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Researchers at Stanford University Discover Gene Variant That Appears to Protect Individuals from Both Alzheimer’s and Parkinson’s Disease

Study findings may lead to new clinical laboratory tests, as well as vaccines and immunotherapies for neurodegenerative diseases

Research into the human genome continues to produce useful new insights. This time, a study led by researchers at Stanford University identified a genetic variation that is believed to help “slow or even stall” progression of neurodegenerative diseases, including Alzheimer’s and Parkinson’s, according to a press release. Because these genetic variations are common, it is likely that diagnostic tests can be developed for use by clinical laboratories.

Researchers at Stanford Medicine led the study which discovered that approximately one in five individuals carry the gene variant, a protective allele identified as DR4 (aka, HLA-DR4). It’s one of a large number of alleles found in a gene known as DRB1.

DRB1 is part of a family of genes collectively known as the human lymphocyte antigen complex or HLA. The HLA-DRB1 gene plays a crucial role in the ability of the immune system to see a cell’s inner contents.

The Stanford scientists published their findings in the journal PNAS titled, “Multiancestry Analysis of the HLA Locus in Alzheimer’s and Parkinson’s Diseases Uncovers a Shared Adaptive Immune Response Mediated by HLA-DRB1*04 Subtypes.” Approximately 160 researchers from roughly 25 countries contributed to the work. 

Emmanuel Mignot, MD, PhD

“In an earlier study, we’d found that carrying the DR4 allele seemed to protect against Parkinson’s disease,” said Emmanuel Mignot, MD, PhD (above), Director of the Stanford Center for Narcolepsy, in a Stanford press release. “Now, we’ve found a similar impact of DR4 on Alzheimer’s disease.” Clinical laboratories may soon have new vaccines for both neurodegenerative diseases. (Photo copyright: Stanford University.)


DR4 Found to Impact Both Parkinson’s and Alzheimer’s Diseases

To perform their research, the team examined a large collection of medical and genetic databases from 176,000 people who had either Alzheimer’s or Parkinson’s disease. The people involved in the study were from numerous countries located in East Asia, Europe, the Middle East and South America. Their genomes were then compared with people who did not have the diseases, focusing on the incidence and age of onset.

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

The team found that about 20% to 30% of people carry DR4, and that they have around a 10% risk reduction for developing the two diseases. 

“That this protective factor for Parkinson’s wound up having the same protective effect with respect to Alzheimer’s floored me,” said Emmanuel Mignot, MD, PhD, the Craig Reynolds Professor of Sleep Medicine in the Department of Psychiatry and Behavioral Sciences at Stanford University and the Director of the Stanford Center for Narcolepsy, in the Stanford Medicine press release. “The night after we found that out, I couldn’t sleep.”

The scientists also analyzed data from autopsied brains of more than 7,000 Alzheimer’s patients and discovered that individuals who carry DR4 had fewer neurofibrillary tangles and that those tangles are composed mainly of modified tau proteins, a common biomarker for Alzheimer’s.

The presence of these tangles corresponds with the severity of Alzheimer’s disease. They are not typically seen in Parkinson’s patients, but the Stanford team found that Parkinson’s patients who did carry DR4 experienced later onset of symptoms.

Mignot stated that tau, which is essential in Alzheimer’s, may also play a role in Parkinson’s, but that further research is required to prove its function.

Both diseases are characterized by the progressive loss of certain nerve cells or neurons in the brain and are linked to an accumulation of abnormal proteins. The Stanford researchers suggested that the DR4 gene variant may help protect individuals from Alzheimer’s and Parkinson’s by preventing the buildup of tau proteins.

“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,” neurologist Wassim Elyaman, PhD, Assistant Professor of Neurological Sciences in Neurology, the Taub Institute and the Institute for Genomic Medicine at Columbia University, told Live Science.

New Vaccines and Immunotherapies

According to the Alzheimer’s Association, more than six million Americans are currently living with Alzheimer’s disease and approximately one in three Americans die with Alzheimer’s or another dementia. 

The Parkinson’s Foundation states that nearly one million Americans are currently living with Parkinson’s disease, and that number is expected to rise to 1.2 million by 2030. Parkinson’s is the second-most common neurodegenerative disease after Alzheimer’s disease.

Even though the genetic analysis of the Stanford research is strong, more immune cell and blood-based research is needed to definitively establish how tau is connected to the two diseases.

This research could have implications for clinical laboratories by giving them biomarkers for a useful new diagnostic test, particularly for diagnosing Alzheimer’s and Parkinson’s.

Further, Mignot suggested that an effective vaccine could delay the onset or slow the progression of both diseases. He hopes to test his hypothesis on genetically modified mice and eventually human subjects.

—JP Schlingman

Related Information:

Stanford Medicine-led Study Finds Genetic Factor Fends Off Alzheimer’s and Parkinson’s

Gene Variant Carried by One in Five People May Guard Against Alzheimer’s and Parkinson’s, Massive Study Finds

Multiancestry Analysis of the HLA Locus in Alzheimer’s and Parkinson’s Diseases Uncovers a Shared Adaptive Immune Response Mediated by HLA-DRB1*04 Subtypes

Alzheimer’s Disease: Tau Biology and Pathology

Tau Protein and Alzheimer’s Disease: What’s the Connection?

C₂N Diagnostics Releases PrecivityAD, the First Clinical Laboratory Blood Test for Alzheimer’s Disease

Danish Study Finds Anti-Viral Paxlovid May Be Triggering Drug-to-Drug Interactions, Particularly in Elderly COVID-19 Patients

These findings may be useful to clinical laboratory professionals when physicians want guidance in effective treatments for COVID-19 patients, particularly when there are concerns about a rebound of the infection

Drug interactions are a major concern for physicians and clinical laboratories. That is especially true given the push for nearly universal COVID-19 vaccinations and boosters. Now, a study conducted in Denmark may show that the use of Paxlovid as an antiviral drug to treat early SARS-CoV-2 infection could trigger drug-drug interactions (DDI) in some patients.

For clinical laboratory managers, insights into the issues associated with Paxlovid may be useful in helping client physicians diagnose their patients and anticipate possible negative drug reactions where other anti-viral drugs are involved.

Also of interest to medical laboratory leaders is the fact that the federal Centers for Disease Control and Prevention (CDC) in May released a Health Alert Network (HAN) Health Advisory about the potential for COVID-19 rebound after Paxlovid treatment.

COVID-19 Rebound, according to the CDC, “has been reported to occur between two and eight days after initial recovery and is characterized by a recurrence of COVID-19 symptoms or a new positive viral test after having tested negative.”

The Danish researchers published their findings in the International Journal of Infectious Diseases, titled, “Assessing the Proportion of the Danish Population at Risk of Clinically Significant Drug-Drug Interactions with New Oral Antivirals for Early Treatment of COVID-19.”

Joan Susan Bregstein, MD

In an article she penned for STAT, Joan Susan Bregstein, MD (above), a pediatric emergency medicine physician and professor of pediatrics at Columbia University Irving Medical Center in New York, wrote, “Is Paxlovid worth it? The CDC advisory states in black, bold, and no uncertain terms that, despite the risk of rebound COVID, ‘Paxlovid continues to be recommended for early-stage treatment of mild to moderate COVID-19 among persons at high risk for progression to severe disease.’ But the definition of ‘high risk’ in this situation has been a moving target since the first days of COVID-19.” Clinical laboratory leaders can attest to the accuracy of that statement. (Photo copyright: Columbia University.)

Do Anti-Viral Drugs Interact with Other Medications?

Paxlovid is the retail name for a combination of two anti-viral drugs: nirmatrelvir and ritonavir. The medication for COVID-19 was developed by American pharmaceutical company Pfizer (NYSE:PFE) and received Emergency Use Authorization from the US Food and Drug Administration in August of this year.  

The drug is taken orally for five days by people who test positive for the SARS-CoV-2 coronavirus to head off disease progression as well as serious illness, according to the CDC advisory.

But a “sizeable proportion” of elderly people are on medications that could interact with Paxlovid, Reuters reported.

“Two oral antiviral drugs—nirmatrelvir/ritonavir (NMV/r) and molnupiravir—have been approved for early outpatient treatment of COVID-19 to prevent severe disease. Ritonavir, contained in NMV/r is known to have significant DDI with several drugs frequently used by the elderly. This communication puts the problem with DDI with oral antiviral COVID-19 treatment into perspective,” the study authors wrote.

Their analysis of prescription data from Denmark residents found “extensive use of drugs likely to interact with NMV/r” as follows:

  • Anticoagulants (blood thinners): used by 20% of people over age 65 and by 30% of people over 80.
  • Statins (cholesterol-lowering medications): taken by 15% to 18% of people over 65.
  • Analgesics (for pain), calcium channel blockers (used to decrease blood pressure in patients with hypertension), or digoxin (used to treat heart conditions): taken by 20% of those studied.

In their paper, the researchers offered guidance to physicians. “Before prescribing NMV/r, the patient’s full medical history, including herbals and over-the-counter and recreational drugs, must be known and co-treatment carefully managed by the treating physician or by a specialist to avoid detrimental effects.” 

However, one infectious disease specialist told Scientific American it may just take the elderly who were taking Paxlovid more time to completely get over COVID-19.

“Being of an elderly age and then having other risk factors—like diabetes, heart disease, kidney disease, or some sort of cancer—does put you at higher risk of rebound,” Aditya Shah, MBBS, Mayo Clinic Infectious Disease Physician and Researcher, told Scientific American.

Rebounding after Molnupiravir, Too

COVID-19 rebound is not exclusive to people who took Paxlovid, according to a paper published on medRxiv, titled, “Rebound after Paxlovid and Molnupiravir during January-June 2022.”

That study’s researchers retrospectively reviewed 92 million electronic health records (EHR) from US patients. They found most people (11,270) had been treated with Paxlovid. However, 2,374 patients took molnupiravir, which also was granted EUA status by the FDA and is marketed as Lagevrio.

That COVID-19-rebound study found:

  • After nirmatrelvir/ritonavir (Paxlovid) treatment: 3.53% had rebound infections, 2.3% with rebound symptoms, and .44% were hospitalized.
  • After molnupiravir (Lagevrio) treatment: 5.86% had rebound infections, 3.75% with rebound symptoms, and .84% were hospitalized.

“Patients who took molnupiravir were significantly older and had more comorbidities than those who took Paxlovid,” the researchers wrote. “Results further suggest that rebound was not unique to Paxlovid and may be associated with persistent viral infection in some patients treated with either of these two antivirals. There has been more attention to COVID-19 rebound following Paxlovid treatment than molnupiravir, which may be attributable to more people being treated with Paxlovid,” they concluded.

Clinical Laboratories Can Guide Doctors

In an article she penned for STAT, titled, “Paxlovid Rebound Happens, Though Why and to Whom Are Still a Mystery,” Joan Susan Bregstein, MD, a pediatric emergency medicine physician and professor of pediatrics at Columbia University Irving Medical Center in New York, wrote of COVID-19 rebound, “My emergency medicine physician colleagues are seeing tons of it. Although people tend to think of medical care as something that is certain, it is actually a real-time experiment. Paxlovid, like a lot of COVID-19 care, is a reminder of this.”

Similarly, Mayo Clinic’s Shah acknowledged difficulty in identifying a COVID-19 rebound case. “You need real documentation of three tests—a positive, a negative, a positive—and clear documentation of symptoms—all symptoms gone, symptoms come back,” Shah told Scientific American.

Thus, clinical laboratories play a vital role in diagnosing and treating COVID-19 rebound patients, because that is what clinical labs do: test, document, and report. And as the study of the Danish population pointed out, doctors need guidance as they prescribe oral antivirals to COVID-19 patients who are on other drugs and at possible risk of drug-drug interactions. 

Donna Marie Pocius

Related Information:

Assessing the Proportion of the Danish Population at Risk of Clinically Significant Drug-Drug Interactions with New Oral Antivirals for Early Treatment of COVID-19

CDC Health Advisory: COVID-19 Rebound after Paxlovid Treatment

Wastewater Study Technique Finds Virus Variants Sooner; Many Patients Are Using Meds Affected by Paxlovid

What Is Paxlovid Rebound and How Common Is It?

COVID-19 Rebound after Paxlovid and Molnupiravir during January-June 2022

Paxlovid Rebound Happens, Though Why and To Whom are Still a Mystery

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