In the panel of genes that increase the risk of Alzheimer's, one dominates: APOE ε4. But there is a second player that is quickly rising to the top of the ladder: TREM2. The mutations in it can increase the risk 3 times or more.
What is TREM2?
TREM2 is a receptor on the microglial cells (the immune cells of the brain). It is the "switch" that activates them to ingest cellular waste, respond to injury, and repair tissue. Without it, the microglia are powerless.
Why is this important for Alzheimer's?
Alzheimer's is characterized by the accumulation of two proteins: Amyloid-β (plaques) and Tau (tangles). The role of the microglia: to collect and swallow them. When TREM2 is damaged, they fail, and debris builds up.
The problematic mutations
- R47H: 3-5 times risk (~0.5% of the population)
- R62H: 2-3 times risk (~1-2%)
- D87N: 2x risk (rare)
The positive side: Soluble TREM2
High-sTREM2 in the MCI stage is linked to a significant slowing of Alzheimer's progression: less amyloid, less tau, longer maintenance of cognitive function. This suggests: if we can boost TREM2, we can slow Alzheimer's.
Drugs in development
- AL002 (Alector + AbbVie): an antibody that activates TREM2. In experiments stage 2-3
- Denali ATV:TREM2: with blood-brain barrier transport technology
- Sangamo / Pfizer: a gene-therapy approach
Genetic testing
23andMe and MyHeritage sometimes include TREM2. Nebula Genomics and Sequencing.com offer full sequencing. Genetic counseling before testing is recommended.
If you have an increased risk
More than 50% of the risk is controlled by the environment: Mediterranean diet, physical activity 150 minutes a week, cognitive stimulation, quality sleep, routine neurological monitoring.
The bottom line
TREM2 is a control node in Alzheimer's disease. If we can balance the brain's immune system, we may be able to stop or reverse the disease. It is already in research.
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