A new gene linked to TREM2 reinforces the microglial receptor's role in Alzheimer's and could offer a way to treat the disease.
As the Alzheimer's field looks beyond β amyloid for new pathways and targets, companies are increasingly turning to neuroinflammation to explain the disease's development and identify therapies (see "The Next Wave in Neurodegeneration Expands Beyond Neurons").
TREM2 was first linked to Alzheimer's in two 2013 studies that showed a rare loss-of-function variant in the gene almost tripled the risk of developing the disease.
TREM2 is only expressed in microglia, and the receptor induces the immune cells' proliferation, survival and phagocytic activity. Other rare variants of TREM also have been associated with AD risk, and the studies consistently suggest the protein is protective.
A new genome-wide association study (GWAS) finds genetic support for TREM2 outside of the target itself, lending support to the idea that the TREM2 activation may be broadly useful.
“One of the most important findings of this study is that we demonstrate that TREM2 is involved in AD in general, and that higher TREM2 levels are protective,” study author Carlos Cruchaga told BioCentury. Cruchaga is professor of psychiatry and neurology at Washington University School of Medicine in St. Louis.
In a GWAS of 1,390 AD patients, healthy individuals and people with varying levels of cognitive impairment, WUSTL researchers identified an association between the MS4A locus and TREM2, in particular two variants in the MS4A4A gene. One variant was associated with increased concentrations of soluble TREM2 in cerebral spinal fluid (CSF), decreased risk of AD and delayed age of onset, while the other variant was associated with reduced TREM2 in CSF, increased AD risk and accelerated age at onset of AD.
"We demonstrate that TREM2 is involved in AD in general, and that higher TREM2 levels are protective."
Subjects with previously identified TREM2 variants were excluded from the study. Results were reported in a Science Translational Medicine paper on Wednesday.
Cruchaga said the study reveals the link between previous findings. "The identification of TREM2 clearly demonstrated that microglia play an important role in AD pathogenesis, and previous studies also reported that MS4A4A is associated with AD risk." The new work demonstrates "MS4A4A affects AD risk by modifying TREM2 levels," he said.
Digging deeper into the connection, the team showed expression of the two genes was highly correlated in brain tissue from AD patients, and MS4A4A co-localized with TREM2 in human macrophages, which were used as a proxy for microglia.
Overexpression of MS4A4A in the macrophages increased release of soluble TREM2 in culture.
The findings suggest MS4A4A offers a new approach to modulating TREM2. And like TREM2, MS4A4A is exclusively expressed in microglia, which means targeting it could avoid off-cell toxicity.
Cruchaga said his team plans to further investigate the interaction between MS4A4A and TREM2 to identify ways to modulate the receptor to treat AD. "We have just scratched the surface about the relationship between MS4A4A and TREM2," Cruchaga said.
The WUSTL team also is looking for compounds that target MS4A4A, he said.
Companies targeting TREM2 to treat AD include Alector Inc., which has TREM2-activating antibody AL002 in Phase I testing in healthy volunteers and patients with mild to moderate AD. According to ClinicalTrials.gov, the trial is taking all patients, not just those with TREM2 risk variants. Denali Therapeutics Inc. has an activating antibody, ATV:TREM2, in preclinical development for AD.
Targets: MS4A4A - Membrane spanning 4-domains A4A; TREM2 - Triggering receptor expressed on myeloid cells 2