Parkinson’s disease is best known for its impact on movement—tremors, stiffness, and slowed motion.
But many people living with the condition also experience cognitive problems such as poor concentration and forgetfulness.
Over time, these symptoms can progress to dementia, which is often one of the most feared complications for patients.
For years, scientists believed that both the movement and memory problems in Parkinson’s disease came from the buildup of a protein called alpha-synuclein in the brain.
But a new study published in Nature Communications has uncovered a different explanation for the cognitive side of the disease.
Researchers at Yale School of Medicine found that mutations in a gene called GBA, which are already known to raise the risk of developing Parkinson’s, may be directly responsible for cognitive decline.
These mutations seem to interfere with the way brain cells communicate, leading to memory and thinking problems that are separate from the motor symptoms caused by alpha-synuclein.
The team tested this idea in a series of experiments using mouse models. Some mice were genetically altered to produce high levels of alpha-synuclein, while others carried GBA mutations, and a third group carried both.
The results were clear: movement problems were linked to alpha-synuclein, while memory and learning deficits were tied to GBA mutations.
Mice with GBA mutations—whether alone or combined with alpha-synuclein—showed cognitive problems as early as three months of age, long before major motor issues appeared.
This discovery highlights that Parkinson’s disease does not arise from a single pathway in the brain. Instead, its motor and cognitive symptoms are driven by different mechanisms.
“This gives us confidence that we can use GBA mutations as a window to understand cognitive dysfunction in Parkinson’s disease,” said first author D. J. Vidyadhara, PhD.
The researchers then dug deeper to understand how GBA mutations cause these cognitive problems. Using advanced genetic analysis, they discovered that many genes linked to synapses—the junctions where nerve cells communicate—were less active in GBA mutant brains. Synapses rely on tiny packages called vesicles to deliver chemical messages from one cell to another. In the GBA mutant models, these vesicles were disrupted, leading to weakened communication between neurons.
Further analysis confirmed a loss of synapses in the brain’s cortex, a region crucial for memory and thought. “GBA mutations cause cognitive deficits by modulating synaptic vesicle trafficking,” explained senior investigator Sreeganga Chandra, PhD, professor of neurology and neuroscience at Yale.
The findings suggest that dementia in Parkinson’s disease may not always be caused by protein buildup, but also by faulty communication between brain cells driven by genetic mutations.
This opens the door to new ways of studying and potentially treating cognitive decline in Parkinson’s patients—focusing not only on alpha-synuclein but also on the GBA pathway.
