Lancet Sub-Issue: 20 Years of Protection! An early marker of Alzheimer's disease, will it be?

▎ WuXi AppTec content team editor

Alzheimer's disease (AD) is the most common form of dementia and is a highly occurring neurodegenerative disease in older adults. At present, there is a lack of effective treatment for patients with AD, but intervention in early patients can delay disease progression, so it is extremely important to diagnose AD effectively at an early stage.

Recently, The Lancet Neurology published a blockbuster study confirming that microglia in the brain have begun to play a protective role 21 years before the first appearance of AD symptoms. Not only that, the accelerated increase in the free level of the cell surface receptor TREM2 in the cerebrospinal fluid slowed down β the deposition of amyloid (Aβ) plaques in people at high risk of AD- amyloid (Aβ), the pathogenic effect of Aβ-dependent tau protein, cerebral cortex atrophy and cognitive decline.

The study pointed out that based on the protective role of microglia-mediated TREM2 in the early development of the disease, TREM2 level changes may be a key marker of clinical research on AD, and targeted TRIM2 therapy is expected to become a potential future direction against AD!

Screenshot source: The Lancet Neurology

TREM2 is a microglia surface receptor protein that plays an important role in microglia activation, survival, and phagocytosis, and free TREM2 (soluble TREM2) can be detected in cerebrospinal fluid.

Previous animal model studies have shown that TREM2 levels in cerebrospinal fluid can be used to measure microglia activity, and as TREM2 levels increase, so does the protective effect of microglia on the brain.

Human studies have shown that higher levels of TREM2 may be shown in the cerebrospinal fluid of patients with AD compared to healthy controls. In addition, the results of genome-wide association studies suggest that TREM2 genetic variants are associated with the onset of AD, and its rare missense mutations can even increase the risk of AD disease by nearly 3 times!

Based on cerebrospinal fluid analysis and cognitive assessment results, the researchers conducted a longitudinal analysis of data from 248 subjects in the dominant Alzheimer's Disease Network (DIAN) observational study (dian observational study registered family members affected by autosomal dominant AD, such as PSEN1, PSEN2, APP pathogenic mutation carriers).

▲Baseline characteristics of subjects (Image source: References[1])

The researchers extrapolated the age of onset of AD symptoms from the age of onset of the subject's parents or other family members, and used this to analyze the characteristics of changes in the soluble TRIM2 of cerebrospinal fluid in the pre-AD stage of AD disease, as well as its correlation with other biomarkers of AD.

Unlike previous studies, the researchers used the new technique to effectively exclude the transmembrane domain TREM2 produced by selective splicing, so that the level of soluble TREM2 in the cerebrospinal fluid (rather than all forms of TREM2 protein) can be more accurately analyzed.

The study found that as early as 21 years before the onset of symptoms (estimated age of symptom onset), the soluble TREM2 in the cerebrospinal fluid of carriers of AD dominant genetic mutations began to increase. Combined with other amyloid proteins as well as tau protein analysis, the faster TREM2 increases, the slower the rate at which typical brain-related progression events of AD occur.

Not only that, but lower levels of β in cerebrospinal fluid in the very early stages of the disease, amyloid 42 (Aβ42), are associated with a faster increase in subsequent soluble TREM2. This may suggest that amyloid deposition has triggered the production of soluble TREM2 when AD has not yet been detected on imaging (i.e., the piB-PET uptake value has not been elevated), and microglia may be abnormally sensitive to amyloid-related pathogenic pathways.

PiB-PET examination showed that the subjects' rapidly increased levels of soluble TREM2 in the cerebrospinal fluid reduced the rate of amyloid accumulation, and trem2 levels may be an early protective response to β amyloid accumulation. Combined with the results of cognitive assessment, the rapid increase in the level of soluble TREM2 has a beneficial effect on reducing brain structure atrophy and slowing down cognitive decline.

Overall, the current findings suggest that in the very early stages of Alzheimer's disease, the deposition of amyloid triggers the protective effects of microglia, which may be mediated by their cell surface TREM2 receptors. The findings are also consistent with previous results from the Alzheimer's Disease Neuroimaging Project (ADNI), where higher levels of soluble TREM2 in baseline cerebrospinal fluid are associated with subsequent cognitive decline and slower development of brain structural atrophy in subjects.

It is worth noting that the results of previous studies suggest that soluble TREM2 has a strong association with changes in tau protein, p-tau181 and so on in cerebrospinal fluid. The current analysis shows that the level of soluble TREM2 begins to increase in the preclinical stage and is related to the amyloid detected in the cerebrospinal fluid, but not with the phosphorylation of tau protein and tau protein on threonine 181 (p-tau181).

The paper notes that the findings of the current study provide the clearest evidence to date for the complex kinetic characterization of soluble TREM2. Carriers of AD dominant genetic mutations may have experienced a rapid increase in soluble TREM2 levels long before symptoms appear.

TREM2 may have an important protective role in the early development of Alzheimer's disease, and targeted TREM2 therapy is expected to be a potential future direction in the fight against Alzheimer's disease!