Is Alzheimer’s Linked To The Cold-Sore-Causing Herpes Virus?

For this study, Shemesh and his team used various modeling techniques to investigate how HSV-1 might be linked to Alzheimer’s disease.

“Alzheimer’s disease is usually diagnosed by finding clumps of a protein called beta-amyloid outside brain cells and another protein called tau inside the cells,” Shemesh explained. “Tau is found modified and pathogenic in Alzheimer’s disease. Recent studies suggest that infections might play a role in Alzheimer’s disease, with HSV-1 being a strong suspect.”

“In our study, we detected HSV-1-related proteins in postmortem human brain samples,” he continued. “We found that the viral proteins increase as Alzheimer’s disease worsens and are found in the same areas as the tau, but not with [beta-amyloid]. In experiments using miniature human brain models (organoids), we saw that HSV-1 infection increases the amount of tau,” he told us.

Interestingly, Shemesh said, the modified tau seems to reduce the levels of herpes proteins and lower the number of neurons dying after infection, as if the neurons were not infected at all.

“This led us to explore a specific immune response pathway in the brain, the cGAS-STING pathway,” he detailed. “We found that molecules of this pathway are present where HSV-1 and modified tau are found in Alzheimer’s disease.”

“We also discovered that activating this immune pathway boosts tau modification while blocking it stops the tau modification,” Shemesh continued. “These results suggest that tau may be a part of the brain’s immune response in Alzheimer’s disease, and that therapeutic interventions might aim at helping it, not necessarily blocking it.”

Shemesh said he believes that these findings may one day lead to new treatment options for Alzheimer’s disease:

“The discovery that tau phosphorylation can act as a protective mechanism against HSV-1 infection suggests that enhancing this immune response could help mitigate the impact of viral infections in the brain, which are increasingly being implicated in Alzheimer’s pathology. A promising strategy could be to mimic the beneficial effects of tau phosphorylation without triggering its harmful aggregation, which is associated with Alzheimer’s progression.”

“This approach could help bolster the brain’s innate immune response while avoiding the formation of neurofibrillary tangles that exacerbate the disease,” he continued. “By understanding the specific mechanisms through which tau provides this protection, we can work toward therapeutic interventions that leverage its positive effects while mitigating its detrimental impact on neuronal health.”

“We plan to further explore the mechanisms behind tau’s protective role, investigate other pathogens that might interact with tau (or [beta-amyloid]) in Alzheimer’s, and test potential therapies that can harness or mimic tau’s protective effects,” he added.

This study echoes the findings from another study, published in the journal BMJ Open, which found that older adults diagnosed with HSV-1, particularly those above 75 years of age, have a higher risk of developing Alzheimer’s.

This large United States-based study included 395,654 patients with Alzheimer’s and 1,039,683 patients with Alzheimer’s disease and related dementia (ADRD). The participants were mostly women, on average age 73, and had multiple health issues compared to controls.

The researchers also found that people who used antiherpetic medications after an HSV-1 diagnosis had a lower likelihood of developing Alzheimer’s.

The findings emphasize the importance of monitoring and treating herpes infections as a public health priority for managing Alzheimer’s in individuals with a family history of dementia.

MNT spoke with Manisha Parulekar, MD, FACP, AGSF, CMD, director of the Division of Geriatrics at Hackensack University Medical Center and co-director of the Center for Memory Loss and Brain Health at Hackensack University Medical Center in New Jersey, who was not involved in this research, about these findings.

“As we understand, Alzheimer’s is a multifactorial disease, and though amyloid plaques and tau protein play an important part in the pathogenesis there are many other factors that impact this disease. This study highlights various possible pathways that HSV-1 can play in both starting and progression of Alzheimer’s disease in addition to the amyloid and tau protein.”

— Manisha Parulekar, MD, FACP, AGSF, CMD

“It’s important to note that while these mechanisms are plausible and supported by research, the exact role of viruses like HSV-1 in Alzheimer’s is still being investigated,” she continued.

“It will be helpful to investigate this on a larger scale to help establish specific pathways for progression of Alzheimer’s pathology. It is essential to understand other processes that contribute to the disease in addition to amyloid and tau protein.This will allow us to explore effective interventions,” Parulekar pointed out.

MNT also spoke with Clifford Segil, DO, a neurologist at Providence Saint John’s Health Center in Santa Monica, CA, who was also not involved in the studies. Segil urged caution when interpreting the results and said that no clinical neurologists believe there is an association between a prior viral infection with cytomegalovirus (CMV) neurologic disease.

“It is a large leap to assign a virus, HSV, which causes encephalitis, bloody infections in brains, white matter changes and death, and cognitive complaints, to cause memory loss from dementia when HSV is known to cause hemorrhagic encephalitis and brain damage,” Segil explained.

“Viral encephalitis causes confusion due to brain damage, not dementia. There is no clinical validity to HSV causing dementia as proposed by [the Cell Reports] paper’s author,” he said.

“I would like to investigate if the use of acyclovir, an anti-HSV medication, can be associated with any reduced cognitive issues due to acyclovir being used for treating viral encephalitis,” he continued. “If acyclovir decreases cognitive complaints, it would prove viral encephalitis from HSV are causing cognitive issues rather than HSV causing Alzheimer’s dementia.”