NIA-funded research on the APOE gene suggests that the APOE ε2 allele may confer protection against Alzheimer’s disease

NIA-funded research on the APOE gene suggests that the APOE ε2 allele may confer protection against Alzheimer’s disease.  The APOE gene encompasses three different versions, or alleles: ε2, ε3, and ε4.  The ε2 allele is the rarest and is associated with decreased AD risk; the ε3 allele is the most common and appears to neither increase or decrease AD risk; and the less common ε4 allele is associated with increased AD risk.  Researchers in the current investigation aimed to clarify the precise role of APOE ε2 in AD risk.  They calculated risk estimates based on data from over 5,000 autopsy-confirmed AD cases and controls from the NIA-funded Alzheimer’s Disease Genetics Consortium (ADGC).  Of the 5,000+ cases, only 24 individuals had two copies of APOE ε2, but these individuals showed a 66% reduction in AD risk compared with ε2/ε3 carriers; an 87% risk reduction compared with ε3/ε3 carriers; and a 99% risk reduction compared with ε4/ε4 carriers.  In an additional ADGC sample, ε2/ε2 carriers again showed decreased AD risk.  These results point towards an opportunity to elucidate the molecular mechanisms through which APOE ε2 lowers AD risk, which could in turn assist in the development of broader AD treatment and prevention strategies.  This study was published in Nature Communications.

New NIA Study Suggests Mutations in Mitochondrial DNA Could Give Rise to Age-Related Diseases

A new study from the NIA Intramural Research Program (IRP) suggests that mutations in mitochondrial DNA could give rise to age-related diseases.  Mitochondria, which create energy to power our cells and bodies, contain their own DNA.  IRP investigators sought to assess whether a specific type of mitochondrial DNA sequence known as a G-quadruplex could generate mutations in mitochondrial DNA.  These G-quadruplexes, or G4s, are complex four-strand DNA structures which are hypothesized to interfere with normal DNA synthesis due to their bulky structure, potentially leading to DNA mutations.  In order to test this hypothesis, the investigators first analyzed genomic data from two NIA-supported Italian studies, SardiNIA and InCHIANTI, and discovered that the G4 sequences contained a significant proportion of mitochondrial DNA mutations.  Follow-up laboratory tests showed that G4 sequences create these mutations by halting normal DNA synthesis.  Mitochondrial mutations, in turn, can disrupt normal cellular functioning and cause brain, nervous, cardiovascular, and muscular diseases, including those associated with aging.  This study was published in Human Molecular Genetics.

Clinical Trial Launched to Evaluate the Safety and Efficacy of the Antiviral Drug Remdesivir Plus the Anti-Inflammatory Drug Baricitinib for Treatment of SARS-CoV-2 Infection.

A clinical trial has recently been launched to evaluate the safety and efficacy of the antiviral drug remdesivir plus the anti-inflammatory drug baricitinib for treatment of SARS-CoV-2 infection.  The clinical trial, which is also sponsored by NIAID, represents the next phase of NIAID’s Adaptive COVID-19 Treatment Trial, or ACTT.  This new trial, known as ACTT2, will recruit participants with confirmed SARS-CoV-2 infection and evidence of lung involvement.  Participants will be randomized to receive either remdesivir plus baricitinib, or remdesivir alone.  Among other outcomes, investigators will determine if there are significant differences in recovery time across the two treatment groups.  To learn more about the clinical trial, please visit the study site on ClinicalTrials.gov, or search by identifier NCT04280705.

New Investigational Vaccine Against SARS-CoV-2 ChAdOx1 Shown to Protect Rhesus Monkeys from Infection with SARS-CoV-2-Induced Pneumonia

A new investigational vaccine against SARS-CoV-2, ChAdOx1, was recently shown to protect rhesus monkeys from infection with SARS-CoV-2-induced pneumonia.  The ChAdOx1 vaccine has proven successful in protecting against Middle East respiratory syndrome (MERS), which is closely related to the novel coronavirus SARS-CoV-2, and was recently modified for use with SARS-CoV-2.  Early evaluations of the vaccine in rhesus monkeys revealed that treated animals showed no viral replication in lungs, no pulmonary damage, and significantly reduced respiratory disease, all of which are consistent with protection against SARS-CoV-2-induced pneumonia.  These findings were shared ahead of print in order to inform and accelerate the public health response to COVID-19.

Treatment with a Repurposed Drug Can Help Mice to Lose Weight

An NIA-sponsored study has shown that treatment with a repurposed drug can help mice to lose weight and improve metabolic functioning.  This drug, disulfiram, is normally prescribed to treat alcohol addiction, but was investigated in the current study as an off-label means of treating obesity and metabolic dysregulation in mice.  Researchers fed middle-aged mice a high-fat diet across a period of 12 weeks, which induced obesity and metabolic dysfunction.  Then, they divided the mice into four treatment groups, including: (1) a standard diet group; (2) a high-fat diet group; (3) a high-fat diet + low disulfiram dose group; and (4) a high-fat diet + high disulfiram dose group.  Mice in the high-fat diet group continued to gain weight and experience metabolic dysregulation, while those who switched to the standard diet eventually lost weight and saw a return of normal metabolic function.  Mice in the two disulfiram groups, however, showed more dramatic weight loss and a near reversal of metabolic damage, including restoration of insulin sensitivity.  The research team hypothesized that these benefits may be due to the anti-inflammatory properties of disulfiram, which appeared to protect the mice from the harmful effects of the high-fat diet.  The researchers noted that treatment with disulfiram could represent a potential therapy for obesity and related metabolic dysfunction in humans, should clinical trial evidence support it.  This study was published in Cell Metabolism.