TREM2: The Gene That Influences Alzheimer's Risk and Brain Health

In the panel of genes that increase the risk of Alzheimer's, one dominates: APOE ε4. But there is a second player gaining increasing attention in research: TREM2. Certain rare mutations in it can significantly increase the risk of Alzheimer's. It is important to emphasize: TREM2 is only a small part of the picture. Alzheimer's risk is determined by a combination of many genes (APOE first and foremost), along with lifestyle factors, and there is no single gene that determines fate.

What is TREM2?

TREM2 is a receptor on microglia (the brain's immune cells). It is the "switch" that activates them to engulf cellular waste, respond to injury, and repair tissue. When the receptor is defective, the microglia's ability to function is impaired.

Why is this important for Alzheimer's?

Alzheimer's is characterized by the accumulation of two proteins: Amyloid-β (plaques) and Tau (tangles). One of the roles of microglia is to collect and engulf them. When TREM2 is defective, this ability weakens, and waste tends to accumulate.

Mutations linked to risk

• R47H: The most established mutation. Carriers have about a 3-fold increased risk of Alzheimer's (~0.5% of the population). This is the mutation on which most research focuses.
• R62H: Linked only to a mild risk, much lower than R47H (in large studies, odds ratio around 1.4).
• D87N: Its link to Alzheimer's is inconsistent and controversial. Some studies found no significant association.

The positive side: Soluble TREM2

High levels of soluble TREM2 (sTREM2) in the mild cognitive impairment (MCI) stage have been linked in studies to slower disease progression: less amyloid and tau accumulation and longer preservation of cognitive function. This direction of effect suggests a hypothesis: if we can support TREM2 activity, we might influence the disease course. This is still an observed association, not proof of causality.

Drugs in development: The promise and the obstacles

TREM2 is a promising therapeutic target in theory, but clinical attempts so far have faced significant obstacles. It is worth knowing the full picture, including the failures:

• AL002 (Alector and AbbVie): An antibody designed to activate TREM2. In a phase 2 trial called INVOKE-2 (results November 2024), the drug did not meet the primary endpoint and did not slow Alzheimer's progression in early-stage patients, despite observed microglial activation. Development of this program was discontinued following the results.
• Denali / Takeda (DNL919): A TREM2-activating antibody with technology to cross the blood-brain barrier. Development was discontinued in August 2023 after a phase 1 trial, partly due to a "narrow therapeutic window" and safety signals (reversible hematological effects at the high dose).

The bottom line currently: The leading drugs targeting TREM2 have not shown clinical benefit, and some have been discontinued. This is an active research area, but still far from an approved treatment.

Genetic testing

Some genetic testing services (like 23andMe and MyHeritage) may include partial information, and full sequencing companies like Nebula Genomics and Sequencing.com offer broader analysis. Genetic counseling is recommended before such testing, also to understand that a TREM2 mutation is only a risk factor, not a death sentence.

If you have increased risk

A significant portion of dementia risk is influenced by modifiable factors. According to the Lancet Commission (2024), up to about 45% of dementia cases may be preventable or delayed by addressing a range of risk factors throughout life. Evidence-based steps include: a Mediterranean diet, physical activity of about 150 minutes per week, cognitive stimulation, quality sleep, and managing factors like blood pressure, diabetes, and smoking. Routine neurological follow-up is recommended for those concerned about their risk.

The bottom line

TREM2 is an interesting control point in Alzheimer's disease and a target for therapeutic research. The hypothesis is that supporting brain immune system function may help delay disease onset or slow progression, but leading clinical trials in this direction have failed so far. It is not a switch that turns the disease on or off, nor a promise to stop or reverse it. The most proven tools for protecting the brain remain, for now, a healthy lifestyle and managing modifiable risk factors.