NIA-supported research has shown that the APOE gene may play a role in the breakdown of the blood-brain barrier in Alzheimer’s disease. The blood-brain barrier (BBB) is a semi-permeable barrier which facilitates the selective entry of materials into the brain from the adjacent blood supply. Prior studies suggest that the BBB breaks down in AD, and researchers in the current study wanted to understand if APOE genetic status might influence BBB breakdown. 245 participants were recruited to undergo a specific type of magnetic resonance imaging (MRI) which can identify leakiness in the BBB. Of the 245 participants, those who had one or more copies of the high-risk APOE ε4 allele showed increased breakdown of the BBB relative to those with two copies of the APOE ε3 allele. In addition, the researchers also tracked damage to pericytes, or cells which help to maintain the BBB, and they saw that pericyte damage predicted cognitive decline and increased inflammatory activity in APOE ε4+ participants. Notably, BBB breakdown appeared to occur independently from the accumulation of amyloid-beta and tau proteins, two known AD biomarkers, suggesting that it may be an independent contributor to cognitive decline, dementia, and AD. This study was published in Nature.
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.
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.
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.
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.