TREM2 Protein May Slow Memory Impairment in Alzheimer’s, Study Suggests

Higher concentrations of a protein produced exclusively by the brain’s immune cells, called TREM2, may prevent memory decline and lessen brain degeneration in people with Alzheimer’s disease, according to a recent study.

The results of the study, “Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease,” were published in Science Translational Medicine.

Microglia, a type of brain immune cell that also provides support to other neurons, selectively expresses a receptor known as TREM2. Recent studies have found that certain immune responses in the brain can contribute to Alzheimer’s characteristic cognitive decline.

Evidence also indicates that loss-of-function mutations in the TREM2 gene — which cause the resulting protein’s activity to become reduced or non-existent — dramatically increase the risk for late onset Alzheimer’s. Thus, in theory, boosting TREM2 function could be regarded as a potential therapeutic strategy.

Previous work from researchers at the German Center for Neurodegenerative Diseases in Munich, Germany, has shown that TREM2 activates microglia to selectively destroy Alzheimer’s-related toxic protein aggregates in mice. That indicates a protective role for TREM2 in this disease.

Importantly, TREM2’s concentration is elevated in the cerebrospinal fluid (CSF) — the liquid surrounding the brain and spinal cord — of Alzheimer’s patients, probably due to the activation of microglia in response to disease-related molecular changes.

Researchers now investigated whether soluble TREM2 levels present in the cerebrospinal fluid were associated with rates of cognitive decline and clinical progression in people with Alzheimer’s or mild cognitive impairment.

In other words, scientists sought to determine whether TREM2 baseline levels are predictive of subsequent alterations in the hippocampus — the brain’s memory center, which is significantly damaged in Alzheimer’s — as well as changes in cognition and clinical progression to mild cognitive impairment or Alzheimer’s dementia.

Researchers quantified soluble TREM2 levels in CSF samples of 385 senior individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Among them were 100 healthy controls (45 women, 55 men; mean age of 72.8 years) and 285 Alzheimer’s patients (126 women, 159 men; mean age of 73.5 years). Follow-up time ranged from 1.5 to 11.5 years.

Participants were considered to have a neurodegenerative disorder based on their CSF concentrations of amyloid-beta and tau — two key proteins involved in Alzheimer’s — regardless of their clinical symptoms. Therefore, the patient sample included people with mild cognitive impairment and Alzheimer’s disease dementia.

Higher levels of soluble TREM2 in the cerebrospinal fluid were associated with less memory decline in individuals with mild cognitive impairment and Alzheimer’s dementia.

Such association was consistently observed in those who were positive for two known toxic forms of amyloid beta and tau protein in the CSF — specifically amyloid-beta 1-42 and p-tau₁₈₁.

Within the p-tau₁₈₁ subsample of people, those with higher levels of solube TREM2 and less CSF phosphorylated tau levels had a slower progression from cognitively normal to cognitively impaired, and from mild cognitive impairment to Alzheimer’s dementia. Such CSF composition also was associated with reduced hippocampal neurodegeneration, as revealed by magnetic resonance imaging (MRI).

“Our findings are of clinical relevance, because these patients displayed a consistently reduced risk of developing dementia over a period of 11 years,” Michael Ewers, PhD, professor at the Ludwig Maximilian University of Munich and first author of the study, said in a press release.

“However, activation of the microglia is a double-edged sword. In addition to providing protective effects, it can lead to inflammation processes. Nevertheless, TREM2 could play a key role in triggering a protective immune response in the brains of patients with Alzheimer’s disease,” Ewers added.

TREM2’s concentration in the cerebrospinal fluid often increases during Alzheimer’s early stages. According to Christian Haass, PhD, the study’s lead author: “TREM2 production is a response to brain damage that has already occurred. The protein stimulates the microglia to protect the brain. However, this protection does not seem to be sufficient in patients with Alzheimer’s disease.”

“Our findings have important implications for therapeutic attempts that aim to modulate microglial function, suggesting that stimulating TREM2-mediated microglial activity may be most beneficial within the early symptomatic phase of [Alzheimer’s disease],” the researchers said.

“We are currently developing a therapeutic antibody that stimulates the TREM2 function and thus improves its protective effect,” Haas added.