The recent finding that the brain's immune system is linked to Alzheimer's lends support to the idea that pathogens such as viruses could be one cause of the disease. Yet even in healthy older people, genetic changes occur in the immune system that make immune cells less functional and less able to stave off any attack on the brain.
All is not lost, however, as we have a good deal of control over whether these changes occur.
Connection Between Brain and Immune System in Neurodegenerative Disease
After gaining a PhD in brain sciences, David Gate joined the lab of noted neuroscientist Tony Wyss-Coray at Stanford University. His research focus was the connection between the brain and the immune system in neurodegenerative disease.
He first studied immune cells in the blood to see if there were any differences in Alzheimer's patients, but later turned his attention to the immune system of the brain via the cerebrospinal fluid (CSF), which has a different and more specialized composition of immune cells compared to the blood. His findings led to an important discovery.
CSF Immune Cells Linked to Alzheimer's
CSF floats in and around the spinal cord and brain, protecting them from physical damage and bathing them in nutrients. Although CSF also provides immune protection to the brain, this has yet to be well-studied in neurological diseases.
In his first paper, published in 2020, Gate found elevated levels of CD8 T-cells in the blood and CSF of Alzheimer's patients. Some of these immune cells had proliferated rapidly, targeting Epstein-Barr virus (EBV), a common herpes virus.1 This is in line with previous reports linking herpes viruses to Alzheimer's disease.
While it's not possible to draw a causal link between EBV and Alzheimer's, the link between CSF immune cells and Alzheimer's was a significant discovery.
With this success, Northwestern University invited Professor Gate to start his lab in September 2021. In his next paper, he showed that immune cells in the brain and spinal fluid get ' a little angry' as we age.2
T-Cells: The Good, The Bad, The Ugly
Using single-cell RNA sequencing, the team examined CSF immune cells in 45 healthy people aged 54 to 83 and compared them to those in 14 adults with cognitive impairment. They found genetic changes in older healthy individuals, making their immune cells more activated and inflamed.
"The immune cells appear to be a little angry in older individuals," Gate said. "We think this anger might make these cells less functional, resulting in dysregulation of the brain's immune system."
But these cells were far angrier in those with cognitive impairment.
Professor Gate said that the inflamed T-cells cloned themselves and flowed into the CSF and brain as if following a radio signal. These cells had an overabundance of a cell receptor called CXCR6 that acts as an antenna. This receptor receives a signal — CXCL16 — from the degenerating brain's microglia cells to enter the brain.3
"It could be the degenerating brain activates these cells and causes them to clone themselves and flow to the brain," Professor Gate said. "They do not belong there, and we are trying to understand whether they contribute to damage in the brain."
3For the next study, Professor Gate would return to where he started to examine the immune system in the blood, also known as the peripheral immune system, to understand the genetic changes and immune responses further. Yet again, he and his team came up with a new finding that's good news for those who want to prevent Alzheimer's.
Immune Genes Altered in Alzheimer's
Professor Gate and his team examined every immune cell type in Alzheimer's patients. They discovered that every cell had epigenetic changes, meaning that the patient's behavior or environment caused changes affecting the way their genes work. Many of these altered immune genes are the same ones known to increase an individual's risk for Alzheimer's disease. The researchers saw these epigenetic changes when they looked at chromatin, which packages the DNA within cells. They found the chromatin open (exposed), which made the cells' genome vulnerable to alterations. A receptor — CXCR3 — on the T-cells was more exposed and, like CXCR6, acts as an antenna on T-cells, signaling them to enter the brain, which they wouldn't normally do because they can cause inflammation. These findings are in line with Professor Gate's previous study. T-cells act upon a signal that there's damage and enter the brain. They enter presumably to carry out repairs, yet T cells can be toxic to the brain. More work is required to find out if the changes seen reflect pathology in the brain or whether they take place before the disease process begins. Professor Gate said, "These findings indicate that immune function in Alzheimer's patients is significantly altered. It could be that environmental factors, like pollutants, or infections that a person has in their lifetime cause these epigenetic changes."
Our Takeaway
Professor Gate's findings put us in the driver's seat when it comes to preventing Alzheimer's disease. Genes change in response to their environment. They need good raw materials to work with, or they won't function correctly. These good raw materials depend on a healthy diet and lifestyle, keeping pollution levels and toxins to a minimum, minimizing stress, and taking supplements that can boost our immune system, so we don't allow any latent viruses already within us to reawaken.
