Two studies involving researchers at the University of Eastern Finland highlight a central role for the PLCγ2 signalling pathway in Alzheimer’s disease. Protective PLCG2 variants, encoding the signalling enzyme PLCγ2, were found to delay disease onset, including in APOE ε4 carriers. Furthermore, a genome-wide meta-analysis identified a potential APOE-dependent protective disease mechanism associated with the DDHD1 gene, which encodes phospholipase A1. Together, the findings suggest that PLCγ2- and phospholipase A1-related pathways may converge on lipid signalling and metabolism, offering new opportunities for targeted Alzheimer’s disease therapies.
Alzheimer’s disease is the most common form of dementia worldwide. Although the APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, not all carriers develop dementia, indicating that other genetic factors can modify disease risk. In recent years, PLCG2 has emerged as one of the most important protective genes associated with Alzheimer’s disease.
In two recent studies published in Alzheimer’s Research & Therapy and Nature Genetics, researchers investigated how protective PLCG2 variants influence Alzheimer’s disease risk and how the APOE genotype shapes the underlying genetic architecture of the disease. The studies combined data from FinnGen, UK Biobank, EADB, FINGER and several other international Alzheimer’s disease cohorts comprising hundreds of thousands of individuals.
Protective PLCG2 variants delay Alzheimer’s disease onset
The researchers found that the Alzheimer’s disease-protective PLCG2-P522R variant and a common PLCG2-3’UTR variant were associated with a later age at onset of Alzheimer’s disease. The protective effects were also evident among individuals carrying one APOE ε4 allele. Carriers of the PLCG2-P522R variant showed a substantially lower risk of developing Alzheimer’s disease and experienced disease onset at a later age than non-carriers. These findings suggest that enhanced PLCγ2 signalling may mitigate some of the detrimental effects associated with APOE ε4 and promote resilience against neurodegeneration. The researchers also identified elevated levels of the neuroprotective hormone ghrelin in carriers of the protective PLCG2-P522R variant, suggesting additional biological mechanisms that may contribute to disease resilience.
APOE-stratified analyses reveal new disease genes
The Nature Genetics study reports one of the largest APOE-stratified genetic analyses of Alzheimer’s disease to date, identifying several genetic signals that were not apparent in previous genome-wide association studies. Among the newly identified genes were HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1. Particularly notable was DDHD1, a gene involved in lipid and phospholipid metabolism. A protective DDHD1 variant reduced Alzheimer’s disease risk specifically in APOE ε4 carriers and was associated with lower DDHD1 expression in human brain tissue.
PLCγ2 and phospholipase A1 may converge on lipid metabolism pathways
Although the two studies examined different genetic mechanisms, their findings point toward a potentially important connection between PLCG2 and DDHD1 variants. Both targets participate in pathways linked to lipid biology, which has emerged as a central process in Alzheimer’s disease. PLCγ2 is known to regulate microglial responses and cellular lipid handling, whereas phospholipase A1 belongs to a family of phospholipase enzymes involved in phospholipid metabolism and neuronal function. Notably, the Nature Genetics study identified DDHD1 as an APOE ε4-dependent protective locus and highlighted that DDHD1 encoding for phospholipase A1 is linked to the same broader biological pathway network as PLCγ2. This observation raises the intriguing possibility that the protective effects of PLCγ2 signalling may partly involve mechanisms regulating phospholipid turnover, membrane homeostasis and cellular energy metabolism. Given that APOE ε4 is known to disrupt lipid homeostasis in the brain, the convergence of protective PLCG2 variants and DDHD1-associated mechanisms on lipid metabolic pathways may represent a particularly important avenue for future research.
These studies were supported by the Research Council of Finland and by grants from the Sigrid Jusélius Foundation, the Jane and Aatos Erkko Foundation and the Alzheimer’s Association.
For further information, please contact:
Postdoctoral Researcher Heli Jeskanen, heli.jeskanen (at) uef.fi
University of Eastern Finland, Institute of Biomedicine, Kuopio
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
Research Director Sami Heikkinen, sami.heikkinen (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 articles:
https://pubmed.ncbi.nlm.nih.gov/41620758/
https://pubmed.ncbi.nlm.nih.gov/42736378/
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
