Lewy bodies are abnormal clumps of protein that build up inside nerve cells in the brain. Their primary ingredient is a misfolded form of a protein called alpha-synuclein, and when enough of them accumulate, they damage and eventually kill the neurons they occupy. Lewy bodies are the hallmark of two major conditions: Parkinson’s disease and Lewy body dementia, the second most common form of dementia after Alzheimer’s, accounting for about 5 percent of all dementia cases in older adults.
What Lewy Bodies Are Made Of
Alpha-synuclein is a normal protein found in healthy brains, concentrated at the junctions where nerve cells communicate. Problems begin when this protein misfolds, meaning it takes on the wrong three-dimensional shape. Once misfolded, alpha-synuclein molecules stick together, forming increasingly larger clusters: first small clumps called oligomers, then longer chains called fibrils, and eventually dense masses visible under a microscope.
But Lewy bodies aren’t just balls of alpha-synuclein. They contain dozens of other proteins, including components of the cell’s waste-disposal machinery (the systems normally responsible for breaking down and recycling damaged proteins), proteins associated with the cell’s internal skeleton, heat shock proteins that act as molecular chaperones, and fragments of cellular structures like mitochondria. Researchers have described Lewy bodies as starting out as a disorganized mass of tiny internal compartments called vesicles, which gradually become more structured over time, with lipids (fats) concentrated in the center and concentric rings of alpha-synuclein and other proteins layered around them.
How They Form Inside Neurons
The formation of a Lewy body appears to be more than just loose proteins clumping together in the cell’s fluid interior. Evidence points to a process driven by the accumulation of vesicles, the small membrane-bound packages that neurons use to shuttle materials around internally. When alpha-synuclein misfolds, it can block these vesicles from reaching their destinations, particularly the handoff between the cell’s manufacturing center and its shipping department. Vesicles pile up, and the growing mass begins to attract other cellular components.
Mitochondria, the structures that generate energy for the cell, are drawn toward the developing Lewy body. Early on, they cluster in a ring around its edges. As the Lewy body grows and takes up more of the neuron’s interior space, it pulls the mitochondria inward, destroying their structure in the process. This means the neuron progressively loses its energy supply. At the same time, misfolded alpha-synuclein can trigger a stress response in the part of the cell responsible for building new proteins, pushing the neuron closer to death.
Whether Lewy bodies themselves are directly toxic, or whether they represent the cell’s attempt to wall off dangerous material, remains an open question. The smaller, soluble clumps of alpha-synuclein that form before a full Lewy body develops may actually be more damaging than the mature inclusions.
Where They Appear in the Brain
Lewy bodies don’t strike one area uniformly. They can develop across multiple brain regions, and the symptoms a person experiences depend on which regions are most affected:
- Midbrain and basal ganglia: These regions control movement. Lewy body damage here causes the tremor, stiffness, and slow movement seen in Parkinson’s disease.
- Cerebral cortex: Responsible for thinking, language, and processing information. Damage here drives cognitive decline.
- Limbic cortex: Involved in emotions and behavior. Lewy bodies in this area contribute to depression, apathy, and anxiety.
- Hippocampus: Essential for forming new memories, though memory problems in Lewy body disease often appear later than in Alzheimer’s.
- Brainstem: Regulates sleep and alertness. Damage here can cause vivid, physically active dreams years before other symptoms emerge.
- Olfactory pathways: Loss of smell is one of the earliest signs of Lewy body disease, often showing up a decade or more before diagnosis.
The Diseases Lewy Bodies Cause
Lewy bodies are central to what researchers increasingly call “Lewy body disease,” a spectrum that includes Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies (DLB). The traditional distinction between these conditions is largely based on timing: if movement symptoms come first and cognitive decline follows later, it’s labeled Parkinson’s disease dementia. If cognitive problems and hallucinations appear first, or alongside movement issues, it’s called dementia with Lewy bodies.
That distinction is fading. A large longitudinal study found that patients diagnosed with either condition show virtually identical rates of cognitive and motor decline over five years. Brain imaging reveals the same patterns of reduced activity in the back of the brain, the same loss of dopamine-producing nerve pathways, and the same depletion of a chemical signaling system originating deep in the brain. The neuropsychiatric profiles are strikingly similar too: depression affects roughly half of patients with either diagnosis, hallucinations occur in 54 to 76 percent, and apathy in about 55 percent. The one notable difference is that Alzheimer’s-type brain changes are found alongside Lewy body pathology more often in DLB (about 68 percent of cases) than in Parkinson’s disease dementia (about 34 percent).
Why Lewy Bodies Cause Hallucinations
One of the most distinctive symptoms of Lewy body disease is recurrent visual hallucinations, often vivid and detailed. People may see animals, people, or objects that aren’t there. This happens because Lewy bodies don’t just kill neurons in isolated spots. They damage the connections between multiple brain regions involved in vision and perception simultaneously. As neurons die and their connections weaken across the visual processing areas in the back of the brain, the memory centers in the temporal lobe, and the frontal cortex, the brain’s ability to correctly interpret what the eyes are seeing breaks down. The system becomes unstable, and the brain essentially fills in gaps with stored images, generating perceptions that have no basis in the real world. Chemical signaling disruptions across widely branching nerve fibers make these perception networks even less reliable.
How Lewy Body Disease Is Diagnosed
Diagnosis relies on a combination of clinical features and, increasingly, biological testing. The 2017 diagnostic criteria identify four core symptoms that doctors look for: fluctuating attention and alertness (where a person may seem sharp one hour and confused the next), recurrent detailed visual hallucinations, a sleep disorder called REM sleep behavior disorder (where people physically act out their dreams), and Parkinson’s-like movement symptoms such as tremor, stiffness, or slowed movement. Two or more of these core features point to a probable diagnosis.
Early in the disease, significant memory loss may not be present. Instead, difficulties with attention, problem-solving, and visual-spatial tasks (like judging distances or recognizing shapes) tend to be more prominent. Other common features include extreme sensitivity to antipsychotic medications, frequent falls, drops in blood pressure upon standing, constipation, and excessive daytime sleepiness.
A newer diagnostic tool, the alpha-synuclein seed amplification assay, can detect tiny amounts of misfolded alpha-synuclein in spinal fluid. Across multiple laboratories, this test has shown sensitivity between 86 and 96 percent and specificity between 93 and 100 percent, making it one of the first reliable biological tests for Lewy body disease in living patients.
Current Treatment and Experimental Therapies
No treatment currently stops or reverses Lewy body formation. Management focuses on symptoms. For cognitive problems like confusion and memory difficulties, a medication originally developed for Alzheimer’s disease, rivastigmine, is the only drug specifically approved by the FDA for Parkinson’s disease dementia. It works by boosting levels of a chemical messenger involved in memory and attention. Side effects can include nausea, diarrhea, and dizziness. For movement symptoms, levodopa (a Parkinson’s medication) can help with walking, getting out of bed, and general mobility, typically starting at a low dose and increasing gradually. Other Parkinson’s drugs are used less often because people with Lewy body disease tend to experience more side effects from them.
Several experimental therapies are in clinical trials aimed at the root cause: alpha-synuclein itself. One approach uses vaccines designed to train the immune system to recognize and clear misfolded alpha-synuclein before it accumulates. Another uses lab-made antibodies delivered by infusion that bind directly to alpha-synuclein clumps. Prasinezumab, the furthest along in this category, is in a Phase IIb trial after preclinical studies showed it could reduce toxic forms of the protein and prevent its spread between cells. Other strategies aim to reduce the amount of alpha-synuclein the brain produces in the first place, or to use small molecules that block the protein from clumping. None have yet proven effective enough for approval, but they represent the first serious attempts to treat the disease at its source rather than manage its downstream effects.