Nikhil Prasad Fact checked by:Thailand Medical News Team Aug 05, 2026 45 minutes ago
Long COVID continues to affect millions of people worldwide, but one of the biggest mysteries has been why some individuals experience severe brain fog, fatigue, and worsening symptoms after even mild activity while others recover more successfully. A new study has now identified inherited Haptoglobin types as a potential biological factor that may help explain these striking differences.
Researchers found that inherited Haptoglobin phenotypes are associated with differences in post-exertional cognitive
function, brain oxygen utilization, and metabolic responses in people with Long COVID
Researchers from the Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal; the Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine; the Open Medicine Foundation ME/CFS Collaborative Center at CHU Sainte-Justine/Université de Montréal; the ICanCME Research Network; PO-Laboratories in Montreal; the Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biochemistry Institute, University of Melbourne; and the Faculty of Dentistry, Université de Montréal, have discovered that different inherited Haptoglobin phenotypes are associated with major differences in cognitive performance, brain oxygen use, symptom severity, and metabolic responses following physical stress in people with Long COVID.
Why Haptoglobin Matters
Haptoglobin is a protein found in the blood that helps bind and remove free hemoglobin released from damaged red blood cells. It also plays an important role in controlling oxidative stress and protecting blood vessels.
People naturally inherit one of three common Haptoglobin phenotypes—Hp1-1, Hp2-1, or Hp2-2—and these forms differ in how effectively they perform these protective functions.
Previous research from the same group had shown that Haptoglobin phenotypes influenced symptom severity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Because Long COVID shares many features with ME/CFS, including post-exertional malaise and cognitive dysfunction, the researchers wanted to determine whether Haptoglobin phenotypes also influenced Long COVID.
Hp2 Carriers Experienced More Severe Long COVID
The study followed 44 individuals with Long COVID and compared them with 20 people who recovered quickly from COVID-19 without lingering symptoms.
Participants underwent Haptoglobin phenotyping, cognitive testing, measurements of cerebral oxygen utilization, and plasma metabolomic analysis before and after a standardized 90-minute passive post-exertional challenge.
Patients carrying the Hp2 allele, particularly those with the Hp2-2 phenotype, consistently had more severe disease. Compared to individuals with Hp1-1, they reported greater physical fatigue, poorer physical functioning, reduced activity, and more severe post-exertional malaise. Importantly, these associations remained significant even after adjusting for age, sex, body mass index, and duration of illness, indicating that Haptoglobin phenotype independently contributed to differences in disease severity.
trong>Cognitive Function Declined After Exertion
One of the study's most important findings involved objective cognitive testing.
At baseline, there were no significant differences in cognitive performance among the different Haptoglobin groups. However, immediately after the post-exertional challenge, participants with the Hp2-2 phenotype showed a significant reduction in their overall BrainCheck cognitive scores, indicating acute post-exertional cognitive dysfunction. In contrast, participants with Hp1-1 did not experience this decline.
Long-term follow-up further strengthened these findings. Individuals with Hp1-1 demonstrated more favorable cognitive trajectories over repeated study visits, including improvements in overall cognitive scores and delayed memory recognition. By comparison, Hp2 carriers accounted for 90 percent of participants whose cognitive performance deteriorated during follow-up, suggesting that the Hp2 phenotype is associated with greater long-term cognitive vulnerability.
Study highlights Brain Oxygen Differences
This Medical News report also highlights an important physiological discovery that may help explain these cognitive differences.
Using near-infrared spectroscopy, researchers measured cerebral fractional tissue oxygen extraction, which reflects how efficiently brain tissue extracts oxygen from circulating blood. Following the post-exertional challenge, individuals with the Hp1-1 phenotype maintained significantly higher oxygen extraction in the right cerebral hemisphere than Hp2-1 and Hp2-2 carriers. Total cerebral hemoglobin remained stable across all groups, indicating that the differences reflected altered oxygen utilization rather than changes in blood volume.
The researchers suggest that reduced cerebral oxygen extraction may represent a physiological signature accompanying post-exertional cognitive dysfunction in Long COVID, although they emphasized that the study was not designed to establish a direct cause-and-effect relationship.
Distinct Metabolic Changes Were Identified
Blood metabolomic analysis revealed further biological differences between the Haptoglobin phenotypes.
After the exertion challenge, Hp2 carriers had significantly lower plasma concentrations of citric acid, isethionate, and glucosamine than individuals with the Hp1-1 phenotype. Citric acid and isethionate remained statistically significant even after correction for multiple testing, making them the strongest metabolic candidates identified in the study.
Higher concentrations of these metabolites were associated with better cognitive performance after exertion. Individuals with higher citric acid levels achieved better overall BrainCheck scores, while higher isethionate and glucosamine levels were also linked with improved cognitive performance. The researchers noted that these metabolic signatures likely reflect differences in how patients respond biologically to physiological stress rather than proving that the metabolites themselves directly cause cognitive impairment.
The investigators also found that circulating Haptoglobin levels increased after the exertion challenge only in Long COVID participants, suggesting a disease-specific stress response, while the inherited structural organization of the Haptoglobin protein itself remained unchanged.
Conclusions
The findings demonstrate that inherited Haptoglobin phenotypes are associated with biologically distinct forms of Long COVID. Individuals carrying Hp2 phenotypes, especially Hp2-2, were more likely to experience severe fatigue, greater post-exertional symptom worsening, objective cognitive decline after exertion, reduced cerebral oxygen extraction, and less favorable metabolic responses. While the study does not establish that Haptoglobin causes these abnormalities, it identifies Haptoglobin phenotyping as a promising biomarker that could help biologically stratify Long COVID patients and guide future precision medicine research. Larger independent studies will be needed to validate these findings before they can be translated into routine clinical practice.
The study findings were published in the peer reviewed International Journal of Molecular Sciences.
https://www.mdpi.com/1422-0067/27/15/7000
Read Also:
https://www.thailandmedical.news/articles/long-covid
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