How gene mutations drive dementia in Parkinson’s disease

Cell type distribution and differential gene expression in the cortex. Uniform Manifold Approximation and Projection (UMAP) dimension reduction for A Gba (Amber), B Gba-SNCA (Green) and C SNCA tg (Red) overlayed over WT (Black) mouse cortical snRNAseq expression. D UMAP showing clusters of cortical cell types identified by expression signatures. In A–D, UMAP 1 is shown on the x-axis and UMAP 2 on the y-axis. E Proportions of the cell types in the cortices of wild type and transgenic mice. F The number of differentially expressed genes (DEGs) per cell type in Gba, Gba-SNCA, and SNCA mutant mice after correction for genome-wide comparisons and filtering out of genes with log2FC < 0.2. n = 4 for WT and Gba mice, and n = 3 for Gba-SNCA and SNCA tg mice. Credit: Nature Communications (2025). DOI: 10.1038/s41467-025-63444-9

Parkinson’s disease causes both movement and cognitive deficits, and for a long time both were thought to be caused by the accumulation of a protein called alpha-synuclein in the brain. But a new Nature Communications study has found that the cognitive deficits arise through a different—and unexpected—mechanism.

The new findings suggest that mutations in a gene called GBA—which are a risk factor for developing Parkinson’s disease—drive cognitive decline by disrupting how neurons communicate with each other in the brain. Patients living with Parkinson’s disease can experience cognitive symptoms such as difficulty with concentrating and forgetfulness. Over time, many go on to develop dementia, in which they experience profound memory loss among other symptoms.

“Dementia is often the scariest thing for many patients with Parkinson’s disease, more so than motor symptoms,” says Sreeganga Chandra, PhD, professor of neurology and of neuroscience at Yale School of Medicine (YSM) and the study’s principal investigator. “We are trying to understand the basis of cognitive dysfunction and whether we can find targets to ameliorate it.”

GBA mutations drive cognitive dysfunction in Parkinson’s disease

In the study, the researchers analyzed three types of mouse models: animals that overexpressed a gene called SNCA that encodes the alpha-synuclein protein, GBA mutants, and crossbred GBA-SNCA double mutants. Using these models, the team conducted a series of experiments that tested the animals’ motor and cognitive functions over time between three and 12 months of age.

The experiments showed that motor dysfunction was linked to elevated alpha-synuclein. SNCA and GBA-SNCA mutants—the two models that had elevated alpha-synuclein—experienced motor deficits that worsened over time, but GBA mutants did not develop any motor deficits.

Cognitive deficits, on the other hand, were associated with GBA mutations. GBA and GBA-SNCA mutants developed comparable cognitive deficits as early as three months that persisted at 12 months, while SNCA mutants did not show any dysfunction.

The findings highlight that Parkinson’s disease symptoms are driven by different mechanisms, with motor deficits tightly linked to alpha-synuclein buildup and cognitive deficits caused by GBA mutations.

“This gives us confidence that we can use GBA mutations as a window to understand cognitive dysfunction in Parkinson’s disease,” says D J Vidyadhara, PhD, former postdoctoral associate at YSM and the study’s first author.

Cognitive deficits may start at the synapse

Next, the researchers dug further into what might be driving cognitive deficits. Through single-cell RNA sequencing of brain tissue, they found many genes associated with the function of synapses were downregulated in GBA and GBA-SNCA mutants. Synapses are the tiny junctions between neurons. To communicate, one cell releases little packages called vesicles that contain chemical messengers into the synapse, which are then received by the other cell.

The researchers further confirmed synapse loss in the cortex tissue of GBA and GBA-SNCA models.

“GBA mutations cause cognitive deficits by modulating synaptic vesicle trafficking,” says Chandra.

Chandra’s laboratory is conducting further research on the synaptic vesicles of GBA mutants and human neurons to better understand the pathology driving cognitive dysfunction.

While alpha-synuclein aggregations are a common hallmark of Parkinson’s disease, there is a growing recognition among neuroscientists that not all cases present with this pathology, says Chandra. “There are aspects of the disease that are not driven at all by alpha-synuclein pathology, and we should be investigating these.”