About 20% to 30% of people carry versions of an immune-related gene that may protect against Alzheimer's and Parkinson's disease, a massive new study across a diverse set of ethnic groups has found.
In the study, people carrying a version of the human leukocyte antigen (HLA) gene known as HLA-DRB1*04, or DR4 for short, had 8% to 15% lower odds of developing these neurodegenerative diseases.
What's more, these individuals harbored fewer of the abnormally folded brain proteins, such as tau tangles, that are hallmarks of these conditions. That hints that the gene variants may protect against such diseases by preventing these proteins from accumulating.
The findings, published Aug. 29 in the journal PNAS, could have implications for the development of novel vaccines against Alzheimer's and Parkinson's.
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Alzheimer's and Parkinson's are characterized by the progressive loss of specific neurons, or nerve cells in the brain, and both conditions are linked to a buildup of abnormal proteins. In Alzheimer's, these proteins include so-called tau tangles and amyloid-beta plaques, while in Parkinson's, a protein called alpha-Synuclein misfolds and clumps to form "Lewy bodies." There's also growing evidence that tau tangles play a role in Parkinson's.
And past research suggests that misfiring immune responses may underpin the development of both Parkinson's and Alzheimer's.
Shape-shifting HLA proteins lie at the core of the adaptive immune system, which tailors the body's responses to pathogens, like viruses. In a smaller, past study, study co-author Dr. Emmanuel Mignot, a neuroimmunologist and professor at Stanford University, found that certain variants of a gene called HLA-DRB1, which codes for an HLA protein, were linked to a reduced risk of both Alzheimer's and Parkinson's.
This was striking because the two diseases are so different, Mignot told Live Science.
To pin down the connection, Mignot and his colleagues looked at a massive collection of genome-wide data from 176,000 people of European, Asian, Latin American and African American ancestry. These individuals had either Alzheimer's or Parkinson's, and their genetics were compared to those of people without the conditions.
They found a strong protective effect for those who carried the DR4 gene variant. Certain subtypes of the variant — specifically HLA-DRB1*04:04 and HLA-DRB1*04:07 — showed the strongest correlation, while HLA-DRB1*04:01 and HLA-DRB1*04:03 had intermediate effects.
To explain how these gene variants may protect against neurodegenerative diseases, the researchers homed in on tau. Studies have shown that abnormal tau proteins are more likely to misfold, aggregate and then spread between cells, causing tau in those cells to misfold too. Mignot and his team hypothesized that an immune response against tau may confer protection from both Alzheimer's and Parkinson's.
In lab experiments, they found that the HLA-DRB1*04:04 and HLA-DRB1*04:01 subtypes bind a tau fragment called PHF6, which is found primarily in Alzheimer's. Specifically, these subtypes latch onto an altered version of PHF6 that's been tied to tao tangles. Binding PHF6 could jumpstart an immune response against the fragment and, in theory, reduce the spread of tau tangles and thus delay the onset and progression of neurodegeneration, the authors hypothesized.
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In further support of this idea, the HLA variants were tied to having fewer tau tangles in the brain, the team found by reviewing data gathered from autopsied brains of people who'd died of Alzheimer's. To a lesser extent, those people also had fewer amyloid beta plaques.
"This is a very interesting study … providing additional evidence of the involvement of the immune system in the pathogenesis of … Alzheimer's and Parkinson's," Wassim Elyaman, a neurologist at Columbia University Irving Medical Center who was not involved in the research, told Live Science in an email.
But although the genetic analysis is strong, the researchers need to do more immune cell- and blood-based studies to pin down how certain versions of tau are connected to Alzheimer's and Parkinson's, Elyaman added. Someday, the innovative study may pave the way for developing novel immunotherapies or vaccines, he said.
Mignot envisions vaccinating people who carry HLA-DRB1*04 with tiny bits of the tau fragment PHF6. This would trigger an immune response against tau and possibly "delay the onset of Alzheimer's and Parkinson's or reduce disease progression, because you would delay the spreading of tau," he explained.
As next steps, Mignot hopes to test that hypothesis in genetically modified mice made to carry the protective HLA gene variant. If it works in mice, it could then be tried in humans.
