Dementia Prevention Linked to Disposal of Pathogenic Debris

Aged man

What if surviving an infection like herpes, pneumonia, or Lyme disease set you up for dementia later in life?

For some people that is, sadly, the case, studies by two University of Minnesota researchers indicate. Evidence is mounting that proteins in fragments of bacteria, viruses, or other pathogens left over from battles with our immune system can harm the brain and raise the chance of dementia. These proteins are all termed "antigenic"—i.e., able to provoke an immune response, especially one involving antibody production.

But Lisa James, PhD, and Apostolos Georgopoulos, MD, PhD, have also found that many people have genes that shield against such an outcome. And now they have demonstrated their beneficial effects across the populations of entire countries.

“These genes have evolved to fight infections, and prevent their reoccurrence,” said James, Kunin Professor of Women’s Healthy Aging in the Department of Neuroscience and researcher at the Brain Sciences Center of the Minneapolis VA. “If we could develop treatments that mimic the functions of these genes—that is, eliminate fragments of viruses or other pathogens—we may be able to soften the scourge of dementia, which is now the fifth leading cause of death worldwide.”

In previous work, the researchers linked the presence of one gene, called DRB*13:02, to protection from dementia in aging women. In their current work, they show statistically that it protects throughout the entire populations of 14 Western European countries. Also, they have discovered that two related genes—DRB1*01:01 and DRB1*15:01—also protect against dementia in those countries. Others doubtless remain to be discovered.

The 14-country studies appear in December 2019 and January 2020 issues of the Journal of Neurology and Neuromedicine.

Protecting Under 14 Flags

The genes—which are actually alleles (variants) of a gene—belong to a family of genes called human leucocyte antigen (HLA) genes. HLA genes enable the immune system to produce antibodies that recognize and help destroy disease organisms and other harmful foreign material.

The researchers found that in going from country to country, as the proportion of people carrying any of the three HLA alleles rose, the prevalence of dementia—the proportion of people affected—fell exponentially.

Also, the prevalence of dementia in all 14 countries dropped between 1990 and 2016. The higher the combined proportions of the alleles in a population, the bigger the drop.   

The countries were Austria, Belgium, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Norway, Portugal, Spain, Sweden, and Switzerland.

“Statistics indicated that the three alleles accounted for much of the variance in dementia prevalence between countries, and for its decline,” said James. “It is likely that the remaining variance is attributable to other genetic influences and lifestyle factors like diet and exercise.” 

How They Work

In order to protect someone, the HLA proteins bind to antigenic proteins of infectious agents to mount an immune response. If the process fails, fragments of viruses or other disease organisms may persist indefinitely, ultimately causing cell damage resulting in neurodegeneration and dementia, the researchers said.

“The protection conferred by the three alleles is most probably due to the successful elimination of the offending fragments, which would prevent cell damage up front,” said James. “Remarkably, this protection is independent of the prevalence of the apolipoprotein E4 (apoE4) gene, a known genetic risk for Alzheimer’s disease.” 

“Our current findings bolster our previous findings showing that HLA genes are intimately involved in brain health,” said Georgopoulos, Regents Professor of Neuroscience and director of the Brain Sciences Center. “And it strongly suggests that identifying and eliminating potentially harmful foreign material would be critical for preventing dementia.”