New research has demonstrated a mechanistic link between the immune response to herpesviruses - the family of viruses related to cold sores, childhood infections and glandular fever - and increased risk of Alzheimer's disease.
A team of scientists from Cardiff University's School of Medicine, Systems Immunity Research Institute and Dementia Research Institute has provided a vital new insight into a long-standing theory that Alzheimer's disease risk is increased through viral infections, including herpesviruses.
Together, they have shown that infection with herpesvirus leads to accelerated cognitive decline, and that specific groups of immune cells - T cells - play an important role in increased dementia risk.
The researchers used a mouse model of Alzheimer's disease to investigate the immune response to the herpesvirus and uncover the underlying mechanism between infection and dementia - highlighting the importance of infection control and antiviral treatments as a way of mitigating dementia risk.
Dr Mathew Clement, Cardiff University School of Medicine, said: "Infections, including chronic human herpesviruses which can be associated with cold sores, have long been suspected as increasing the risk of developing Alzheimer's disease. However, the mechanisms underlying this association have remained largely unknown."
We wanted to add new detail to this picture, to help understand how infections and viruses can play a role in developing this type of dementia, with the ultimate goal of enriching our understanding of how we could provide prevention and treatments in the future.
During the study, the scientists used mice that carry genes linked to Alzheimer's disease, called 3xTg-AD mice, and infected the mice with β-herpesvirus murine CMV.
Some of the infected mice were also treated with an anti-viral drug, valganciclovir hydrochloride, and some mice were treated with antibodies which targeted specific T cells called CD4 and CD8 T cells.
After infection, the mice were measured for cognitive decline, build-up of disease-associated proteins tau and amyloid (indicative of Alzheimer's disease), and the loss of brain cells in the hippocampus, a part of the brain involved in memory processing.
The researchers found that infection with the herpesvirus triggered an influx of immune cells into the brain. They were able to identify that the majority of these infiltrating white blood cells, particularly a subset of these called CD8+ T cells, were viral-specific which indicates that these cells in the brain are focused on fighting the herpesvirus. This finding supports earlier research that identified the same type of immune cells in the brains and spinal fluid of people with Alzheimer's disease.
Preclinical models that develop AD were treated with either antiviral drugs or had their white blood cells removed. This then resulted in improved cognitive performance, which is a hallmark measure used to determine human AD disease. The team say these results provide direct evidence that a virus-induced immune response can accelerate the progression of Alzheimer's disease.
Professor Ian Humphreys, Professor of Viral Pathogenesis and Lead Co-Director of Cardiff University's Systems Immunity Research Institute, said: "It remains unclear how virus-induced T cell presence in the brain leads to disease progression and understanding this may lead to new insights into Alzheimer's Disease development."
These results should be viewed as one piece of a much larger puzzle rather than proof that herpesviruses cause Alzheimer's disease. These findings help us better understand the range of biological factors that may contribute to the condition and identify new avenues for future investigation.
Dr Clement added: "Not only does this research broaden the understanding of the link between herpesviruses and Alzheimer's disease, and further strengthens the link between viruses and dementia more generally, but it raises the importance of prevention of infectious disease and how this, in the long term, may prevent or delay dementia onset.
"This study bolsters the argument that dementia risk is not as simple as genetic predisposition, but that environmental factors play an important part. By preventing disease, through vaccines, antiviral treatments and immune support, we can not only be treating and preventing us from getting short-term illnesses – such as cold sores - but those same disease preventions are playing an important role in reducing dementia risk for the later parts of our lives as well."
This highlights the ultimate significance of disease and infection interventions like vaccines
This work was supported by the Hodge Centre for Neuropsychiatric Immunology, the Medical Research Council, and the Wellcome Trust. The research, Cytomegalovirus-induced T cell responses accelerate Alzheimer's disease progression in mice, was published in Brain.
