Scientists identify pair of genes linked to Alzheimer's resilience

The newly identified genes influence risk for both late-onset and early-onset Alzheimer's, according to researchers.

Genes linked to Alzheimer’s disease resilience have been identified by scientists.

Researchers have found a pair of genes that influence risk for both late-onset and early-onset Alzheimer’s.

So far most genes implicated in the condition affect neurons that transmit messages, allowing different regions of the brain to communicate with one another.

But researchers say the newly identified genes – MS4A4A and TREM2 – affect an entirely different population of cells.

Published in the journal Science Translational Medicine, the findings could provide scientists with new targets and a strategy for delaying the onset of Alzheimer’s symptoms.

The newly identified genes influence Alzheimer’s risk by altering levels of a protein that is believed to help microglia cells – the brain’s immune cells – clear excessive amounts of the Alzheimer’s proteins amyloid and tau from the brain.

Co-senior investigator Professor Carlos Cruchaga, said: “The findings point to a new therapeutic strategy.

“If we can do something to raise levels of the TREM2 protein in the cerebrospinal fluid, we may be able to protect against Alzheimer’s disease or slow its development.”

In the study, researchers from the Washington University School of Medicine measured soluble TREM2 levels in the cerebrospinal fluid of 813 older adults, most of whom were aged 55 to 90.

Of those subjects, 172 had Alzheimer’s disease, 169 were cognitively normal, and another 183 had early mild cognitive impairment.

They also analysed the participants’ DNA, conducting genomewide association studies to look for regions of the genome that may influence TREM2 levels in the cerebrospinal fluid.

Although variants in TREM2 are found in a very small percentage of patients with Alzheimer’s disease, the gene previously had been linked to the disorder.

People who carried those previously identified risk mutations were excluded from the study.

Common variants in the MS4A4A gene had also been associated with risk for Alzheimer’s, but this study connects those genes.

The scientists also noted that variants in the MS4A4A gene cluster linked to an increased risk for developing Alzheimer’s disease were associated with lower levels of soluble TREM2 protein.

The other variant, associated with higher levels of TREM2 in the cerebrospinal fluid, seemed to protect against Alzheimer’s.

Co-senior author, Bruno Benitez, an assistant professor of psychiatry, said: “These findings give us a new therapeutic strategy to pursue, one focusing not only on neurons but on how the microglia may be involved in helping to clear damaging proteins, such as beta amyloid and tau, that are linked to Alzheimer’s disease.”

Those variants may also play a role in other diseases of the central nervous system, according to Dr Laura Piccio, an associate professor of neurology and another co-senior author.

She said: “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.

“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.”

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