TREM2 and Alzheimer’s Disease Risk

Alzheimer’s disease is the most common form of dementia in older adults. It causes a progressive loss of memory and cognitive function, and many families know the heartbreak that a diagnosis of Alzheimer’s brings.

Researchers think that genetic susceptibility combines with environmental factors to cause Alzheimer’s disease. Understanding your genetic risk can help you prioritize how you work towards preventing Alzheimer’s.

TREM2, Microglia, and Alzheimer’s risk:

There are two types of Alzheimer’s:

  • an early-onset, familial Alzheimer’s caused by rare mutations in the APP, PSEN1, and PSEN2 genes. This type is the least common.
  • a late-onset form of dementia associated with several genetic variants, including the APOE gene and the TREM2 gene. If you would like to know your APOE genotype, you can check it here.

Genetics research over the past decade has highlighted the importance of the immune response as being central to Alzheimer’s disease. Most of the genetic risk factors discovered for Alzheimer’s involve the brain’s immune system.[ref]

Microglia:

Microglia cells are an important type of cell in the brain and spinal cord. Microglia are the main immune defense cells, fighting off pathogens in the brain. But they are also important in reacting to cellular stress in the neurons of the brain and cleaning up cellular debris.

The blood-brain barrier does a pretty good job of keeping most bacteria out of the brain. In turn, the blood-brain barrier also blocks the rest of the body’s immune cells, like white blood cells, from crossing into the brain also. Thus, the microglia are the resident brain immune cells. When activated, microglia release cytokines.

Within the different regions of the brain, up to 16% of the cells can be microglia. The microglia react to and interact with other molecules around them – such as molecules associated with pathogens (PAMPs) and molecules associated with cellular damage in the brain (DAMPs).[ref]

Like many immune system responses, the activation of microglia can be a double-edged sword. Initially, activating microglia can help to clean up any cellular debris. Overactivation, though, causes the secretion of inflammatory cytokines that can injure neurons.[ref]

The TREM2 gene:

The TREM2 gene codes for a receptor on the microglia, which receives signals from nearby neurons and then activates several important functions of the microglia. For example, TREM2 is integral in activating autophagy or phagocytosis in microglial cells, both of which are needed in cleaning up cellular debris in the brain.[ref]

TREM2 can be activated by several different molecules, include APOE, bacterial lipopolysaccharides, and amyloid-β. So you can see how it is at an integral junction in how the brain responds to several important molecules in Alzheimer’s pathogenesis.

 


Genetic variants in TREM2 associated with Alzheimer’s disease:

Several genetic variants have links to an increased risk for Alzheimer’s disease. The R47H variant has been linked in numerous studies to Alzheimer’s. Study results show that the increase in relative risk is 2-3 fold.[ref]

Members: Select your data file if you don’t see your data below

 

Check your genetic data for rs75932628 R47H(23andMe v4, v5; AncestryDNA):

  • C/C: typical risk
  • C/T: reduced intracellular signaling, increased risk of Alzheimer’s disease
  • T/T: reduced intracellular signaling, increase risk of Alzheimer’s disease[ref][ref][ref][ref]

Members: Your genotype for rs75932628 is .

 

Check your genetic data for rs143332484 R62H (23andMe v4, v5):

  • C/C: typical
  • C/T:  reduced intracellular signaling, slightly increased risk for Alzheimer’s
  • T/T: reduced intracellular signaling, moderately increased risk for Alzheimer’s[ref][ref]

Members: Your genotype for rs143332484 is .

 


Lifehacks:

Diet, exercise, and a healthy lifestyle are all important in preventing Alzheimer’s disease. Seriously- I know it sounds like just the same old general advice, but research studies do show that all of the lifestyle factors do matter in Alzheimer’s disease.

Don’t be a binge drinker:  A new study out shows that binge drinking causes a shift in the oral microbiome. Excessive ethanol affects the oral microbiome and couples with increased permeability to the blood-brain barrier, possibly increasing the ability for bacteria to reach the brain.[ref]

Specific to TREM2, moderate exercise has been shown to increase soluble TREM2 levels, which is associated with a possible decreased risk of Alzheimer’s.[ref]

Sleeping well may also be really important with TREM2. Animal studies show that sleep disruption after a traumatic brain injury alters TREM2 levels.[ref]

Avoid air pollution: Animal research shows a link between TREM2 expression and exposure to diesel exhaust in air pollution.[ref]

Keep an eye out for new research: Keep on top of the new research as it comes out — there is a lot of hope for solutions coming soon.

There is a lot of interest right now in targeting TREM2 for Alzheimer’s prevention, and researchers are investigating soluble forms of TREM2 as a preventative.[ref]

Additionally, TREM2 activation with antibodies is also being investigated for preventing Alzheimer’s in people with the TREM2 variants.[ref]

Animal research is showing that TNF-alpha may also play a role in altering Alzheimer’s pathology in TREM2 variants. Decreasing TNF-alpha may end up being important in Alzheimer’s prevention.[ref]


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Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.