Genes linked to Alzheimer’s risk, resilience ID’d

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Genes linked to Alzheimer’s risk, resilience ID’d

Genes in the brain’s immune cells may point to strategy to protect against the disease

MS4A4A and TREM2 genes
Most of the genes involved in Alzheimer's disease so far affect the neurons that transmit messages, allowing different regions of the brain to communicate with each other. But newly identified genes affect a completely different population of cells: the immune cells of the brain. This discovery could provide scientists with new targets and a strategy to delay the onset of Alzheimer symptoms.

Genes - known as MS4A4A and TREM2 - act in the microglia, the immune cells of the brain. They influence the risk of developing Alzheimer's disease by altering levels of TREM2, a protein that is believed to help microglial cells eliminate excessive amounts of amyloid and tau proteins in the brain.

"Our results suggest a new therapeutic strategy," said Principal Investigator Carlos Cruchaga, PhD, Professor of Psychiatry and Director of the NeuroGenomics and Informatics Group. "If we can do something to increase levels of TREM2 protein in the cerebrospinal fluid, we may be able to protect neurons against Alzheimer's disease or slow its development. »

They measured TREM2 levels
In this study, researchers measured the levels of TREM2 soluble in cerebrospinal fluid in 813 elderly people aged 55 to 90 years. Of these subjects, 172 had Alzheimer's disease, 169 were cognitively normal and 183 had early mild cognitive impairment. They also analyzed participants' DNA and conducted genome-wide association studies to identify regions of the genome that could influence TREM2 levels in cerebrospinal fluid.

Although variants of TREM2 are found in a very small percentage of patients with Alzheimer's disease, this gene had already been linked to the disease. People with these previously identified risk mutations were excluded from the study. Common variants of the MS4A4A gene have also been associated with an increased risk of Alzheimer's disease, but this study connects them.

"We have observed TREM2 risk variants more often in people with Alzheimer's disease or mild cognitive impairment than in people with normal cognitive behaviour," said Celeste Karch, PhD, Associate Researcher and Assistant Professor in the Department of Psychiatry.

High levels of TREM2 are protective and lower levels increase risk
"It was found that approximately 30% of the population targeted by this study had variations in the MS4A4A gene that appear to affect their risk of developing Alzheimer's disease. Some variants protect people from Alzheimer's disease or make them more resilient, while others increase their risk. »

When the researchers further investigated, they found that MS4A4A gene group variants associated with an increased risk of developing Alzheimer's disease were associated with lower levels of the TREM2 protein. The other variant, associated with higher levels of TREM2 in cerebrospinal fluid, appeared to protect against Alzheimer's disease.

The research team validated its results in the DNA of 580 other elderly people. Again, they found that higher levels of TREM2 in cerebrospinal fluid that appeared protective, while lower levels increased the risk. And these protein levels - high or low - were linked to variants of the MS4A4A gene.

"In recent years, we have examined TREM2 and placed greater emphasis on the involvement of brain immune cells in Alzheimer's disease," said another lead co-author, Bruno A. Benitez, MD, Assistant Professor of Psychiatry. "These results give us a new therapeutic strategy to pursue, one that focuses not only on neurons but also on how microglia can help eliminate harmful proteins, such as beta-amyloid and tau, that are linked to Alzheimer's disease. »

These variants may play a role in other diseases
According to Laura Piccio, MD, PhD, Associate Professor of Neurology and other lead co-author, these gene variants could also play a role in other diseases of the central nervous system.

“By combining large genetic and spinal fluid analyses with laboratory work, we have provided strong evidence of a biological link between TREM2 and proteins in the MS4A gene cluster, both of which previously had been associated with Alzheimer’s disease,” Piccio said. “We are beginning to elucidate a molecular pathway in microglia that could be critical not only in Alzheimer’s disease but also in other neurodegenerative and inflammatory diseases in the central nervous system.”