In a new study, researchers have identified a pair of genes that influence risk for both late-onset and early-onset Alzheimer’s disease.
The finding could provide scientists with new targets and a strategy for delaying the onset of Alzheimer’s symptoms.
The research was done by an international team led by scientists at Washington University School of Medicine in St. Louis.
Most genes implicated thus far in Alzheimer’s affect neurons that transmit messages, allowing different regions of the brain to communicate with one another.
But the newly identified genes affect an entirely different population of cells: the brain’s immune cells.
In the study, the team measured soluble TREM2 levels in the cerebrospinal fluid of 813 older adults, most of whom were ages 55 to 90.
Among those subjects, 172 had Alzheimer’s disease, 169 were cognitively normal, and another 183 had early mild cognitive impairment.
The team also analyzed the participants’ DNA, conducting genomewide association studies to look for regions of the genome that may influence TREM2 levels in the cerebrospinal fluid.
They found the genes—known as MS4A4A and TREM2—operate in the microglia, the brain’s immune cells.
The genes could influence Alzheimer’s risk by altering levels of TREM2, a protein that is believed to help microglia cells clear excessive amounts of Alzheimer’s proteins amyloid and tau from the brain.
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.
The team observed TREM2 risk variants more often in people who had Alzheimer’s or were mildly cognitively impaired, compared with those who were cognitively normal
Common variants in the MS4A4A gene also had been linked to risk for Alzheimer’s, but this study connects those genes.
About 30% of the population in the study had variations in the MS4A4A gene that appear to affect their risk for developing Alzheimer’s disease.
Some variants protected people from Alzheimer’s or made them more resilient while others increased their risk.
When the researchers dug further, they noted that variants in the MS4A4A gene cluster linked to an increase in risk for developing Alzheimer’s disease are linked to lower levels of soluble TREM2 protein.
The other variant, linked to higher levels of TREM2 in the cerebrospinal fluid, seemed to protect against Alzheimer’s.
The team says the findings point to a new therapeutic strategy.
If scientists can raise levels of the TREM2 protein in the cerebrospinal fluid, they may be able to protect against Alzheimer’s disease or slow its development.
The lead author of the study is Carlos Cruchaga, Ph.D., a professor of psychiatry.
The study is published in the journal Science Translational Medicine.
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