The virus that causes cold sores, herpes simplex virus 1 (HSV-1) or human herpes virus 1 (HHV-1) is extremely common. We are probably exposed to it in childhood, usually through oral contact and kissing. It can also be sexually transmitted from mouth-to-genital contact and as it is highly contagious, it is thought that up to 70% of us are exposed to it by the age of 50, increasing to 80% by the age of 60.
Herpesviruses also have a latent stage to their infection whereby they reside in areas of the body protected from the immune system, making them very hard to eradicate. For HSV-1 which causes cold sores around the mouth, it resides in the ganglion of the trigeminal nerve which innervates the skin around the mouth. It is thought to travel to the brain in older people as the immune system declines. HSV-2 (or HHV-2) is the virus that causes genital herpes and that tends to reside in the ganglia in the sacral area, near the genital tract.
Alzheimer’s disease
Alzheimer’s disease (AD) is the commonest form of dementia in elderly people. Based on the age of onset of AD, it can be classified as either familial or sporadic. The main hallmarks that can be found in the Alzheimer’s brain are extracellular amyloid plaques which are made up of deposits of beta amyloid peptide and tau or neurofibrillary aggregates/tangles within the neurons. These, in combination with shrinkage of the brain (atrophy), loss of neurons and neuroinflammation (together with other pathological features) form part of the pathology seen in Alzheimer’s.
[Bruno F, Abondio P, Bruno R et al. Alzheimer’s disease as a viral disease : Revisiting the infectious hypothesis. Ageing Res Rev 2023; 91: 102068]
Head trauma and Alzheimer’s disease
We still don’t fully know what causes Alzheimer’s disease. However there does seem to be pretty consistent data that head trauma is a risk factor for AD. The evidence does seem to suggest that the risk of AD increases when the severity and number of head trauma increases. Also the closer in time the head trauma is to the onset of AD, a so called shorter lag time, the higher the likelihood the head trauma will be detrimental. And then if head trauma were to occur in someone who were genetically predisposed to AD, for example possessing the Alzheimer’s risk allele, Apoe4, this would further increase the risk of AD occurring earlier.
[Klomparens K, Ding Y. Updates on the association of brain injury and Alzheimer’s disease. Brain Circ 2020; 6(2):65-69.]
So how are the three (HSV-1, head trauma and Alzheimer’s) linked?
In early January 2025, researchers from the University of Oxford and Tufts University, Massachusetts, USA used human brain organoids to show that head injuries can reactivate dormant HSV-1 in the brain, which in turn triggers the onset of the pathological features of Alzheimer’s disease.
[Cairns DM, Smiley BM, Smiley JA et al. Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model. Sci Signal. 2025;18(868):ead06430]
What is a human brain organoid?
These are three-dimensional cultures that resemble miniature brains providing an ideal human brain model. The researchers created them from neural stem cells from humans that carry one copy of the Alzheimer’s risk allele, Apoe4. They then infected them with HSV-1 and treated them with antivirals to induce latency.
How did they subject them to head trauma?
They encased them in a cap created by mechanical engineers, somewhat resembling a skull and added fluid to mimic cerebrospinal fluid.
They then used small pistons to deliver controlled blows to the skulls, mimicking brain injuries and then examined the brains for the changes seen in AD.
What did they find?
In the control cases (non HSV-1 infected) they just found the usual post injury inflammation.
In the HSV-1 infected cases, they found reactivation of HSV-1 after the controlled blows and also the production and accumulation of beta amyloid, tau and the other pathological changes seen in Alzheimer’s.
So the future?
It could be that for our young people or for professional athletes who sustain head trauma, instead of just rest and painkillers, antiviral therapy could be considered as a measure to stave off dementia in later life.
Kind regards,
Sandy
Dr Sandy Flann, Consultant Dermatologist.
