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 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 disease is caused by rare mutations in the APP, PSEN1, and PSEN2 genes. This type is the least common.
  • A late-onset form of dementia is associated with several genetic variants, including the APOE gene and the TREM2 gene. If you want 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 central to Alzheimer’s disease. Most 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 crucial 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. Thus, 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 cellular damage in the brain (DAMPs).[ref]

Like many immune system responses, microglia activation can be a double-edged sword. Initially, activating microglia can help to clean up any cellular debris. However, overactivation 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, which are needed to clean up cellular debris in the brain.[ref]

TREM2 can be activated by several different molecules, including 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]

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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 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 of 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 latest research as it comes out — there is a lot of hope for solutions coming soon.

There is a lot of interest 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 shows 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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References:

Bachiller, Sara, et al. “Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response.” Frontiers in Cellular Neuroscience, vol. 12, 2018. Frontiers, https://www.frontiersin.org/article/10.3389/fncel.2018.00488.

Gray, Sophie C., et al. “Shifting Equilibriums in Alzheimer’s Disease: The Complex Roles of Microglia in Neuroinflammation, Neuronal Survival and Neurogenesis.” Neural Regeneration Research, vol. 15, no. 7, Jan. 2020, pp. 1208–19. PubMed Central, https://doi.org/10.4103/1673-5374.272571.

Greve, Hendrik J., et al. “Diesel Exhaust Impairs TREM2 to Dysregulate Neuroinflammation.” Journal of Neuroinflammation, vol. 17, no. 1, Nov. 2020, p. 351. PubMed, https://doi.org/10.1186/s12974-020-02017-7.

Guerreiro, Rita, et al. “TREM2 Variants in Alzheimer’s Disease.” The New England Journal of Medicine, vol. 368, no. 2, Jan. 2013, pp. 117–27. PubMed, https://doi.org/10.1056/NEJMoa1211851.

Hall-Roberts, Hazel, et al. “TREM2 Alzheimer’s Variant R47H Causes Similar Transcriptional Dysregulation to Knockout, yet Only Subtle Functional Phenotypes in Human IPSC-Derived Macrophages.” Alzheimer’s Research & Therapy, vol. 12, Nov. 2020, p. 151. PubMed Central, https://doi.org/10.1186/s13195-020-00709-z.

Jay, Taylor R., et al. “TREM2 in Neurodegenerative Diseases.” Molecular Neurodegeneration, vol. 12, Aug. 2017, p. 56. PubMed Central, https://doi.org/10.1186/s13024-017-0197-5.

Jensen, Camilla Steen, et al. “Exercise as a Potential Modulator of Inflammation in Patients with Alzheimer’s Disease Measured in Cerebrospinal Fluid and Plasma.” Experimental Gerontology, vol. 121, July 2019, pp. 91–98. PubMed, https://doi.org/10.1016/j.exger.2019.04.003.

Ren, Siqiang, et al. “TNF-α-Mediated Reduction in Inhibitory Neurotransmission Precedes Sporadic Alzheimer’s Disease Pathology in Young Trem2R47H Rats.” The Journal of Biological Chemistry, vol. 296, June 2021, p. 100089. PubMed, https://doi.org/10.1074/jbc.RA120.016395.

Sims, Rebecca, et al. “Rare Coding Variants in PLCG2, ABI3 and TREM2 Implicate Microglial-Mediated Innate Immunity in Alzheimer’s Disease.” Nature Genetics, vol. 49, no. 9, Sept. 2017, pp. 1373–84. PubMed Central, https://doi.org/10.1038/ng.3916.

Tapp, Zoe M., et al. “Sleep Disruption Exacerbates and Prolongs the Inflammatory Response to Traumatic Brain Injury.” Journal of Neurotrauma, vol. 37, no. 16, Aug. 2020, pp. 1829–43. PubMed, https://doi.org/10.1089/neu.2020.7010.

Wang, Shoutang, et al. “Anti-Human TREM2 Induces Microglia Proliferation and Reduces Pathology in an Alzheimer’s Disease Model.” The Journal of Experimental Medicine, vol. 217, no. 9, Sept. 2020, p. e20200785. PubMed, https://doi.org/10.1084/jem.20200785.

Yussof, Ayuni, et al. “A Meta-Analysis of the Effect of Binge Drinking on the Oral Microbiome and Its Relation to Alzheimer’s Disease.” Scientific Reports, vol. 10, no. 1, Nov. 2020, p. 19872. www.nature.com, https://doi.org/10.1038/s41598-020-76784-x.

Zhong, Li, and Xiao-Fen Chen. “The Emerging Roles and Therapeutic Potential of Soluble TREM2 in Alzheimer’s Disease.” Frontiers in Aging Neuroscience, vol. 11, 2019. Frontiers, https://www.frontiersin.org/article/10.3389/fnagi.2019.00328.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.