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Two Gene Variants Modulate Risk for Alzheimer's Disease, Providing Potential New Target

Article In Brief

Two gene variants influence Alzheimer's disease risk by altering levels of TREM2, a protein that is believed to help microglia cells clear excessive amounts of the Alzheimer's proteins amyloid and tau from the brain.


MS4A4A and TREM2 influence Alzheimers disease risk by altering levels of sTREM2, a protein (shown stained in red) that is believed to help microglia cells clear excessive amounts of the Alzheimers proteins amyloid and tau from the brain. The MS4A4A protein is shown stained in green.

Scientists at Washington University School of Medicine have identified a new genetic player in Alzheimer's disease (AD) that modulates triggering receptor expressed on myeloid cells (TREM2), a gene involved with microglial activation, survival, and phagocytosis.

In 2013, TREM2 was identified as a significant risk gene for late-onset disease and scientists have been trying to figure out why and how.

The researchers, led by Carlos Cruchaga, PhD, conducted a genome-wide association study (GWAS) and identified two variants in the MS4A gene cluster that includes MS4A4A and MS4A6A. These variants modify (soluble) sTREM2 in the cerebrospinal fluid (CSF).

Additional analyses demonstrated that overexpressing MS4A4A led to increased levels of TREM2 and reducing the gene variant led to decreased levels of the sTREM2 protein. “These higher levels appear to be protective in the disease, but it is still unclear why,” said Dr. Cruchaga.

TREM2 is expressed in microglia and is involved in the immune response. MS4A4A had emerged in other studies but no one knew how it related to Alzheimer's.

These findings, reported in the August 14 issue of Science Translational Medicine, suggest that they work on the same pathway in setting the stage for AD.

“There are multiple genes in this MS4A region and we didn't know that this variant was associated with risk,” said Dr. Cruchaga. “The association is very strong.”

He added that the hope is that the MS4A4A variant can be a novel target for developing AD treatments that can increase its expression, which in turn would lead to higher levels of CSF sTREM2.

Study Methods, Findings

The Washington University team conducted a GWAS looking for an association between CSF sTREM2 and single nucleotide polymorphisms (SNPs) from 813 patients and controls enrolled in the Alzheimer's Disease Neuroimaging Initiative. (These were not TREM2 risk-variant carriers.)

They identified a SNP in the MS4A region, and it brought them to MS4A4A and MS4A6A. They went on to replicate their findings in other data sets, and accumulated data from almost 1400 individuals. Patients with the variants had increased CSF sTREM2 concentrations and appeared older at the time of diagnosis, suggesting a delayed age at onset of disease.

Next, they wanted to determine which genes in the MS4A region were modulating sTREM2 production. In the lab, they used human macrophages as a proxy for microglia (since human microglia are difficult to work with). They obtained human macrophages from blood monocytes from healthy individuals.

The investigators observed in cell plates as MS4A4A, but not MS4A6A, and TREM2 colocalized on lipid areas at the plasma membrane. They saw that sTREM2 increased with MS4A4A overexpression. When they silenced MS4A4A, sTREM2 levels decreased.

“What these findings suggest is that TREM2 is involved in the pathology of sporadic AD, even beyond patients with TREM2 risk genes,” said Dr. Cruchaga. “Our studies confirm that MS4A4A modulates TREM2 levels, but other MS4A genes, including MS4A6A, could be also involved. Additional studies are needed to confirm this.”

Like apolipoprotein E4 (APOE4), people with one copy of the TREM2 risk gene have a three-fold increased risk for AD. The TREM2 variant p.R47H has been linked to many AD phenotypes, including advanced behavioral symptoms, gray matter atrophy, and more advanced stages of the disease. Since its identification in 2013, other rare TREM2 variants have been identified. TREM2 encodes a protein intimately involved in regulating the immune response of microglia. There is growing evidence that it also is involved with clearing out or segregating amyloid-beta and tau to stop its spread.

But the studies on TREM2 and AD suggest that its relationship to AD is dynamic and changing. Some studies have shown a loss of TREM2 protein leads to fewer microglia around amyloid plaques and more diffuse plaques and neuronal damage. Other studies suggest that low TREM2 levels protect against neuronal loss when tau is present.

In the researchers' previous studies, and replicated in this series of experiments, CSF sTREM2 concentrations positively correlated with CSF tau and phosphorylated tau, but not with CSF amyloid-beta 42 concentrations.

Other studies from several groups have found that CSF TREM2 levels first decrease in the early stages of AD, to later increase and decrease again in later disease stages. Scientists are still trying to figure out this complex and changing relationship, which is critically important in developing treatments to regulate TREM2.

They also looked to see whether APOE genotype was associated with CSF sTREM2 and did not find a clear relationship.

Expert Commentary

“It is interesting that they were able to connect these two AD genes. This is another piece of the puzzle,” said Alison Goate, DPhil, the Willard T.C. Johnson research professor of neurogenetics and director of the Ronald M. Loeb Center for Alzheimer's Disease at the Icahn School of Medicine at Mount Sinai.

“TREM2 variants and MS4A loci have been identified in GWAS studies but this is the first study linking the two of them. No one knows much about the MS4A proteins or their functions.”

Dr. Goate's lab is also studying both genes and their relationship to microglia and Alzheimer's.

“MS4A4A seems to be a surface receptor and could be a useful therapeutic target,” she added. “It is important to establish how MS4As regulate sTREM2 levels and whether this can be manipulated to regulate TREM2 activity.”

“It's an important paper as it elaborates the connectivity between Alzheimer susceptibility loci,” said Philip De Jager, MD, PhD, professor of neurology at the Taub Institute for Research on Alzheimer's disease and the Aging Brain and the Columbia Precision Medicine Initiative. He is also director of Columbia's Center for Translational & Computational Neuro-Immunology.

“It provides robust evidence that different regions of the genome that have been implicated in the onset of Alzheimer are working together. The CD33 Alzheimer variant was previously shown to influence TREM2 on the cell surface of myeloid cells, and this new MS4A cluster observation and the subsequent functional analyses genetically elaborate an Alzheimer susceptibility network in myeloid cells. These observations point us towards soluble TREM2 levels as being potentially causally involved in the onset of Alzheimer's.

“Overall, this emerging network map will help to prioritize targets for Alzheimer drug development as TREM2 itself, for example, may not be the best or most effective point to modulate in the network to reduce the risk of Alzheimer's that is attributed to altered myeloid cell function,” Dr. De Jager added.

Dr. De Jager holds equity in an emerging biotech company that will focus on studying microglia and neurodegenerative diseases.


Dr. Cruchaga receives research support from Biogen, EISAI, Alector, and Parabon; he also serves on the advisory board of ADx Healthcare and Vivid Genomics. Dr. Goate has received honoraria and travel expenses for talks on behalf of AbbVie, Biogen, Eisai, and GSK Pharmaceuticals.

Link Up to More Information

• Deming Y, Filipello F, Cignarella F, et al. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk Sci Transl Med 2019; 11(505): eaau2291.
• Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer's disease N Engl J Med 2013;368(2):117–127.
• Cantoni C, Bollman B, Licastro D, et al. TREM2 regulates microglial cell activation in response to demyelination in vivo Acta Neuropathol 2015;129(3):429–447.
• Lee CYD, Daggett A, Gu X, et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer's disease models Neuron 2018; 97(5):1032–1048.