Epidemiological evidence for a relationship between microbial environment and age-adjusted disease burden

Background and objectives: Alzheimer’s disease (AD) shares certain etiological features with autoimmunity. Prevalence of autoimmunity varies between populations in accordance with variation in environmental microbial diversity. Exposure to microorganisms may improve individuals’ immunoregulation in ways that protect against autoimmunity, and we suggest that this may also be the case for AD. Here, we investigate whether differences in microbial diversity can explain patterns of age-adjusted AD rates between countries. Methodology: We use regression models to test whether pathogen prevalence, as a proxy for microbial diversity, across 192 countries can explain a significant amount of the variation in age-standardized AD disability-adjusted life-year (DALY) rates. We also review and assess the relationship between pathogen prevalence and AD rates in different world populations. Results: Based on our analyses, it appears that hygiene is positively associated with AD risk. Countries with greater degree of sanitation and lower degree of pathogen prevalence have higher age-adjusted AD DALY rates. Countries with greater degree of urbanization and wealth exhibit higher age-adjusted AD DALY rates. Conclusions and implications: Variation in hygiene may partly explain global patterns in AD rates. Microorganism exposure may be inversely related to AD risk. These results may help predict AD burden original research article 173 The Author(s) 2013. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. in developing countries where microbial diversity is rapidly diminishing. Epidemiological forecasting is important for preparing for future healthcare needs and research prioritization. K E Y W O R D S : Alzheimer’s disease; hygiene hypothesis; inflammation; dementia; pathogen prevalence; Darwinian medicine INTRODUCTION Exposure to microorganisms is critical for the regulation of the immune system. The immunodysregulation of autoimmunity has been associated with insufficient microorganism exposure [1]. Global incidence patterns of autoimmune diseases reflect this aspect of their etiology: autoimmunity is inversely correlated to microbial diversity [1, 2]. The inflammation characteristic of Alzheimer’s disease (AD) shares important similarities with autoimmunity [3, 4]. The similarity in immunobiology may lead to similarity in epidemiological patterns. For this reason, here we test the hypothesis that AD incidence may be positively correlated to hygiene. The possibility that AD incidence is related to environmental sanitation was previously introduced by other authors [5, 6], and remains as of yet untested. The ‘hygiene hypothesis’ [7] suggests that certain aspects of modern life (e.g. antibiotics, sanitation, clean drinking-water, paved roads) are associated with lower rates of exposure to microorganisms such as commensal microbiota, environmental saprophytes and helminths than would have been omnipresent during the majority of human history [8]. Low amount of microbe exposure leads to low lymphocyte turnover in the developing immune system, which can lead to immunodysregulation. Epidemiological studies have found that populations exposed to higher levels of microbial diversity exhibit lower rates of autoimmunities as well as atopies [9], a pattern that holds for countries with differing degrees of development [10, 11]. Differences in environmental sanitation can partly explain the patterns of autoimmunity and atopy across history and across world regions [2, 12]. Patient-based studies have demonstrated that individuals whose early-life circumstances were characterized by less exposure to benign infectious agents exhibit higher rates of autoimmune and atopic disorders. This pattern has been demonstrated for farm living versus rural non-farm living [13–15], daycare attendance [16, 17], more siblings [7, 18], later birth order [19–21] and pets in the household [22], exhibiting lower rates of atopic and autoimmune disorders. Low-level persistent stimulation of the immune system leads naı̈ve T-cells to take on a suppressive regulatory phenotype [23] necessary for regulation of both type-1 inflammation (e.g. autoimmunity) and type-2 inflammation (e.g. atopy) [12, 24, 25]. Individuals with insufficient immune stimulation may experience insufficient proliferation of regulatory T-cells (TRegs) [26, 27]. AD has been described as a disease of systemic inflammation [28], with the AD brain and periphery exhibiting upregulated type1 dominant inflammation [29]: a possible sign of TReg deficiency. Immunodysregulation as a consequence of low immune stimulation may contribute to AD risk through the T-cell system. Altogether, we suggest that a hygiene hypothesis for Alzheimer’s disease (HHAD) predicts that AD incidence may be positively correlated to hygiene. The period from gestation through childhood is typically thought to be a critical window of time during which the immune system is established [14, 30, 31], with some authors limiting this critical window to the first 2 years of life [32]. However, proliferation of TRegs occurs throughout the life course: there are age-related increases in number of TRegs [30, 33] with peaks at adolescence and in the sixth decade [34]. Therefore, it may be not only early-life immune stimulation that affects AD risk (and perhaps risk of other types of immunodysregulation) but also immune stimulation throughout life. Our study is designed based on the hypothesis that microorganism exposure across the lifespan may be related to AD risk. At an epidemiological level, our prediction is opposite to Finch’s [6] hypothesis that early-life pathogen exposure should be positively correlated to AD risk. Both their and our predictions are based on speculation about T-cell differentiation, although we reached opposite suppositions. It is clear that inflammation is upregulated in AD, and Finch suggested that pathogen exposure, which is proinflammatory, may increase AD risk [6]. We propose 174 | Fox et al. Evolution, Medicine, and Public Health