What Causes Lewy Body Dementia
Lewy body dementia is caused by the abnormal accumulation of alpha-synuclein protein within brain cells, forming pathological deposits called Lewy bodies, along with alpha-synuclein-immunoreactive neurites and diffuse cytoplasmic immunoreactivity. 1
Pathological Mechanism
The disease follows a characteristic progression pattern in the brain:
- Initial deposition begins in the medulla oblongata, pontine tegmentum, and olfactory system 1, 2
- Secondary involvement spreads to the substantia nigra and other deep gray nuclei 1, 2
- Final stage shows deposition in the cortex, where neocortical Lewy body disease is considered adequate explanation for cognitive impairment or dementia 1
The distribution of Lewy bodies can be classified into five categories: none, brainstem-predominant, limbic (transitional), neocortical (diffuse), or amygdala-predominant 1. Importantly, brainstem-predominant Lewy body dementia in the setting of cognitive impairment should prompt consideration of other diseases, while amygdala-predominant Lewy body dementia typically occurs in the context of advanced Alzheimer's disease 1.
Coexisting Pathology
Lewy body dementia frequently coexists with Alzheimer's disease pathology, particularly in older individuals. 1 This overlap suggests that many patients have mixed pathology, with both alpha-synuclein deposits and amyloid plaques contributing to their clinical presentation 3. The presence of both Lewy bodies and amyloid plaques with deficiencies in both acetylcholine and dopamine neurotransmitters suggests that dementia with Lewy bodies represents the middle of a disease spectrum ranging from Alzheimer's disease to Parkinson's disease 3.
Risk Factors
While the provided evidence focuses primarily on the pathological mechanisms rather than risk factors, age is the best-studied and strongest risk factor for dementia generally 4. The disease predominantly affects older people, with prevalence rates increasing steeply with age 4.
Clinical Implications
Understanding the underlying pathology is crucial because:
- Immunohistochemistry for alpha-synuclein is strongly preferred over H&E staining for detecting Lewy bodies due to greater sensitivity 1
- The progressive nature of alpha-synuclein deposition explains why the first brain changes occur long before the first memory complaint appears 4
- Alpha-synuclein-specific biomarkers in spinal fluid, skin, plasma, and brain imaging are in active development with some available for clinical use 5
The pathological process spans decades, with autosomal dominant forms showing a series of pathophysiological changes over decades in cerebral spinal fluid biochemical markers, brain metabolism, and progressive cognitive impairment 4. This means that by the time clinical symptoms appear, the disease process has already been underway for a substantial period 4.