Scientists have uncovered new clues about a gene that may help protect the brain from Alzheimer’s disease.
The findings suggest that when this gene stops working properly, the risk of developing Alzheimer’s may rise sharply.
Alzheimer’s disease is the most common cause of dementia. It gradually damages memory, thinking and the ability to carry out everyday activities, and millions of people around the world are living with the condition.
There is no single cause of Alzheimer’s. Age is the strongest known risk factor, but genes, heart and blood vessel health, lifestyle and environmental factors can all influence whether a person develops the disease.
One gene attracting growing scientific interest is called PLCG2. It provides instructions for making an enzyme known as PLCγ2, which helps cells respond to signals and carry out important functions.
Previous research found that a rare version of PLCG2 called P522R is linked to a lower risk of Alzheimer’s disease. This protective version appears to make the PLCγ2 enzyme more active, raising the possibility that stronger PLCγ2 activity helps the brain resist disease.
An international research team led by scientists at the University of Eastern Finland and France’s INSERM research institute has now examined the gene in much greater detail. The study was published in Nature Genetics.
The researchers combined large European genetic data sets with laboratory experiments using human neurons grown from stem cells. This allowed them to study both what happens to Alzheimer’s risk in people carrying unusual PLCG2 variants and what happens inside nerve cells when PLCG2 activity is reduced.
One of the strongest findings involved rare changes that cause PLCG2 to lose some or all of its normal function. People carrying these loss-of-function variants had approximately 10 times the risk of developing Alzheimer’s disease compared with people who did not carry them.
That is a large difference in relative risk, although these genetic variants are rare. A 10-fold increase does not mean that every carrier will develop Alzheimer’s, because a person’s actual risk also depends on age, other genes and many additional factors.
The researchers then studied an Alzheimer’s-linked PLCG2 variant in human neurons grown in the laboratory. The variant reduced the amount of PLCγ2 protein inside the cells and was associated with changes resembling those seen in Alzheimer’s disease.
To investigate further, the scientists deliberately reduced PLCG2 activity in the laboratory-grown neurons. The nerve cells developed changes in their branching structures, which neurons normally use to receive information from other cells.
The connections between neurons were also weakened. These connections, called synapses, allow brain cells to communicate with one another and are essential for learning, memory and normal thinking.
Damage to synapses is believed to begin early in Alzheimer’s disease, sometimes before severe memory problems become obvious. This makes the finding especially interesting because it suggests that PLCG2 may help maintain the communication system between brain cells.
Reduced PLCγ2 activity was also linked with higher levels of beta-amyloid and increased changes to tau protein. Abnormal beta-amyloid and tau are two of the best-known biological features found in the brains of people with Alzheimer’s disease.
Beta-amyloid can collect into deposits between brain cells, while abnormal tau can form harmful structures inside neurons. Scientists are still working to understand exactly how these processes interact and which changes are causes, consequences or both.
The team also examined gene activity inside individual cell nuclei. Lower PLCG2 activity disturbed several groups of genes involved in communication between neurons, the formation of cell connections and systems that help brain cells send signals to one another.
These results broaden scientists’ understanding of PLCG2. Much previous Alzheimer’s research focused on the gene’s role in microglia, immune cells in the brain that help remove waste and respond to injury.
The new study suggests that PLCG2 also has an important job inside neurons themselves. If its activity becomes too low, nerve cells may lose healthy connections and become more vulnerable to several changes associated with Alzheimer’s.
This raises an intriguing treatment possibility. Because a naturally occurring PLCG2 variant that increases enzyme activity appears protective, scientists may eventually be able to develop medicines that safely increase PLCγ2 signaling.
However, the research is still at an early stage and does not show that increasing PLCγ2 will prevent or treat Alzheimer’s in people. Much of the biological evidence came from neurons grown in the laboratory, which cannot reproduce the full complexity of an aging human brain.
The rare high-risk variants also need to be studied in larger and more diverse populations. Genetic associations can be powerful clues, but researchers must determine exactly how much risk they carry across different groups and how they interact with other Alzheimer’s genes.
Overall, the study is important because the genetic and laboratory findings point in the same direction: stronger PLCG2 function may be protective, while reduced function may make the brain more vulnerable. That consistency makes PLCγ2 a promising target for future research, but years of additional work will be needed before scientists know whether it can be turned into a safe and effective treatment.
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Source: University of Eastern Finland.
