Virus World

Alzheimer’s disease (AD) is characterized pathologically by amyloid-beta (Aβ) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA)) and by neurofibrillary tangles of hyperphosphorylated tau. Compelling genetic and biomarker evidence supports Aβ as the root cause of AD. We previously reported human transmission of Aβ pathology and CAA in relatively young adults who had died of iatrogenic Creutzfeldt–Jakob disease (iCJD) after childhood treatment with cadaver-derived pituitary growth hormone (c-hGH) contaminated with both CJD prions and Aβ seeds. This raised the possibility that c-hGH recipients who did not die from iCJD may eventually develop AD. Here we describe recipients who developed dementia and biomarker changes within the phenotypic spectrum of AD, suggesting that AD, like CJD, has environmentally acquired (iatrogenic) forms as well as late-onset sporadic and early-onset inherited forms.

Although iatrogenic AD may be rare, and there is no suggestion that Aβ can be transmitted between individuals in activities of daily life, its recognition emphasizes the need to review measures to prevent accidental transmissions via other medical and surgical procedures. As propagating Aβ assemblies may exhibit structural diversity akin to conventional prions, it is possible that therapeutic strategies targeting disease-related assemblies may lead to selection of minor components and development of resistance. A small number of patients who received growth hormone preparations contaminated with seeds of the amyloid-beta protein developed Alzheimer’s disease many years after treatment.

Published in Nature Medicine (Jan. 29, 2024):

https://doi.org/10.1038/s41591-023-02729-2 

Researchers at Baylor College of Medicine report today in the journal Neuron evidence that refutes the link between increased levels of herpes virus and Alzheimer's disease. In addition, the researchers provide a new statistical and computational framework for the analysis of large-scale sequencing data. About 50 million people worldwide are affected by Alzheimer's disease, a type of progressive dementia that results in the loss of memory, cognitive abilities and verbal skills, and the numbers are growing rapidly. Currently available medications temporarily ease the symptoms or slow the rate of decline, which maximizes the time patients can live and function independently. However, there are no treatments to halt progression of Alzheimer's disease.

"Like all types of dementia, Alzheimer's disease is characterized by massive death of brain cells, the neurons. Identifying the reason why neurons begin and continue to die in the brains of Alzheimer's disease patients is an active area of research," said corresponding author Dr. Zhandong Liu, associate professor of pediatrics at Baylor and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital. One theory that has gained traction in the past year is that certain microbial infections, such as those caused by viruses, can trigger Alzheimer's disease. A 2018 study reported increased levels of human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) in the postmortem brain tissues of more than 1,000 patients with Alzheimer's disease when compared to the brain tissues of healthy-aging subjects or those suffering from a different neurodegenerative condition. Presence of elevated levels of genetic material of herpes viruses indicated active infections, which were linked to Alzheimer's disease. In less than a year, this study generated a flurry of excitement and led to the initiation of several studies to better understand the link between viral infections and Alzheimer's disease. 

Surprisingly, when co-author Dr. Hyun-Hwan Jeong, a postdoctoral fellow in Dr. Liu's group and others, reanalyzed the data sets from the 2018 study using the identical statistical methods with rigorous filtering, as well as four commonly used statistical tools, they were unable to produce the same results. The team was motivated to reanalyze the data from the previous study because they observed that while the p-values (a statistical parameter that predicts the probability of obtaining the observed results of a test, assuming that other conditions are correct) were highly significant, they were being ascribed to data in which the differences were not visually appreciable. Moreover, the p-values did not fit with simple logistic regression—a statistical analysis that predicts the outcome of the data as one of two defined states. In fact, after several types of rigorous statistical tests, they found no link between the abundance of herpes viral DNA or RNA and likelihood of Alzheimer's disease in this cohort...

Published in Neuron (December 18, 2019):

https://doi.org/10.1016/j.neuron.2019.11.009

A new finding that even took the study’s authors by surprise lends support to the controversial idea that microbes play a role in Alzheimer’s disease. The research published June 21 in Neuron, found convincing signs that certain types of herpes virus may promote the complex process that leads to the disease that afflicts some 5.7 million Americans. The study points to the viruses as possible accomplices that drive disease progression but does not suggest that Alzheimer’s may begin after they are transmitted through casual contact. 

Joel Dudley, a geneticist and genomic scientist at the Icahn School of Medicine at Mount Sinai and senior author of the new paper, had not intended to investigate this theory when his lab began working on the newly published study in 2013. The plan he had made with colleagues was to identify possible new Alzheimer’s drug targets by looking at the molecular changes in the brain that occur during the disease. Thanks to a new NIH-led public-private partnership called the Accelerating Medicines Partnership Alzheimer's Disease (AMP-AD), the team had access to data from 876 brains—some healthy and some with early- or late-stage Alzheimer’s. They used DNA and RNA sequencing to parse out genetic differences between the groups as well as differences in how inherited genes were expressed or made into RNA. That’s when they started getting strange results. “The algorithms kept returning this pattern for viral biology,” Dudley says.

The team found more viral DNA in Alzheimer’s brains compared with healthy brains—specifically, high levels of DNA from human herpesvirus 6A (HHV-6A). RNA of both HHV-6A and HHV-7 were also higher in the Alzheimer’s brains than in healthy brains, and viral RNA levels tracked with the severity of clinical symptoms. HHV-6A is a usually symptom-less virus that infects people later in life. HHV-7 infects more than 80 percent of infants, often causing a rash.

Original research Published in Neuron on June 21, 2018

https://doi.org/10.1016/j.neuron.2018.05.023

A recent study of more than 6 million people 65 and older found that seniors who had Covid-19 had a substantially higher risk of being diagnosed with Alzheimer's disease within a year.  The study does not show that Covid-19 causes Alzheimer's, but it adds to the growing body of research drawing links between coronavirus infection and cognitive function. In the Alzheimer's disease brain, the pathology starts to build up about 20 years before the symptoms begin," said Dr. David Holtzman, a neurologist who leads a research lab focused on Alzheimer's disease at the Washington University School of Medicine in St. Louis. People would have to be followed for decades after a Covid-19 infection to prove it as a cause, he said.  Instead, a Covid-19 infection could cause inflammation that may exacerbate changes that are already happening in the brain, experts say.  "The brain has its own immune response to the pathology that's involved in [Alzheimer's] disease progressing," said Holtzman, who was not part of the new study. "When there are other things that cause inflammation that are in the body that can affect the brain, likely what happens is that can even amplify the process that's already going on." Other viruses can cause similar inflammation, experts say.