DR4 Allele Reveals Potential Shield against Alzheimer’s and Parkinson’s Risk

A groundbreaking investigation into medical and genetic data has unveiled a fascinating revelation: individuals possessing a specific variant of a gene linked to immune response exhibit a diminished susceptibility to Alzheimer’s and Parkinson’s diseases.

In an unanticipated twist, nearly 20% of the population carries an inconspicuous gene variant that seems to provide a shield against both Alzheimer’s and Parkinson’s diseases. Stanford Medicine researchers collaborated with their counterparts and made this enlightening discovery. The fortunate bearers of this gene could potentially reap even greater benefits from a future vaccine designed to decelerate or hinder the advancement of these prevalent neurological disorders.

A meticulous scrutiny of medical and genetic information sourced from an extensive array of individuals representing various lineages across multiple continents has divulged that harboring this specific gene version, known as an allele, can significantly curtail the risk of contracting Parkinson’s or Alzheimer’s by more than 10% on an average basis.

Strikingly, the indications imply a potential link between a protein called tau, notorious for amassing in the brains of Alzheimer’s patients, and the enigmatic pathogenesis of Parkinson’s disease.

The comprehensive findings and their far-reaching implications have been comprehensively elucidated in a research article released digitally on August 29th via the Proceedings of the National Academy of Sciences. Leading the research are Emmanuel Mignot, MD, PhD, who holds the esteemed Craig Reynolds Professorship in Sleep Medicine and is also a distinguished professor of psychiatry and behavioral sciences; Michael Greicius, MD, the illustrious Iqbal Farrukh and Asad Jamal Professor of Neurology and Neurological Sciences; and Jean-Charles Lambert, PhD, the esteemed director of research for Inserm at the University of Lille in France. The foremost contributors to the paper include Yann Le Guen, PhD, who serves as the assistant director of computational biology within Stanford Medicine’s quantitative sciences unit; Guo Luo, PhD, an adept instructor of sleep medicine; Aditya Ambati, PhD, a former postdoctoral scholar; and Vincent Damotte, PhD, a proficient bioinformatician associated with Lambert’s distinguished group.

The genetic variant identified as a shield in this study goes by the name DR4, holding the potential to revolutionize our understanding of neurodegenerative diseases.

“In an earlier study we’d found that carrying the DR4 allele seemed to protect against Parkinson’s disease,” Mignot said. “Now, we’ve found a similar impact of DR4 on Alzheimer’s disease.”

Pooling together an extensive array of medical and genetic databases garnered from diverse corners of the globe — spanning Europe, East Asia, the Middle East, and South and North America — the adept team at Stanford Medicine embarked on an ambitious endeavor. Their cumulative effort incorporated data from over 100,000 individuals grappling with Alzheimer’s disease and an additional 40,000 contending with Parkinson’s disease. The focal point of their inquiry was the interplay between DR4, a genetic factor, and the prevalence and onset of these neurodegenerative conditions. Remarkably, their meticulous analysis revealed a noteworthy outcome: those harboring DR4 exhibited a discernible reduction of about 10% in the risk associated with Alzheimer’s and Parkinson’s diseases.

“That this protective factor for Parkinson’s wound up having the same protective effect with respect to Alzheimer’s floored me,” Mignot said. “The night after we found that out, I couldn’t sleep.”

Venturing deeper into the investigation, the researchers meticulously dissected data derived from the autopsied brains of over 7,000 individuals diagnosed with Alzheimer’s disease. Intriguingly, among carriers of DR4, fewer neurofibrillary tangles were observed. These tangled accumulations, predominantly composed of tau protein, are a hallmark of Alzheimer’s and are closely correlated with disease severity. Notably, DR4 carriers also experienced a delayed onset of symptoms compared to their non-DR4 counterparts.

Interestingly, the implications extended to Parkinson’s disease as well, despite the absence of typical neurofibrillary tangles in that context. Carrying the DR4 variant corresponded with a postponed appearance of symptoms among Parkinson’s patients.

Intriguingly, this study provides a tantalizing suggestion: the pivotal role of tau, a central figure in Alzheimer’s disease, might extend its influence to the perplexing landscape of Parkinson’s. According to Emmanuel Mignot, one of the researchers, while the exact nature of this connection remains elusive, the study opens the door to the intriguing possibility of tau’s involvement in Parkinson’s as well.

 The Cell’s Surface as a Display Window

Within the spectrum of abundant alleles comprising the gene named DRB1, the presence of DR4 stands out. This gene, in turn, finds its place amidst a vast assembly of genes known as the human lymphocyte antigen complex (HLA). This complex plays a pivotal role in enabling the inner constituents of cells to become discernible to the immune system.

While the outer membrane of a cell acts as a protective barrier, segregating its internal components from the external environment, its function transcends mere containment. In fact, it serves as an intricate display window, offering a glimpse into the inner realm by presenting fragments of its internal protein makeup to the vigilant immune system.

Regular presentation of these fragments, scientifically referred to as peptides – independent fragments resulting from the segmentation of proteins – on the outer layer of a cell’s membrane provides a chance for vigilant immune cells to peruse them. Through the scrutiny of these peptides on the cell’s surface, these vigilant immune cells can ascertain whether there are any peculiar occurrences within the cell’s interior. They specifically assess the presence of foreign substances or modified proteins, which could imply an infection or a state of malignancy, respectively.

Making this surveillance possible are distinct proteins with the remarkable ability to grasp and encapsulate these peptides, subsequently exhibiting them on the cell’s surface in an optimal manner for immune identification. These exceptional proteins are the direct outcomes of the HLA genes, orchestrating the immune system’s intricate processes.

Diversity blooms within the expanse of numerous HLA genes, each adorned with an expansive array of alleles. Uniquely, we each inherit a distinctive medley of these alleles. Thanks to the diverse binding preferences of protein products resulting from distinct HLA alleles, the panorama of peptides showcased mirrors the individual variations within immune systems.

When a surface peptide emerges that the immune system perceives as novel, it can trigger a formidable assault against any cell that exhibits this unfamiliar peptide. Yet, occasionally, this perception proves to be a case of mistaken identity, unveiling the enigma of autoimmunity.

Emmanuel Mignot proposes that DR4 takes part in what scientists term “protective autoimmunity.” Essentially, this entails a particular peptide that DR4 adeptly captures and presents, albeit as a chemically altered segment of a normal protein our cells synthesize, specifically tau. The predicament stems from this chemical modification, which sparks disruptions in the system.

Alzheimer’s and Parkinson’s – The tau connection?

With keen interest piqued by the positive influence of DR4 on both tau levels and the associated pathologies within Alzheimer’s and Parkinson’s diseases, the researchers turned their focus towards tau itself. Their approach involved fragmenting the protein into 482 distinct peptides, encompassing the entire tau sequence. These fragments were carefully arranged into separate receptacles alongside the protein product of DR4 (also referred to as DR4) to explore potential strong binding interactions.

Concurrently, the scientists delved into the domain of conceivable chemical modifications that these peptides could undergo following their generation within cells.

A standout revelation emerged as DR4 exhibited an exceptional affinity for a specific peptide, PHF6. This segment of the tau protein undergoes frequent alterations after its synthesis through a process known as acetylation. This involves adding a minute chemical group to one of the building blocks of that protein segment. Remarkably, acetylated PHF6 has already been implicated in the tendency of tau molecules to aggregate into the characteristic neurofibrillary tangles.

“The only peptide DR4 bound to strongly was PHF6 — and then only when this peptide was acetylated,” Mignot said. According to his observations, the details that acetylation of PHF6 contributes to the aggregation of tau into neurofibrillary tangles has been established in prior research.

Interestingly, this acetylation process might deceive the immune system into misidentifying PHF6 as a foreign intruder, provoking the immune response to target and dismantle burgeoning neurofibrillary tangles.

Emmanuel Mignot envisions the potential to enhance DR4’s efficacy in carriers by devising a vaccine centered on acetylated PHF6. This novel approach could redirect the immune system’s focus to the modified peptide, potentially disrupting the aggregation of tau. For individuals possessing any of the protective DR4 variants (notably, not all DR4 variants are protective) and who have already initiated the accumulation of tau aggregates in their brains, such a vaccine could hypothetically delay the onset or decelerate the advancement of Alzheimer’s and conceivably Parkinson’s, Mignot proposed.

Mignot highlighted that the potential efficacy of this vaccine wouldn’t extend to individuals devoid of DR4. Moreover, DR4 encompasses an array of subtypes, outlined by subtle variations in their genetic makeup. Among the six or seven prevailing DR4 subtypes, certain variants might prevail in specific ancestral groups, whereas other subtypes could dominate in different populations. Notably, the DR4 subtype most prevalent in East Asians appears to offer comparatively lesser assistance in deterring neurodegenerative diseases compared to the DR4 subtypes more prevalent in other ethnicities.

Mignot emphasizes the necessity of administering a blood test to determine the suitability of individuals for vaccination.

The findings of this study have prompted Stanford University’s technology licensing office to submit a patent application to safeguard the associated intellectual property.

A collaborative effort involving approximately 160 researchers from nearly 25 different institutions across the globe significantly contributed to this research endeavor.

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