Dementia, Parkinson^aEURTMs disease, multiple sclerosis, and motor neuron diseases cause significant disability and mortality worldwide. Although the etiology of these diseases is unknown, highly correlated disease prevalences would indicate the involvement of common etiologic factors. Here we used published epidemiological data in 195 countries worldwide to investigate the possible intercorrelations among the prevalences of these diseases. All analyses were carried out using nonparametric statistics on rank-transformed data to assure the robustness of the results. We found that all 6 pairwise correlations among the prevalences of the 4 diseases were very high (>.9, P<.001). A factor analysis (FA) yielded only a single component which comprised all 4 disease prevalences and explained 96.3% of the variance. These findings indicate common etiologic factor(s). Next, we quantified the contribution of 3 country-specific factors (population size, life expectancy, latitude) to the common grouping of prevalences by estimating the reduction in total FA variance explained when the effect of these factors was eliminated by using the prevalence residuals from a linear regression where theses factor were covariates. FA of these residuals yielded again only a single component comprising all 4 diseases which explained 71.5% of the variance, indicating that the combined contribution of population size, life expectancy and latitude accounted for 96.3%^a^'71.5%=24.8% of the FA variance explained. The fact that the 3 country-specific factors above accounted for only 24.8% of the FA variance explained by the original (ranked) disease prevalences, in the presence still of a single grouping factor, strongly indicates the operation of other unknown factors jointly contributing to the pathogenesis of the 4 diseases. We discuss various possible factors involved, with an emphasis on biologic pathogens (viruses, bacteria) which have been implicated in the pathogenesis of these diseases in previous studies.

Human Leukocyte AntigenHuman Leukocyte Antigen (HLA)Genes that are located in the Major Histocompatibility Complex (MHC) of chromosome 6 and play a central role in immune recognition. Most investigations of association of HLA to various diseases have focused on evaluating HLA allele frequencies in diseases of interest, as compared to the general, healthy population. Such studies have demonstrated HLA involvement with cancer, autoimmune, and in- fectious diseases. HLA Class I proteins (HLA-A, B, C) are expressed on all nucleated cells and present peptides from endogenous proteins to cytotoxic T lymphocytes engaged in immune surveillance. HLA Class II proteins (HLA-DRB1, DRB3/4/5, DQB1, DPB1) are expressed on antigen-presenting cells and present peptides derived from exogenous proteins to CD4+helper T cells. A previous study of Gulf War syndrome in 27 veterans found that HLA DRB1*15 was more prevalent in cases than controls with an odds ratio of 1.66, although this association was not statistically significant. Class II DRB1*13:02 has recently been found to protect against dementia in Continental Western Europe. Here we extend those findings by evaluating the association between the population frequency of two additional Class II HLAHuman Leukocyte Antigen (HLA)Genes that are located in the Major Histocompatibility Complex (MHC) of chromosome 6 and play a central role in immune recognition. Most investigations of association of HLA to various diseases have focused on evaluating HLA allele frequencies in diseases of interest, as compared to the general, healthy population. Such studies have demonstrated HLA involvement with cancer, autoimmune, and in- fectious diseases. HLA Class I proteins (HLA-A, B, C) are expressed on all nucleated cells and present peptides from endogenous proteins to cytotoxic T lymphocytes engaged in immune surveillance. HLA Class II proteins (HLA-DRB1, DRB3/4/5, DQB1, DPB1) are expressed on antigen-presenting cells and present peptides derived from exogenous proteins to CD4+helper T cells. A previous study of Gulf War syndrome in 27 veterans found that HLA DRB1*15 was more prevalent in cases than controls with an odds ratio of 1.66, although this association was not statistically significant. alleles ^aEUR" DRB1*01:01 and DRB1*15:01 ^aEUR" alone and in combination with DRB1*13:02, on dementia prevalence in Continental Western Europe. Results indicated that the prevalence of dementia in 14 Continental Western European (CWE) countries significantly decreased exponentially with increasing frequency of any of the three alleles alone and in combination (P^aEURTMs < 0.001). When combined, the population frequency of the three alleles accounted for 67% of the variance in dementia prevalence. The combined frequency of DRB1*01:01, DRB1*13:02, and DRB1*15:01 was also significantly associated with dementia prevalence in those aged 65 years and older (P = 0.004) and with a change in dementia prevalence between 1990 and 2016 (P = 0.006). These findings, which document the protective effects of three common Class II HLA alleles on dementia prevalence in CWE, are discussed in terms of the role of HLA class II genes in pathogen elimination. More specifically, we hypothesize that dementia prevalence is higher for countries in which the population frequency of these protective alleles is low, prohibiting the successful elimination of pathogens that may play a causal role in dementia.