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 

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

Researchers found associations between certain viral illnesses and the risk of Alzheimer’s and other neurodegenerative diseases.  Neurodegenerative diseases can damage different parts of the nervous system, including the brain. This may lead to problems with thinking, memory, and/or movement. Examples include Alzheimer’s disease (AD), multiple sclerosis (MS), and Parkinson’s disease (PD). These diseases tend to happen late in life. There are few effective treatments. Previous findings have suggested that viruses may play a role in certain neurodegenerative diseases. For example, a recent study found a link between Epstein-Barr virus infection and the risk of MS. There are also concerns about cognitive impacts from SARS-CoV-2, the virus that causes COVID-19. A research team led by Drs. Mike Nalls, Kristin Levine, and Hampton Leonard of NIH's Center for Alzheimer’s and Related Dementias examined links between viruses and neurodegenerative disease more generally. To do so, they analyzed data from the FinnGen project. This is a repository of biomedical data, or biobank, from more than 300,000 people in Finland. The team searched the biobank for people who had been diagnosed with one of six different conditions: AD, amyotrophic lateral sclerosis (ALS), generalized dementia, vascular dementia, PD, and MS. They then checked how many had been hospitalized for a viral illness before. To confirm their findings, they looked for the same associations in the UK Biobank, which contains data from almost 500,000 people in the United Kingdom. Results appeared in Neuron on January 19, 2023.

The researchers found 45 associations between viruses and neurodegenerative diseases in FinnGen. Of these, 22 also appeared in the UK Biobank. The strongest association was between viral encephalitis—brain inflammation caused by a virus—and AD. A person with viral encephalitis in the FinnGen database was 30 times as likely to be diagnosed with AD as someone without encephalitis. Results were similar in the UK Biobank; people with viral encephalitis were 22 times as likely to develop AD as those without. The team also found, in FinnGen, the association between Epstein-Barr virus and MS that was described before. The association wasn’t seen in the UK Biobank, but this may reflect how the different biobanks use hospital diagnostic codes; Epstein-Barr viruses are common and so often not noted. Influenza with pneumonia was associated with all the neurodegenerative diseases except MS. The researchers only included cases of influenza severe enough to need hospitalization in the study. Thus, these associations only apply to the most severe cases of influenza. FinnGen contains data on the same people over time. The team used this to examine how the associations depended on the time since infection. They found that some viral infections were associated with increased risk of neurodegenerative disease as much as 15 years later. The researchers note that vaccines exist for some of the viruses they identified. These include influenza, varicella-zoster (which causes chickenpox and shingles), and certain pneumonia-causing viruses. Vaccination might thus reduce some of the risk of the conditions they examined. “The results of this study provide researchers with several new critical pieces of the neurodegenerative disorder puzzle,” Nalls says. “In the future, we plan to use the latest data science tools to not only find more pieces but also help researchers understand how those pieces, including genes and other risk factors, fit together.”