Tri-Allelic Human Leukocyte Antigen (HLA) Protection Against Dementia

Abstract

Human Leukocyte Antigen (HLA) 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 HLA alleles -DRB1*01:01 and DRB1*15:01 -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's < 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.

Shared Human Leukocyte Antigen (HLA) Coverage in dementia and Parkinson’s disease

“…Using a publicly available repository 21 containing HLA data pooled from histocompatibility laboratories and published studies, coupled with dementia prevalence obtained from the Global Burden of Disease studies 1 we have examined associations between HLA and dementia prevalence in 14 countries in Continental Western Europe where dementia prevalence is among the highest in the world. We demonstrated that three specific Class II HLA DRB1 alleles -DRB1*01:01, DRB1*13:02, and DRB1*15:01 -are highly protective against dementia, even after accounting for apolipoprotein E4 17 . Moreover, the combined population frequency of the three alleles accounted for 67% of the variance in dementia prevalence and 48% of the change in dementia prevalence in those countries over the last 25 years.…”

“…As in our previous studies 16,17 we focused on the following 14 CWE countries: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Portugal, Norway, Spain, Sweden, and Switzerland.…”

“…HLA alleles. In our previous studies we identified three HLA Class II alleles protective for dementia 17 (DRB1*01:01, DRB1*13:02, DRB1*15:01) and three alleles that are neutral for dementia 21 (DRB1*03:01, DRB1*07:01, DRB1*08:01); in addition, we now identified an allele protective for dementia (DRB1*04:01; Allele Frequency Net Database, http://www.allelefrequencies.net 21 ). To obtain allele frequencies, the Allele Frequency Net Database was queried to provide the 4-digit HLA allele frequency for each country with no further restrictions by region, ethnicity, source of study, or other qualifiers.…”

“…analyses were used to evaluate the association between the population frequency of each the seven HLA alleles above (Table 2), alone and combined, and the prevalence of dementia and Parkinson's disease in Continental Western Europe. Previous analyses 16,17 had documented an exponential relation between dementia prevalence and allele frequency; hence, the prevalences of dementia and Parkinson's disease were natural-log transformed to analyze their relation to allele frequency using linear regression. Pairwise Pearson correlation coefficients were compared by calculating the normal deviate z-statistic 24 .…”

“…In terms of genetic protection, studies have demonstrated that apolipoprotein E2 protects against dementia 12,13 and may protect against Parkinson's disease-related dementia 14,15 . Moving beyond apolipoprotein E, recent studies have also demonstrated robust genetic protection against dementia conferred by specific Class II human leukocyte antigen (HLA) alleles 16,17 . The extent to which those HLA alleles protect against Parkinson's disease is unknown.…”