The most in-depth analysis of human brain tissue ever done in Alzheimer鈥檚 disease has found evidence for the controversial theory that viruses play a role in the condition. If true, it could mean that some instances of Alzheimer鈥檚 might be treated with anti-viral drugs.
Alzheimer鈥檚 is the most common cause of dementia, affecting some 47 million people worldwide. Treatments can temporarily slow its progression, but there is no cure and we still lack a full understanding of what causes it.
Past studies have suggested that viruses, particularly herpes simplex virus 1, are a risk factor, but many Alzheimer鈥檚 researchers are unconvinced.
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In the latest study, at the Icahn School of Medicine at Mount Sinai, New York and colleagues analysed a large collection of molecular data from human brain banks, including DNA, RNA, and proteins, as well as clinical data from 622 brain donors with Alzheimer鈥檚 disease and 322 donors without the condition. Their aim was to build a computer model pulling together all of the data to understand how molecular activity changes in the brain with Alzheimer鈥檚 disease.
鈥淲e weren鈥檛 actually looking for viruses. We were trying to find new drug targets for Alzheimer鈥檚 disease,鈥� says Dudley.
The team were surprised to find that many of the genes that seemed to be affected in Alzheimer鈥檚 were genes involved in the body鈥檚 defence against viruses. So they went back to the raw genetic data to look for viral genes, and found that two in particular, human herpes virus 6 and 7 (HHV6 and HHV7) were significantly聽more abundant in brains with Alzheimer鈥檚.
That doesn鈥檛 tell you whether the viruses are somehow a consequence of Alzheimer鈥檚 disease or if they contribute to it. So they went further, using the data to build a model of how viral genes and human genes influence each other.
That revealed that many human genes previously implicated in Alzheimer鈥檚 are activated or suppressed in response to the presence of viral genes.
鈥淚t鈥檚 hard to say whether it鈥檚 a cause, but we can infer that the activity of the virus seems to be directly connected to the activity of other genes and pathways known to play a role in Alzheimer鈥檚,鈥� says Dudley.
HHV6 and HHV7 are widespread: over have antibodies in their blood that indicate past exposure to HHV6. In most people they are dormant and don鈥檛 cause disease. But in some people they become active and infect neurons in the brain.
It may be that Alzheimer鈥檚 risk genes and the presence of viruses lead collaboratively to the symptoms of disease, says co-author Sam Gandy. 鈥淭here are multiple potential clues like this and we are still trying to see the 30,000-foot view of the whole landscape.鈥�
Primitive immune system
The results also fit with the idea that there is a connection between Alzheimer鈥檚 and the innate immune system, a primitive defence against infections that is active in the brain. Some researchers believe that beta-amyloid plaques 鈥� a hallmark sign of Alzheimer鈥檚 in the brain 鈥� are produced to kill microbes, but cause problems when they are not cleared away fast enough.
鈥淚t could be that the viruses we鈥檝e found are one of many potential environmental factors that could trigger an innate immune reaction that increases the risk of Alzheimer鈥檚 in those with genetic susceptibility,鈥� says Dudley.
Bart De Strooper at UCL thinks the idea is interesting. 鈥淲hile this does not prove a causal role, it draws the attention of the field towards the possibility that an infection could contribute to the disease process,鈥� he says.
If this is a mechanism behind Alzheimer鈥檚, it聽is not yet known聽how many cases of the disease it contributes to.
Although it鈥檚 still unclear how genes, viruses and other factors fit together, the team鈥檚 models give us testable hypotheses about the biology of the disease, paving the way for new treatments.
The team hope to develop tests that identify carriers of HHV6 and HHV7 who have Alzheimer鈥檚 or other risk factors, then see if treating these people with antiviral drugs can change the course of disease.
The findings build on this year by researchers in Taiwan showing that people with herpes virus infections have a higher risk of senile dementia. Crucially, in patients treated with antiviral medications, .
Neuron
