“Genes that Burn Down Your Brain” Extinguish the Fire by Regulating CD33 and TREM2, the “Brain Inflammation Genes” – Part 2

Reader, what were your greatest childhood comforts—the memories you think about that instantly bring a warm, protected feeling back to your heart? Was it the meal your mother used to make for you when you were sick? Or perhaps it was the warm embrace of a grandparent you got to visit during the summers. I was chatting with a friend about this subject earlier this week, and she brought up a warm memory perhaps you can relate to: when she was an energetic, impatient little kid, she’d frequently ask her mom where she’d put her shoes, her bag, her toys, and so on. My friend found great comfort in the fact that her mother would always know. She saw it as one of many superhuman strengths that differentiated her mother as an adult—and she wondered if someday she’d possess the same all-knowing power. My friend brought this up to me because the roles have finally reversed: now, when she visits her mother’s house, she is the one who helps her mother find her misplaced keys. Her mother is in her late sixties—but she has a history of Alzheimer’s disease and vascular dementia in her family. It can be agonizing to try to sort out the difference between the benign memory loss in old age and the type of memory loss that can soon debilitate a person until they become a faint shadow of who they used to be, and a stranger to those they love.

Having had a grandparent go through this already, my friend was concerned—should she start to worry about her mother? But she was also confused—even if she should start worrying, what, exactly could be done? Isn’t Alzheimer’s an inexorable, incurable disease? My friend was left with a sense of powerlessness and fear. There was still some part of her who believed her mother was that superhuman who could remember anything and everything—and recall it at a moment’s notice. She was scared of losing that wonderful, loving presence… but what could she do?

My friend’s feelings of concern, fear, and complete powerlessness are not uncommon in the face of the threat of Alzheimer’s. But emerging science is beginning to show that this dreaded disease may not be as mysterious as we once thought. Research has concluded that the underlying molecular and cellular processes of Alzheimer’s disease begins several decades before diagnosis – can be modifiable—and that an understanding of genetics may hold the key to holding the dreaded disease at bay. Today, we continue with our four-part series on the genetic elements of Alzheimer’s disease and vascular dementia by discussing your TREM2 and CD33 genes.

Your Brain, Inflamed: The Role of Chronic Inflammation in Alzheimer’s Disease

Last week, we discussed an important component in the decades-long process your brain goes through before diagnosis occurs: the buildup of amyloid plaques and tau protein tangles that infest and sit inside your brain cells like plaque on your teeth. We now know that the genes that regulate the processes that flush away that bad “brain plaque”  can be effective or ineffective, depending on which genetic variants you possess—and we also know that if you possess one or more “risk” genes, you can mitigate the consequences through lifestyle changes. Today, in Part 2 of our series, we’ll discuss another component that can steer our fates toward or away from dementia: chronic inflammation of the brain.

You may recall from our prior blog that, in small doses, acute inflammation is actually a crucial part of our body’s defense systems, and the cells leading the charge in protecting our brain are the microglia. Microglia are the immune  cells of the brain: when there’s damage inside our brain—including those amyloid beta protein and tau protein buildups—our microglial cells swoop in to clean things up and destroy these “enemy proteins.” They do this by “upregulating”, feeding off the energy sources of nearby cells in order to do their good work. This works well over short time frames. But when chronic, that upregulation can result in oxidative stress and inflammation. And chronic inflammation can lead to chronic oxidative stress—both of which amplify the buildup of amyloid plaques, tau tangles, cellular damage and eventual brain cell death.[/vc_column_text][/vc_column_inner][/vc_row_inner][vc_column_text]

TREM2 and CD33: Helping Your Brain Fight Back against Alzheimer’s

Considering this information, it makes sense that the genes that play a role in the efficacy of your microglia in fighting damage and defending your brain would hold an important key to your mental health future—and recent genetic research has proven this out. CD33 and TREM2 gene variants are both expressed on the surface of your microglia, and as such, both help regulate your brain’s neuroinflammatory pathway. Let’s take a closer look at how these two genes can impact your risk of developing Alzheimer’s, and what you can do about it.

TREM2

TREM2 is a microglial surface receptor that plays an essential role in removing debris from the brain. The failure of this receptor to function normally is one of a group of core components that may lead to Alzheimer’s progression. One variant in particular confers down expression, which pushes your microglia to the “dark side”, making neuroinflammation more common and causing a three- to four-fold increase in the odds of developing Alzheimer’s.

CD33

CD33 encodes for a protein found on the surface of microglial cells that acts as an essential regulator for microglial activity. Think once again of your microglia as your warrior cells. Warriors can generally be found in one of two states—fighting or resting. The same goes for your microglia. In this case, “fighting” puts your microglia in a constant state of defense and activity. They don’t have much time for anything else. This is your microglia in an inflammatory state—which can lead to oxidative stress and neuronal damage. When your microglia rest, on the other hand, they’re in what is known as the “monophagocytic state”. This rejuvenating state actually increases the clearance of amyloid plaques and waste debris. Think of CD33 as the “on-off” switch between these two states. If you have a resilient CD33 gene that confers a down expression, your microglia are switched “off” more often: leading to more repair and amyloid clearance—and a 10 percent reduced odds of developing Alzheimer’s. A risk gene, however, can lead your microglia to be chronically inflamed resulting in poor clearance and dangerous buildup of waste products that can “light your brain on fire” through oxidative stress, decreased mitochondrial energy production and the destruction of cell membranes and many cellular functions.[/vc_column_text][vc_column_text]

Help, I have a Risk Variant! What Can I Do About My Genes to Stave Off Alzheimer’s?

Say you have a risk variant on your TREM2 or CD33 genes—are you fated to develop Alzheimer’s? Not necessarily. There are things you can do right now to help your body fend off the disease by clearing those amyloid plagues and reducing inflammation. For instance, low levels of Vitamin D have been shown to increase your odds of Alzheimer’s—and effect your TREM2 expression. By increasing Vitamin D levels you can give your body and brain a jump start in protecting against dementia. Lithium supplementation been shown to aid specifically in improved microglial function, and there may be a role for melatonin, carotenoids, and curcumin as well.

Reader: If you’re like my friend and are worried about a parent’s slow loss of memory, I hope you find solace in reading more about these genes and what actions you—and perhaps your parents—can take to fend off Alzheimer’s. The progression to the clinical manifestations of Alzheimer’s disease is not inevitable, and the sooner we take action to arrest the processes that lead to brain cell damage and functional decline, the more of a chance we give ourselves and our loved ones to stave off a dreaded dementia that robs one of their dignity and humanity.

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