An international study led by researchers at the University of Eastern Finland and the French INSERM research institute has found that impaired function of the PLCγ2 enzyme, encoded by the PLCG2 gene, can substantially increase the risk of Alzheimer’s disease. The study demonstrates that PLCγ2 plays an important role in maintaining neuronal function and protecting from Alzheimer’s disease-related pathological changes. The findings open new avenues for understanding disease biology and developing novel therapeutic strategies.
Alzheimer’s disease is the most common form of dementia worldwide, and its development is influenced by a combination of genetic and environmental factors. In recent years, the PLCG2 gene and its encoded enzyme, PLCγ2, have emerged as some of the most important modifiers of Alzheimer’s disease risk, as certain genetic variants in the gene appear to protect against the disease. For example, the protective P522R variant in PLCG2 increases PLCγ2 enzyme activity, suggesting that enhanced enzyme function may help prevent disease development.
In a study now published in Nature Genetics, researchers from the University of Eastern Finland and the French INSERM research institute led an international collaboration investigating the role of PLCγ2 in neuronal function. The study combined European genetic datasets with human stem cell-derived neuronal models. The aim was to understand how Alzheimer’s disease-associated PLCG2 risk variants affect the structure and function of neurons and synapses.
Rare PLCG2 variants increase pathological changes in neurons
Researchers at the University of Eastern Finland identified rare PLCG2 variants that impair gene function and are associated with a substantially increased risk of Alzheimer’s disease. Carriers of these so-called loss-of-function variants had approximately a tenfold higher risk of developing the disease as compared to individuals without such variants. The Alzheimer’s-associated PLCG2 risk variant examined in the study reduced protein levels of PLCγ2 in stem cell-derived neurons and increased Alzheimer’s disease-related pathological changes. These findings suggest that normal PLCγ2 activity in brain is an important component of the natural defense system against neurodegenerative diseases.
Reduced PLCG2 function damages neuronal connections
The study found that reduced PLCG2 expression impaired both the structure and function of neurons. Silencing the gene altered dendritic architecture and weakened synaptic function in human stem cell-derived neurons. Synapses are the connections through which neurons communicate, and synaptic dysfunction is among the earliest changes observed in Alzheimer’s disease. Furthermore, impaired PLCγ2 function increased levels of beta-amyloid and tau protein phosphorylation, two key pathological hallmarks of Alzheimer’s disease.
PLCG2 affects broad neuronal regulatory networks
Analyses based on single-nucleus RNA sequencing showed that reduced PLCG2 expression affected multiple gene networks essential for neuronal function. The observed changes were particularly associated with synaptic signaling, neuronal connectivity, and neurexin-related regulatory pathways, all of which play critical roles in normal brain function.
The findings partly challenge the prevailing view that the role of PLCG2 in Alzheimer’s disease is primarily linked to microglial cells, the immune cells of the brain. Instead, the results suggest that PLCγ2 is also important in neurons, where reduced activity may trigger several molecular processes that contribute to disease progression.
Towards new treatments for Alzheimer’s disease
The study further establishes PLCG2 as one of the key genes influencing Alzheimer’s disease risk and provides important new insights into the biological mechanisms underlying the disease. The findings suggest that enhancing PLCγ2 signaling could represent a novel approach for the prevention or treatment of Alzheimer’s disease in the future. Although further studies and clinical validation are required, the results provide an important foundation for identifying new therapeutic targets.
The study was supported by the Research Council of Finland and by grants from the Sigrid Jusélius Foundation and the Jane and Aatos Erkko Foundation.
For further information, please contact:
University Researcher Mari Takalo, mari.takalo (at) uef.fi
University of Eastern Finland, Institute of Biomedicine, Kuopio
Academy Research Fellow Henna Martiskainen, henna.martiskainen (at) uef.fi
University of Eastern Finland, Institute of Biomedicine, Kuopio
Professor Mikko Hiltunen, tel. +358 40 355 2014, mikko.hiltunen (at) uef.fi
University of Eastern Finland, Institute of Biomedicine, Kuopio
Kuopio University Hospital, Clinical Research Centre, Kuopio
Research article:
Coulon, A., Rabiller, F., Takalo, M. et al. PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures. Nat Genet (2026). https://doi.org/10.1038/s41588-026-02709-5
The research groups are members of the multidisciplinary Neuroscience Research Community (NEURO RC) at the University of Eastern Finland. NEURO RC aims to understand the disease-specific and common molecular mechanisms underlying neurodegenerative diseases and epilepsy and to identify novel biomarkers and therapeutic approaches for their prevention and cure. NEURO RC integrates biological neurosciences with data sciences, neuro-innovations, and neuro-ethics. Learn more and connect with NEURO RC: https://www.uef.fi/en/research-community/neuroscience-neuro
