Lewy body dementia (LBD) is a complex, progressive brain disorder, second only to Alzheimer’s disease as a common neurodegenerative dementia. It accounts for an estimated 10% to 20% of all dementia cases in the elderly population. LBD is defined by a unique combination of cognitive, movement, and sleep disturbances, which complicates diagnosis and care. Understanding the causes of LBD is challenging because it often overlaps pathologically with other neurodegenerative conditions. This article examines whether LBD is inherited, or hereditary, by exploring its underlying biology and genetic associations.
Understanding Lewy Body Dementia
The distinguishing feature of LBD is the presence of abnormal protein deposits known as Lewy bodies, which accumulate inside nerve cells in the brainstem and cortex. These deposits are primarily composed of a misfolded protein called alpha-synuclein. The accumulation of alpha-synuclein disrupts normal cell function and communication, leading to the varied symptoms that characterize the disease.
LBD is clinically defined by a trio of core symptoms that help distinguish it from other dementias.
Core Symptoms of LBD
Cognitive Fluctuations
The first core symptom is pronounced cognitive fluctuations, involving unpredictable changes in attention, concentration, and alertness that shift significantly throughout the day. Patients may experience moments of lucidity followed by periods of confusion or staring into space.
Visual Hallucinations
The second core feature is recurrent, well-formed visual hallucinations, where individuals see detailed and realistic things that are not actually present. This symptom often appears early in the disease course.
Parkinsonism
The third defining feature is parkinsonism, which includes slowness of movement, muscle stiffness or rigidity, and a shuffling walk. While motor symptoms vary in severity, a resting tremor is less frequent in LBD compared to Parkinson’s disease.
The Direct Answer: Familial Versus Sporadic LBD
In the vast majority of cases, Lewy body dementia is considered sporadic, meaning it occurs without a clear pattern of inheritance or known family history. Sporadic LBD accounts for the overwhelming portion of diagnoses and is believed to arise from a complex interplay of environmental factors and genetic risk variants. For most individuals, the disease is not passed down directly through a single, causative gene.
A small fraction of cases are categorized as familial LBD, where the disease appears to be directly inherited within a family. This rare form is linked to specific, highly penetrant genetic mutations that almost guarantee the condition’s development. Familial cases often present with an earlier age of onset and may differ in clinical presentation compared to the sporadic form.
The distinction between sporadic and familial LBD is based on whether a direct genetic cause can be identified. While a family history of LBD or Parkinson’s disease increases an individual’s overall risk, this elevation usually reflects the presence of subtle genetic risk factors rather than a single, dominant inherited mutation.
Known Genetic Links and Associated Genes
The genetic landscape of LBD involves rare mutations that directly cause the disease and common gene variants that increase susceptibility.
Key Genes Associated with LBD
The SNCA gene provides instructions for making the alpha-synuclein protein. Specific mutations or duplications in SNCA are known to cause rare familial forms of LBD, often through an autosomal dominant inheritance pattern. Overexpression of alpha-synuclein, such as from a gene triplication, typically results in a more severe disease and an earlier age of onset.
The GBA gene is another significant genetic factor and a strong risk factor for LBD. Variants in GBA do not directly cause LBD but significantly increase the likelihood of developing the condition. This gene is involved in producing an enzyme that helps cells recycle waste, suggesting a role for impaired cellular waste management in LBD pathology.
LBD shares genetic risk factors with other neurodegenerative disorders. The APOE gene, particularly the $\epsilon 4$ allele, is a strong genetic risk factor for LBD, similar to its association with Alzheimer’s disease. The presence of this allele increases the risk but does not guarantee disease development. Other genes, including BIN1, TMEM175, and SCARB2, also contribute to overall LBD risk.
Non-Genetic Factors Influencing Risk
While genetics play a role, the sporadic nature of most LBD cases highlights the influence of factors external to direct inheritance. Advanced age is the biggest risk factor, with the disease typically beginning after age 50 and risk increasing significantly after age 60. Men are statistically more likely to develop LBD than women.
Several existing health and neurological conditions are strongly associated with a higher risk. Rapid Eye Movement (REM) sleep behavior disorder (RBD), where people physically act out vivid dreams, is a significant predictor and can precede LBD diagnosis by many years. A history of cardiovascular conditions, such as stroke, is also linked to increased risk.
Other potential risk factors include a history of depression or anxiety. Environmental exposures, such as to certain pesticides, have been suggested in ongoing research but are not yet established as causes. Sporadic LBD is thought to arise from a complex combination of these non-genetic factors interacting with a person’s underlying genetic makeup.