Human Leukocyte Antigen as a Key Factor in Preventing Dementia and Associated Apolipoprotein E4 Risk

James, Lisa M.; Georgopoulos, Apostolos P.

doi:10.3389/fnagi.2019.00082

Cited by 15 publications

(23 citation statements)

References 20 publications

(26 reference statements)

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“…That is, in countries for which the frequency of these three HLA alleles are relatively high, the reduced dementia prevalence is presumably due to enhanced pathogen elimination at the population level. Conversely, in countries for which the frequency of these three HLA alleles are relatively low, higher dementia prevalence may be partially due to pathogen persistence [3][4][5][6] . A number of viral and bacterial pathogens have been implicated in dementia 7,8 though findings with regard to specific pathogens have often been inconsistent.…”

Section: Discussionmentioning

confidence: 99%

“…Although apoE4 has been widely associated with dementia, prior studies have demonstrated that the effects of protective HLA alleles are independent of apoE4 [1][2][3] . In light of that, we have speculated that apoE4 effects are secondary to HLA 4 . That is, we have proposed that given an HLA-antigen match (i.e., with sufficient binding affinity and immunogenicity) the risk associated with apoE4 status is minimized.…”

Section: Discussionmentioning

confidence: 99%

“…Antibody production and subsequent elimination of foreign antigens, however, are predicated on good binding affinity between HLA and epitopes of foreign antigens coupled with the resulting immunogenicity. Sufficient affinity/immunogenicity results in immunological memory and host protection in the event of re-exposure; however, poor affinity/ immunogenicity may lead to antigen persistence and, consequently, neuronal damage 4,5 and possibly dementia 4,6 . Indeed, several microbes have been associated with Alzheimer's dementia 7,8 and pathogens have been implicated in other forms of dementia as well 6 .…”

Section: Introductionmentioning

confidence: 99%

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

James¹,

Georgopoulos²

2019

J Neurol Neuromed

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

James¹,

Georgopoulos²

2019

J Neurol Neuromed

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“…Recent evidence suggests that HLA genes, which play a critical in specific immunity, may also influence risk for dementia [13][14][15][16] . Located in the Major Histocompatibility Complex (MHC) of chromosome 6, HLA genes code for glycoproteins that reside on the surface of most cells and facilitate elimination of foreign antigens.…”

Section: Human Leukocyte Antigen (Hla)mentioning

confidence: 99%

The Human Leukocyte Antigen (HLA) DRB1*13:02 Allele Protects against Dementia in Continental Western Europe

James¹,

Georgopoulos²

2019

J Neurol Neuromed

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Human Leukocyte Antigen (HLA) Class II DRB1*13 alleles have recently been found to protect against age-related brain deterioration, even in the presence of apolipoprotein E4 (apoE4), 1,2 suggesting a possible protection against dementia.Here we evaluated the association between the population frequency of common DRB1*13 alleles and the prevalence of dementia in Continental Western Europe. Prevalence of dementia in Continental Western Europe was derived from published reports on dementia frequency from the Global Burden of Disease Study 2016 and population totals obtained from the Population Reference Bureau. DRB1*13:01 and DRB1*13:02 allele frequencies were obtained from a publicly available database (allelefrequency.net) and apolipoprotein E was obtained from published reports on the world distribution of apoE4. The prevalence of dementia in 14 Continental Western European (CWE) countries, where life expectancy is practically identical, significantly decreases exponentially with increasing frequency of DRB1*13:02 (R 2 = 0.452, P = 0.008), even when adjusted for the prevalence of apolipoprotein E4 allele, a known risk factor for Alzheimer's disease. This finding documents the protective effect of DRB1*13:02 on dementia prevalence in CWE. Since the function of HLA class II genes is to aid in the elimination of pathogens by enabling the production of antibodies against their antigens in specific immunity, the protective effect of DRB1*13:02 points to the presence of persistent harmful antigens as causal factors in development of dementia, antigens specific to DRB1*13:02 that could not be eliminated in its absence.

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“…Here we found no differences between dementia and Parkinson's disease prevalence with respect to protective HLA alleles for both conditions; however, the association of susceptibility HLA alleles was stronger with dementia than the association of those same alleles with Parkinson's disease. These findings suggest that similar immunogenetic mechanisms along the lines of those discussed above (i.e., elimination of pathogens) are involved in protection against these conditions but that additional factors are involved in moderating HLA-mediated autoimmunity in dementia and Parkinson's disease, including variations in apoE 51,52 , modifiable risk factors including diet, exercise, and smoking, among others 4,5,53 , and other environmental exposures that have been differentially associated with dementia and Parkinson's disease 4,5 . These issues represent important areas for future investigation.…”

Section: Discussionmentioning

confidence: 75%

Untitled

2021

J Immunological Sci

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Human leukocyte antigen (HLA), which is critically involved in immune response to foreign antigens and in autoimmunity, has been implicated in dementia and Parkinson's disease. Here we report on the correlations between the population frequencies of 127 HLA Class I and II alleles and the population prevalence of dementia and Parkinson's disease in 14 Continental Western European countries, extending previous work 1,2 . We used these correlations to construct and compare HLA profiles for each disease 3 . We found that (a) the HLA profiles of the two diseases were significantly correlated across both HLA Class I and Class II alleles, (b) negative ("protective") HLA-disease correlations did not differ significantly for either HLA class, but (c) positive ("susceptibility") HLAdisease correlations were significantly higher in dementia than in Parkinson's disease for both HLA classes of alleles. These findings indicate that (a) dementia and Parkinson's disease share immunogenetic HLA-related mechanisms, (b) HLA-related protective mechanisms (presumably against pathogens) do not differ between the two diseases, but (c) HLA-related susceptibility mechanisms (presumably underlying autoimmunity) are significantly stronger in dementia than in Parkinson's disease.

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Human Leukocyte Antigen as a Key Factor in Preventing Dementia and Associated Apolipoprotein E4 Risk

Cited by 15 publications

References 20 publications

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

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

The Human Leukocyte Antigen (HLA) DRB1*13:02 Allele Protects against Dementia in Continental Western Europe

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