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Scientists spot gene that may explain why more women get Alzheimer’s

Scientists spot gene that may explain why more women get Alzheimer’s

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Women are disproportionately affected by Alzheimer’s disease. Leonardo Laschera/EyeEm/Getty Images
  • Alzheimer’s disease (AD) affects nearly twice as many women as men.
  • About 60{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of people with AD don’t express apolipoprotein E (APOE ε4), its most established genetic risk factor.
  • New research has shown the MGMT gene may be associated with a higher risk of AD in two different populations, particularly in women without APOE ε4.
  • The study found that the expression of MGMT contributes to the development of toxic proteins associated with Alzheimer’s, especially in women.

AD is the most common form of dementia, a gradual condition that causes the brain to shrink and the cells to die. The condition affects a person’s ability to remember, think, and carry out simple tasks.

According to the Centers for Disease Control and Prevention (CDC), over 5.8 million people in the U.S. are living with AD and dementia, which is predicted to rise to nearly 14 million by 2060.

AD is caused by the toxic buildup of amyloid proteins around the brain cells and tau proteins inside the brain cells.

Genetic studies have linked AD risk to the gene APOE ε4, however, 60{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of people with AD do not carry the gene, suggesting that other genes may be involved in the condition.

A recent study suggests that a new gene could be linked to a higher risk of developing Alzheimer’s, particularly in women.

The study is published in Alzheimer’s Disease & Dementia: The Journal of the Alzheimer’s Association.

According to the Alzheimers Association, women are nearly twice as likely to be affected by AD than men. This is thought to be due to them living longer.

“[..] women over 60 are twice as likely to develop Alzheimer’s disease, […] than they are to develop breast cancer during the rest of their lifetime,” explained Dr. Rosa Sancho, the head of research at Alzheimer’s Research, who was no involved in the study.

Researchers trying to understand these differences have shown changes in the tau gene (MAPT) region in women with breast cancer, people with AD without APOE ɛ4, and women with ovarian cancer.

In a new study using genome-wide sequencing (GWAS), researchers from the Boston University School of Medicine, University of Chicago, and the University of Pennsylvania, among others, found a gene called MGMT which may increase the risk of AD in women.

To understand if other genes involved in tau-related diseases are related to AD risk in women, the researchers performed GWAS on two different populations:

  • 31 members of the Hutterites, a group of people with common ancestry, recognized for their relatively small gene pool, 22 of whom were women.
  • 10,340 women without APOE ɛ4, who were part of the Alzheimers Disease Genetics Consortium (ADGC). These included 3,399 AD cases and 6,905 controls.

Researchers found that in both populations, the MGMT gene was associated with AD risk in women lacking APOE ɛ4.

“[..] The fact that studies with such different designs identified (different) genetic variants that were linked to the same gene was unexpected,” said Dr. Carole Ober, chair of human genetics at the University of Chicagoand joint study lead.

“The different lines of evidence supporting a role for MGMT in Alzheimer’s disease risk increased our confidence,” she said.

The work suggests that the expression of MGMT contributes to the development of toxic amyloid and tau proteins associated with the development of AD.

To understand the mechanisms behind the link, the researchers analyzed the brain tissue of 177 participants of the Framingham Heart Study, 58 with confirmed AD.

Speaking to Medical News Today about the mechanisms behind the findings, Dr. Ober explained:

“Our data suggest that the associated genetic variants affect levels of DNA methylation and/or other epigenetic marks, like open chromatin, and these epigenetic changes impact the expression of MGMT at key developmental stages […] is our current working hypothesis.”

“This research also highlights just how complex Alzheimer’s is, with the MGMT gene involved in a number of cellular processes that could contribute to the development of disease.”
— Dr. Rosa Sancho

According to Ober, the study’s take-home message is “[…] an Alzheimer’s disease gene may impart its risk effects only in females and that epigenetic remodeling in neurons may be an important mediator of this risk.”

The next steps, he says, “are to first directly show that the genetic variants are involved in this epigenetic remodeling and then study the downstream effects of the remodeling in cell models of neuron development.”

“It’s going to take a concerted and global effort to develop life changing treatments, but genetic discoveries like this are a step in the right direction,” noted Dr. Sancho when asked about the significance of the study.

“The more we understand about risk genes and how they affect the development of Alzheimer’s, the closer we can get to new treatment approaches for the disease.”
— Dr. Rosa Sancho

Dr. Jennifer Bramen, senior research scientist at Providence Saint John’s Health Center, who was also not involved in the study, echoed these thoughts.

“Future research may find that the MGMT variants identified by this work […] may potentially lead to the identification of new drug targets or biomarkers—all important in treating and researching Alzheimer’s disease,” she said.

Dr. Bramen went on to say that “Lifestyle factors like walking, regular aerobic exercise, eating a healthy diet filled with fresh produce […] will do a lot to prolong cognition. As at-risk women grow older and lose the brain protection provided by estrogen, it is even more important that they take care of their health.”

“The brain is not separate from the body. Physical health is brain health, and therefore highly impacts cognitive abilities,” she added.

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‘Viral reservoir’ of spike protein may explain long-term symptoms

‘Viral reservoir’ of spike protein may explain long-term symptoms

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Scientists may have identified a potential biomarker for long COVID. Hollie Adams/Bloomberg via Getty Images
  • Researchers investigated the antigens of SARS-CoV-2—the virus that causes COVID-19—present in blood plasma samples collected from individuals with long COVID and typical COVID-19 infection.
  • They found that one particular SARS-CoV-2 antigen—the spike protein—was present in the blood of a majority of long COVID patients, up to a year after they were first diagnosed with COVID-19.
  • In patients with typical COVID-19 infection, however, the spike protein was not detected.
  • This finding provides evidence for the hypothesis that SARS-CoV-2 can persist in the body through viral reservoirs, where it continues to release spike protein and trigger inflammation.

Current data from the World Health Organization (WHO) indicates that around 1 in 4 individuals with COVID-19 continue to experience symptoms 4–5 weeks after diagnosis, and approximately 1 in 10 have continuing symptoms after 12 weeks.

Individuals with post-acute sequelae of COVID-19 (PASC), or long COVID, have reported a range of symptoms, including, but not limited to, fatigue, anosmia (loss of the sense of smell), memory loss, gastrointestinal distress, and shortness of breath.

The underlying mechanism of long COVID is complicated. Identifying a blood biomarker for long COVID, or in other words, a biological molecule that appears in the blood of most long COVID patients, could contribute to a better understanding of the biology of long COVID.

A new study finds evidence of a biomarker that could point toward an active viral reservoir in the body, particularly in the gut after initial SARS-CoV-2 infection.

A preprint of the study was published on medRxiv.

To identify a blood biomarker for long COVID, researchers at Harvard Medical School and the Ragon Institute of MGH, MIT and Harvard, analyzed blood plasma samples collected from patients with long COVID and typical COVID-19 infection over a period of 12 months.

They sought to determine the levels of three SARS-CoV-2 antigens:

  • Spike protein – spike-like molecules that protrude from the surface of the SARS-CoV-2 virus
  • S1 subunit of spike protein – one of two subunits that make up the spike protein
  • Nucleocapsid – nucleic acid (genetic material) and surrounding capsid (protein coat) of the virus

The researchers found that the spike protein, S1 subunit, or nucleocapsid were present in the blood of 65{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of the long COVID patients they tested, up to 12 months after their initial COVID-19 infection.

Out of the three SARS-CoV-2 antigens, the spike protein was the most common, having been detected in 60{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809}—or 3 out of 5—of long COVID patients.

In contrast, the researchers did not detect spike protein in any of the patients with typical COVID-19 infection. The S1 subunit and nucleocapsid were detected in the blood of COVID-19 patients immediately after the COVID-19 diagnosis, but the levels of these antigens quickly dropped below the limit of detection.

“The most logical interpretation [of the data presented in the pre-print] is that spike protein in serum is a surrogate marker for a persistent infection somewhere in the body,” Dr. John P. Moore, professor of microbiology and immunology at Weill Cornell Medicine, who was not involved in the study, told Medical News Today.

The researchers believe that the presence of SARS-CoV-2 spike protein in a majority of long COVID patients up to 12 months post-diagnosis suggests the presence of an active persistent SARS-CoV-2 viral reservoir.

Dr. David R. Walt, one of the study’s authors, told The Guardian that the presence of the spike protein indicated such a reservoir as the half-life of this antigen is “pretty short” in the body.

Dr. Andrew Pekosz, professor of molecular microbiology and immunology at the Johns Hopkins University Bloomberg School of Public Health, who was not involved in the study, told MNT that the existence of reservoirs of SARS-CoV-2 in organs such as the gut could potentially explain the symptoms of long COVID.

“The presence of virus-infected cells at low levels […] would be the “trigger” for continued activation of the immune system. Finding these viral proteins in the blood could also explain why multiple organs can be affected by long COVID. This kind of persistent infection is seen with some viruses but has not been clearly demonstrated with SARS-CoV-2.”
– Dr. Andrew Pekosz

Other researchers have also found evidence of viral persistence (the continuing presence of the virus) in patients with long COVID symptoms.

Dr. Akiko Iwasaki, sterling professor of immunobiology and molecular, cellular and developmental biology at Yale University, who was not involved in the study, told MNT:

“Evidence for persistent virus and viral antigen/RNA reservoirs [is] becoming more and more prevalent […] The presence of the spike protein in circulation in long haulers is adding to this emerging evidence.”

Studies have pointed to the gut as a possible reservoir.

At Stanford University in California, Dr. Ami S. Bhatt and colleagues found that about 4{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of individuals (or 1 out of 25) with mild to moderate COVID-19 continued shedding viral RNA in their stools seven months after COVID-19 diagnosis.

Individuals with detectable viral RNA in their stools also reported ongoing gastrointestinal symptoms such as abdominal pain, nausea and vomiting.

Besides providing compelling evidence for the viral reservoir hypothesis of long COVID, the presence of spike protein in the majority of long COVID patients suggests that spike protein could potentially be used as a biomarker for long COVID. Enabling clinicians to diagnose long COVID through a blood plasma test is a step toward more effective treatment.

However, before coming to solid conclusions, researchers will need to conduct further studies to confirm.

One question to answer is why 35-40{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of the long COVID patients did not have measurable spike protein in their blood.

“Does this mean that their symptoms arise from something other than long COVID or does it mean that long COVID results from a multiplicity of causes? From our studies, we can’t answer that question,” Walt told MNT.

Dr. Pekosz described the study as “intriguing” but cautioned that more investigation is required to truly understand its implication.

“The big questions are really, is this enough [spike] protein to be triggering [long COVID] symptoms? Would treatments like antivirals or booster vaccinations eliminate these sources of viral protein and hence relieve [long COVID] symptoms? Where are these infected cells located and how do the virus proteins get into the blood?” he said.

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Abnormal immune system activity may explain long COVID

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A new study suggests SARS-CoV-2 infections may cause long-term disturbances to the immune system, resulting in long COVID. Image credit: Jenny Evans/Getty Images
  • Researchers worldwide are continually updating the scientific knowledge around SARS-CoV-2, the virus that causes COVID-19.
  • In the most recent update, scientists in Australia report that atypical immune activity persists in people with long COVID 8 months after infection with SARS-CoV-2.
  • Their research shows that long COVID features increased levels of specific immune biomarkers in the body.
  • Their findings provide a crucial foundation to enhance our understanding of long COVID, an emerging chronic condition.

Scientists have spent the last few years trying to understand the novel coronavirus, SARS-CoV-2, which is responsible for the COVID-19 pandemic.

As new variants of the SARS-CoV-2 virus emerge, scientists continue to study their effects to find ways of keeping the global population safe.

In line with ongoing scientific efforts, a new study has reported that individuals with long COVID experience dysfunctional immune activity 8 months after the initial COVID-19 illness.

Long COVID, also known as post-acute COVID-19, is a term to describe the effects of COVID-19 that linger for weeks or months beyond the initial illness. The symptoms often involve respiratory and physical distress and, more recently, cardiovascular distress.

The study, led by scientists at The Kirby Institute, University of New South Wales, Australia, appears in the journal Nature Immunology.

“Our observations provide an important foundation for understanding the pathophysiology of this syndrome and [may suggest] potential therapeutic avenues for intervention,” the study authors write.

“Our study indicates an ongoing, sustained inflammatory response following even mild-to-moderate acute COVID-19, which is not found following prevalent common cold coronavirus infection,” Dr. Chansavath Phetsouphanh, a senior research associate and co-lead author of the study, told Medical News Today.

However, he added that “more research from bigger cohorts is required to validate [their] findings.”

The researchers followed 147 individuals for 8 months following a diagnosis of COVID-19.

They were interested in studying the pathophysiological, immunological, and clinical outcomes following infection with SARS-CoV-2.

In the study, the team defined long COVID as the occurrence of one of three major symptoms of fatigue, chest pain, or shortness of breath in the fourth month of infection. A total of 31 out of 147 individuals fitted the description.

The scientists then matched the individuals using gender and age, with 31 asymptomatic controls from the same cohort who did not report symptoms in the fourth month but were symptomatic during the acute phase of COVID-19.

The researchers also recruited a fresh population of individuals who tested negative for SARS-CoV-2 alongside individuals who had contracted other human coronaviruses but not SARS-CoV-2. This group served as the control.

Finally, the experimenters collected blood samples from each group to examine the biomarkers associated with long COVID. In medicine, a biomarker refers to “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”

At first glance, the scientists noted that the long COVID and control groups had significantly higher levels of six immune biomarkers compared with the control group.

However, from the fourth month, they noticed a drop in the elevated biomarker levels in the control group while the long COVID group still maintained high levels of biomarkers.

Specifically, the team noticed that two types of biomarkers — known as interferons — were elevated in the long COVID group 8 months after infection with SARS-CoV-2. Scientists describe interferons as a type of protein that body cells make in response to the presence of viruses.

As well as elevated levels of interferons, Dr. Phetsouphanh and his team discovered that the long COVID group had highly activated immune cells but lacked naive T and B cells. These cells are responsible for helping the immune system respond to novel pathogens that it has not yet encountered.

Taking these findings into consideration, the scientists concluded that:

“SARS-CoV-2 infection exerts unique prolonged residual effects on the innate and adaptive immune systems and that this may be driving the symptomology known as [long COVID],” the study authors write.

Dr. Deepti Gurdasani, a senior lecturer at the Queen Mary University of London, who was not involved in the research, responded to the study on Twitter, saying that its results “in practical terms [are] unclear — but concerning nevertheless.”

“Understanding [the meaning of the] immune dysregulation that was clearly present at least at 8 months, and possibly longer will take time,” she wrote, pointing out that “long COVID clearly shows a different immunological profile compared to people who don’t have persistent symptoms.”

She added:

“Whether this is because of [the] persistence of [the] virus, virus antigen, or auto-immunity post-infection isn’t known yet. It could be one of these or even a combination — but all possibilities should concern us.”

The study authors report several limitations in their research.

First, because of the timing of ethics approvals and cohort setup, the scientists could not collect samples during the period of acute infection. As a result, they were unable to determine whether elevations in biomarker levels during the recovery period correlated with the levels observed in acute infection.

Additionally, the definition of long COVID in the study was set internally by the researchers, given the lack of international consensus on its definition.

Nevertheless, the scientists note that the inclusion of the most common persisting symptoms of long COVID alongside rigorous research practices helped ensure the validity of their findings.

Needless to say, the research is still largely exploratory, and more studies are necessary to confirm the findings. However, the study results could one day potentially inspire better treatments for people living with long COVID.

For live updates on the latest developments regarding COVID-19, click here.

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Can fitness genes explain differences in workout results?

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New research looks into the role of genes and their variants in workout outcomes. RunPhoto/Getty Images
  • Researchers from Cambridge University published a meta-analysis in PLOS ONE identifying 13 candidate genes associated with fitness outcomes in previously untrained people.
  • Genetic influences accounted for 72{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of the difference in the results of those in the strength training group.
  • Genetic factors had less effect on the outcomes in the aerobic (44{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809}) and anaerobic power groups (10{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809}).
  • Further research is necessary to determine the exact roles of fitness genes and how best to tailor exercise training according to genetic makeup.

Physical activity is essential for maintaining health, reducing chronic diseases, and preventing premature death. The 2018 physical activity guidelines for Americans recommend a combination of moderate intensity and vigorous intensity aerobic exercise alongside muscle-strengthening activities involving the major muscle groups.

The advice is for adults to do 150–300 minutes of moderate intensity aerobic activity, 75–150 minutes of vigorous intensity aerobic activity, or an equivalent mix. They can spread this activity throughout the week and should also engage in strength training on at least 2 days of the week to reap additional health benefits.

The three components necessary to determine health-related fitness are cardiovascular fitness, muscle strength, and anaerobic power. Cardiovascular or cardiorespiratory fitness measures how efficiently the respiratory and circulatory systems supply oxygen to the skeletal muscle for energy production during physical activity.

The maximum oxygen uptake (VO2 max) test is one way to determine cardiorespiratory fitness. The VO2 max test measures the body’s maximum oxygen consumption capacity during a vigorous intensity activity, such as running on a treadmill.

A higher VO2 max indicates an improved ability to supply and utilize oxygen and maintain aerobic activities at an increased intensity for extended periods. Low cardiorespiratory fitness is a predictor of cardiovascular disease and death from all causes in adults.

Muscular strength is the body’s capability to exert a sufficient force against external resistance to perform tasks and maintain mobility.

An anaerobic activity is one that involves the breakdown of glucose for energy without using oxygen. Anaerobic power measures the body’s ability to move with the greatest intensity in a short period.

Increasing cardiorespiratory fitness, muscular strength, and anaerobic power may improve a person’s overall fitness level, but responsiveness to exercise training varies considerably among individuals.

In a session at the 22nd Annual Congress of the European College of Sports Science, Dr. Bernd Wolfarth, professor in the Department of Sports Medicine at Humboldt University, Berlin, explains, “Environment is a major factor [for trainability], and nowadays, we know that about 25–40{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of the variability of phenotype results from genes, and the other 60–75{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} is coming [from] environmental effects.”

Specific genes called candidate genes may predict successful responses to targeted types of exercise training. These genes may influence energy pathways, metabolism, storage, and cell growth in the body.

These findings led researchers from the Cambridge Centre for Sport and Exercise Sciences at Anglia Ruskin University, UK, to conduct a meta-analysis to identify the specific version, or alleles, of candidate genes related to the exercise response in untrained participants. The team analyzed strength, anaerobic power, and cardiopulmonary fitness.

Individuals inherit one allele of each gene from each parent. The individual is homozygous for the gene if both alleles are the same and heterozygous if the two alleles are different.

The study also assessed whether the identified genes and alleles contributed to differences in exercise training response among the participants. The researchers analyzed the results from 24 different studies with a total of 3,012 participants. Of the cohort, 1,512 participants were male, and 1,239 were female. The sex of the remaining 261 participants was not stated.

The mean age of the participants was 28 years. There were 89 groups: 43 aerobic, 29 strength, and 17 power. The researchers identified 13 candidate genes and alleles, of which nine, six, and four were associated with cardiorespiratory fitness, muscular strength, and anaerobic power, respectively.

On average, the participants in the cardiorespiratory fitness studies received aerobic training for 36 minutes on 3 days of the week for a total of 12 weeks. The specified intensity was 77{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of maximum heart rate or 74{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of VO2 max. The researchers attributed 44{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of the difference in aerobic training response to genetic influences.

Strength training, on average, involved 174 repetitions per session at an intensity of 75{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of one-repetition maximum. Sessions took place 3 days per week for a total of 10 weeks. Genes accounted for 72{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of the observed differences in the strength training group.

The participants in the anaerobic power group performed, on average, 4–12 cycle bouts of a specified intensity — 90–110{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} VO2 max or a load of 0.075 per kg body weight — 3 days a week for 5 weeks. Genes had less influence in the power group, with only 10{cfdf3f5372635aeb15fd3e2aecc7cb5d7150695e02bd72e0a44f1581164ad809} of the variability in response being due to genetic influences.

Dr. Bert Mandelbaum, who is a sports medicine specialist and orthopedic surgeon at Cedars-Sinai Kerlan-Jobe Institute in Los Angeles and was not involved in the study, told Medical News Today, “Genomics and the aspects of […] phenotypic and genotypic expression […] with respect to fitness and exercise are now being associated with a variety of genomic patterns.”

“As we learn more about [the] phenotypic expression of a variety of haplotypes in genes, there [will] be a spectrum of how we interpret these […] going forward — this is one of those studies that really demonstrate that.”

The strengths of this meta-analysis included the classification of study groups as either aerobic, strength, or power and the assessment of gene subgroups. As the sample size for some genes was small in this review, further studies are necessary to determine the exact role of these genes in influencing cardiopulmonary fitness, strength, and anaerobic power.

The results of future research may, theoretically, support the individualization and optimization of exercise programs based on a person’s genetic makeup.

Henry C. Chung, lead author of the study and Ph.D. researcher, states:

“Because everyone’s genetic makeup is different, our bodies respond slightly differently to the same exercises. Therefore, it should be possible to improve the effectiveness of an exercise regimen by identifying someone’s genotype and then tailoring a specific training program just for them.”