in children with heavy diarrhea burdens inNortheast Brazil","volume":"57","author":"Ori\u00e1","year":"2005","journal-title":"Pediatr Res"},{"key":"10.3233\/JAD-221218_ref45","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s12974-019-1564-7","article-title":"The endotoxin hypothesis of neurodegeneration","volume":"16","author":"Brown","year":"2019","journal-title":"J Neuroinflammation"},{"key":"10.3233\/JAD-221218_ref46","first-page":"G730","article-title":"Dietary vitamin D3 deficiency alters intestinal mucosal defense and increases susceptibility to Citrobacter rodentium-induced colitis","volume":"309","author":"Ryz","year":"2015","journal-title":"Physiol"},{"key":"10.3233\/JAD-221218_ref47","doi-asserted-by":"crossref","first-page":"3262","DOI":"10.1096\/fj.11-180935","article-title":"APOE \u025b4 is associated with higher vitamin D levels in targeted replacement mice and humans","volume":"25","author":"Huebbe","year":"2011","journal-title":"FASEB J"},{"key":"10.3233\/JAD-221218_ref48","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.jaci.2014.01.032","article-title":"APO\u025b4 is associated with enhanced innate immune responses in human subjects","volume":"134","author":"Gale","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"10.3233\/JAD-221218_ref49","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1038\/s41598-022-05763-1","article-title":"APOE genetics influence murine gut microbiome","volume":"12","author":"Zajac","year":"2022","journal-title":"Sci Rep"},{"key":"10.3233\/JAD-221218_ref50","doi-asserted-by":"crossref","first-page":"200","DOI":"10.3389\/fimmu.2020.00200","article-title":"Murine gut microbiome association with APOE alleles","volume":"11","author":"Parikh","year":"2020","journal-title":"Front Immunol"},{"key":"10.3233\/JAD-221218_ref51","doi-asserted-by":"crossref","first-page":"e89562","DOI":"10.1371\/journal.pone.0089562","article-title":"Apolipoprotein E plays akey role against cryptosporidial infection in transgenicundernourished mice","volume":"9","author":"Azevedo","year":"2014","journal-title":"PLoS One"},{"key":"10.3233\/JAD-221218_ref52","first-page":"a006049","article-title":"Signaling in innate immunity and inflammation","volume":"4","author":"Newton","year":"2012","journal-title":"Harb Perspect Biol"},{"key":"10.3233\/JAD-221218_ref53","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/nature06247","article-title":"Manipulation of host-cell pathways by bacterial pathogens","volume":"449","author":"Bhavsar","year":"2007","journal-title":"Nature"},{"key":"10.3233\/JAD-221218_ref54","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.chom.2008.05.010","article-title":"Commensals, bacterial pathogensand intestinal inflammation: An intriguing m\u00e9nage \u00e0 trois","volume":"3","author":"P\u00e9dron","year":"2008","journal-title":"Cell Host Microbe"},{"key":"10.3233\/JAD-221218_ref55","first-page":"309","article-title":"Listeria monocytogenes and listeric infections","volume":"30","author":"Gray","year":"1966","journal-title":"Rev"},{"key":"10.3233\/JAD-221218_ref56","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1084\/jem.180.4.1307","article-title":"Acute inflammation causes epithelial invasion and mucosal destruction in experimental shigellosis","volume":"180","author":"Perdomo","year":"1994","journal-title":"Exp Med"},{"key":"10.3233\/JAD-221218_ref57","doi-asserted-by":"crossref","first-page":"6164","DOI":"10.4049\/jimmunol.171.11.6164","article-title":"Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms","volume":"171","author":"Bruewer","year":"2003","journal-title":"J Immunol"},{"key":"10.3233\/JAD-221218_ref58","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.chom.2007.09.005","article-title":"Helicobacter pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach","volume":"2","author":"Mimuro","year":"2007","journal-title":"Cell Host Microbe"},{"key":"10.3233\/JAD-221218_ref59","volume-title":"Helicobacter Pylori. Methods in Molecular Biology","author":"FitzGerald","year":"2021"},{"key":"10.3233\/JAD-221218_ref60","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/nature09415","article-title":"Gut inflammation provides a respiratory electron acceptor for Salmonella","volume":"467","author":"Winter","year":"2010","journal-title":"Nature"},{"key":"10.3233\/JAD-221218_ref61","first-page":"985","article-title":"Salmonella Typhimurium exploitsinflammation to its own advantage in piglets","volume":"6","author":"Chirullo","year":"2015","journal-title":"FrontMicrobiol"},{"key":"10.3233\/JAD-221218_ref62","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1590\/S0100-879X2010007500003","article-title":"APOE polymorphisms and diarrheal outcomes in Brazilian shanty town children","volume":"43","author":"Barnich","year":"2010","journal-title":"Braz J Med Biol Res"},{"key":"10.3233\/JAD-221218_ref63","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1371\/journal.pbio.0050244","article-title":"Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota","volume":"5","author":"Stecher","year":"2007","journal-title":"PLoS Biol"},{"key":"10.3233\/JAD-221218_ref64","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.chom.2007.06.010","article-title":"Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae","volume":"2","author":"Lupp","year":"2007","journal-title":"Cell Host Microbe"},{"key":"10.3233\/JAD-221218_ref65","first-page":"337","article-title":"Microbial-gut interactions in health and disease. Antibiotic-associated diarrhea. }","volume":"18","author":"Beaugerie","year":"2004","journal-title":"Gastroenterol"},{"key":"10.3233\/JAD-221218_ref66","doi-asserted-by":"crossref","first-page":"199","DOI":"10.2223\/JPED.2087","article-title":"Persistent diarrhea: Still an important challenge for the pediatrician","volume":"87","author":"Andrade","year":"2011","journal-title":"J Pediatr"},{"key":"10.3233\/JAD-221218_ref67","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0022-3476(96)70390-6","article-title":"Small-bowel bacterial overgrowth in children with chronic diarrhea, abdominal pain, or both","volume":"128","author":"de","year":"1996","journal-title":"J Pediatr"},{"key":"10.3233\/JAD-221218_ref68","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1203\/01.PDR.0000076666.16021.5E","article-title":"Chronic T cell-mediated enteropathy in rural west African children: Relationship with nutritional status and small bowel function","volume":"54","author":"Campbell","year":"2003","journal-title":"Pediatr Res"},{"key":"10.3233\/JAD-221218_ref69","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1093\/jn\/133.5.1332","article-title":"Growth faltering in rural Gambian infants is associated with impaired small intestinal barrier function, leading to endotoxemia and systemic inflammation","volume":"133","author":"Campbell","year":"2003","journal-title":"J Nutr"},{"key":"10.3233\/JAD-221218_ref70","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1017\/S0029665100000173","article-title":"The impact of infection and nutrition on gut function and growth in childhood","volume":"59","author":"Lunn","year":"2000","journal-title":"Proc Nutr Soc"},{"key":"10.3233\/JAD-221218_ref71","unstructured":"Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Foodborne, Waterborne, and Environmental Diseases at CDC (2020) Global diarrhea burden. https:\/\/www.cdc.gov\/healthywater\/global\/ Date accessed November 23, 2020. Date last reviewed December 17, 2015."},{"key":"10.3233\/JAD-221218_ref72","first-page":"508","article-title":"Parasitic infections in the Eskimos at Igloolik, N.W.T.","volume":"41","author":"Brown","year":"1950","journal-title":"Canad J Public Health"},{"key":"10.3233\/JAD-221218_ref73","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.2105\/AJPH.49.11.1441","article-title":"Acute intestinal disease in the Arctic","volume":"49","author":"Gordon","year":"1959","journal-title":"Am J Public Health Nations Health"},{"key":"10.3233\/JAD-221218_ref74","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.2105\/AJPH.48.11_Pt_1.1489","article-title":"Bacteriological and parasitological survey of enteric infections in an Alaskan Eskimo area","volume":"48","author":"Fournelle","year":"1958","journal-title":"Am J Public Health Nations Health"},{"key":"10.3233\/JAD-221218_ref75","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/nri1601","article-title":"A worm\u2019s eye view of the immune system: Consequences for evolution of human autoimmune disease","volume":"5","author":"Dunne","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"10.3233\/JAD-221218_ref76","first-page":"207","article-title":"Factors governing the survival of bushmen worm parasites in the Kalahari","volume":"57","author":"Heinz","year":"1961","journal-title":"S Afr J Sci"},{"key":"10.3233\/JAD-221218_ref77","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1128\/CMR.14.4.689-703.2001","article-title":"Immune responses in hookworm infections","volume":"14","author":"Loukas","year":"2001","journal-title":"Microbiol Rev"},{"key":"10.3233\/JAD-221218_ref78","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1371\/journal.pmed.0020067","article-title":"Hookworm: \u201cThe great infection of mankind\u201d","volume":"2","author":"Hotez","year":"2005","journal-title":"PLoS Med"},{"key":"10.3233\/JAD-221218_ref79","doi-asserted-by":"crossref","first-page":"2684","DOI":"10.1128\/IAI.71.5.2684-2692.2003","article-title":"Persistence of mucosal mast cells and eosinophils in shigella-infected children","volume":"71","author":"Raqib","year":"2003","journal-title":"Infect Immun"},{"key":"10.3233\/JAD-221218_ref80","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/j.1749-6632.2010.05726.x","article-title":"Role of inflammation in cognitive impairment: Results of observational epidemiological studies and clinical trials","volume":"1207","author":"Gorelick","year":"2010","journal-title":"Ann N Y Acad Sci"},{"key":"10.3233\/JAD-221218_ref81","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.mehy.2006.09.036","article-title":"Role of apolipoprotein E4 in protecting children against earlychildhood diarrhea outcomes and implications for later development","volume":"68","author":"Ori\u00e1","year":"2007","journal-title":"Med Hypotheses"},{"key":"10.3233\/JAD-221218_ref82","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1590\/S0100-879X2010007500003","article-title":"APOE polymorphisms and diarrheal outcomes in Brazilian shanty town children","volume":"43","author":"Oria","year":"2010","journal-title":"Braz J Med Biol Res"},{"key":"10.3233\/JAD-221218_ref83","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1590\/S1517-838246120130917","article-title":"Adherence and virulence genes of Escherichia coli from children diarrhea in the Brazilian Amazon","volume":"46","author":"Benevides-Matos","year":"2015","journal-title":"Bras J Microbiol"},{"key":"10.3233\/JAD-221218_ref84","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1096\/fj.201601084R","article-title":"Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden","volume":"31","author":"Trumble","year":"2017","journal-title":"FASEB J"},{"key":"10.3233\/JAD-221218_ref85","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1212\/WNL.0b013e3182896e79","article-title":"Infectious burden and cognitive function: The Northern Manhattan Study","volume":"80","author":"Katan","year":"2013","journal-title":"Neurology"},{"key":"10.3233\/JAD-221218_ref86","doi-asserted-by":"crossref","first-page":"e0116874","DOI":"10.1371\/journal.pone.0116874","article-title":"Interaction between Helicobacter pylori and latent toxoplasmosis and demographic variables on cognitive function in young to middle-aged adults","volume":"10","author":"Gale","year":"2015","journal-title":"PLoS One"},{"key":"10.3233\/JAD-221218_ref87","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.bbi.2015.10.014","article-title":"Infectious disease burden and cognitive function in young to middle-aged adults","volume":"52","author":"Gale","year":"2016","journal-title":"Brain Behav Immun"},{"key":"10.3233\/JAD-221218_ref88","first-page":"493","article-title":"Eosinophilia in infectious diseases","volume":"35","author":"O\u2019Connell","year":"2015","journal-title":"Clin North Am"},{"key":"10.3233\/JAD-221218_ref89","doi-asserted-by":"crossref","first-page":"e6590","DOI":"10.1371\/journal.pone.0006590","article-title":"Inflammation and infection do not promote arterial aging and cardiovascular disease risk factors among lean horticulturalists","volume":"4","author":"Gurven","year":"2009","journal-title":"PLoS One"},{"key":"10.3233\/JAD-221218_ref90","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1080\/19485565.2011.564475","article-title":"Inflammatory gene variants in the Tsimane, an indigenous Bolivian population with a high infectious load","volume":"57","author":"Vasunilashorn","year":"2011","journal-title":"Biodemography Soc Biol"},{"key":"10.3233\/JAD-221218_ref91","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0969-2126(99)80023-9","article-title":"The physiological structure of human C-reactive protein and its complex with phosphocholine","volume":"7","author":"Thompson","year":"1999","journal-title":"Structure"},{"key":"10.3233\/JAD-221218_ref92","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.bbi.2018.02.013","article-title":"Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters","volume":"70","author":"Del","year":"2018","journal-title":"Brain Behav Immun"},{"key":"10.3233\/JAD-221218_ref93","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.humimm.2010.01.008","article-title":"APOE polymorphism and its effect on plasma C-reactive protein levels in a large general population sample","volume":"71","author":"Hubacek","year":"2010","journal-title":"Hum Immunol"},{"key":"10.3233\/JAD-221218_ref94","doi-asserted-by":"crossref","first-page":"12587","DOI":"10.1155\/MI\/2006\/12587","article-title":"ApoE polymorphism is associated with C-reactive protein in low-HDL family members and in normolipidemic subjects","volume":"2006","author":"Kahri","year":"2006","journal-title":"Mediators Inflamm"},{"key":"10.3233\/JAD-221218_ref95","doi-asserted-by":"crossref","first-page":"860","DOI":"10.3346\/jkms.2015.30.7.860","article-title":"APOE polymorphism is associated with C-reactive protein levels but not with white blood cell count: Dong-gu Study and Namwon Study","volume":"30","author":"Yun","year":"2015","journal-title":"J Korean Med Sci"},{"key":"10.3233\/JAD-221218_ref96","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.tree.2018.05.005","article-title":"Did our species evolve in subdivided populations across Africa, and why does it matter?","volume":"33","author":"Scerri","year":"2018","journal-title":"Trends Ecol Evol"},{"key":"10.3233\/JAD-221218_ref97","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1126\/science.aap8369","article-title":"The earliest modern humans outside Africa","volume":"359","author":"Hershkovitz","year":"2018","journal-title":"Science"},{"key":"10.3233\/JAD-221218_ref98","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1126\/science.aao6266","article-title":"Southern African ancient genomes estimate modern human divergence to 350,000 to 260,000 years ago","volume":"358","author":"Schlebusch","year":"2017","journal-title":"Science"},{"key":"10.3233\/JAD-221218_ref99","doi-asserted-by":"crossref","first-page":"J16416","DOI":"10.1073\/pnas.0703874104","article-title":"East African megadroughts between 135 and 75 thousand years ago and bearing on early-modern human origins","volume":"104","author":"Scholz","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.3233\/JAD-221218_ref100","doi-asserted-by":"crossref","first-page":"5243","DOI":"10.1007\/s12035-017-0757-2","article-title":"Transcriptional effects of ApoE4: Relevance to Alzheimer\u2019s disease","volume":"55","author":"Theendakara","year":"2018","journal-title":"Mol Neurobiol"},{"key":"10.3233\/JAD-221218_ref101","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/s41576-018-0012-3","article-title":"The transition to modernity and chronic disease: Mismatch and natural selection","volume":"19","author":"Corbett","year":"2018","journal-title":"Nat Rev Genet"}],"container-title":["Journal of Alzheimer's Disease"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JAD-221218","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:07:42Z","timestamp":1777370862000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JAD-221218"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,30]]},"references-count":100,"journal-issue":{"issue":"3"},"URL":"https:\/\/doi.org\/10.3233\/jad-221218","relation":{},"ISSN":["1387-2877","1875-8908"],"issn-type":[{"value":"1387-2877","type":"print"},{"value":"1875-8908","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,30]]}}}