Recent genetics studies of people with dementia and pathologically confirmed Lewy body disease is shedding light on how a person’s genes may influence their susceptibility to Lewy body dementias. A gene associated with a completely different disorder — Gaucher’s disease — may play a role.
The term Lewy body disease is used by researchers to indicate the presence of Lewy bodies in the brain, and it is the hallmark seen at autopsy in Parkinson’s disease and Lewy body dementia. People with Lewy body disease may have it alone or in combination with neuropathological changes of other diseases like Alzheimer’s or vascular disease. Gaucher’s disease is an inherited metabolic disorder in which lipids (fatty materials including oils, fatty acids, and steroids) accumulate in the spleen, liver, lungs, bone marrow and brain. The disease is caused by genetic changes (mutations) in both copies of the GBA gene. Disorders with mutations in both copies of a gene, one contributed from each parent, is called an autosomal recessive disorder.
Researchers subsequently noted that people with Gauacher’s disease were more likely to develop Parkinson’s disease than normal subjects, which led to studies that revealed that the GBA genetic mutations are present in 7 percent of people with Parkinson’s disease and individuals with this mutation have a five- to sixfold increased risk of developing Parkinson’s disease. It is important to note that most people with genetic changes in one copy of the GBA gene remain asymptomatic, meaning they do not develop symptoms of Lewy body diseases. Previously, several small studies had failed to clarify the relationship between dementia with Lewy bodies (DLB) and the GBA gene.
In a recent large study researchers investigated 562 subjects who were diagnosed during life with Alzheimer’s disease or dementia. Nearly 400 healthy controls were also included in the study. Pathological diagnoses were made upon autopsy and subjects were classified as having Alzheimer’s disease alone, Alzheimer’s disease and Lewy body disease, or pure Lewy body disease. The study excluded people diagnosed with Parkinson’s disease who later developed dementia, so the those with pure Lewy body disease may not have displayed the clinical syndrome of DLB while living.
This new research reveals that 7.6 percent of the 80 subjects with pure Lewy body disease (no co-existing Alzheimer’s pathology) carried a GBA mutation, double that found in 3.6 percent of the 231 subjects with both Lewy body and Alzheimer’s pathology who carried a mutation, and much higher than the less than one percent of the 251 subjects with Alzheimer’s pathology alone who were carriers. The frequency of GBA mutations in the 381 healthy controls was nearly identical to those with Alzheimer’s disease alone, less than one percent. Given that previous studies found that seven percent of Parkinson’s disease subjects carry this mutation, this gene harbors the most commonly found mutations in both Lewy body dementia and Parkinson’s disease.
Until now, research had not yet revealed many clues as to why some individuals have AD or Lewy body pathology alone or in combination. This new study confirms that the GBA mutation is a risk factor across the Lewy body spectrum, but not in Alzheimer’s disease, and that Parkinson’s and DLB may be more similar to one another in genetics and pathology than either disease is to the Lewy body variant of AD.
Members of LBDA's Scientific Advisory Council who collaborated on this study include Debby Tsuang, MD, MSc, James B. Leverenz, MD, Oscar L. Lopez, MD, Doug Galasko, MD, and Cyrus Zabetian, MD, MS. The study was first published online on October 3, 2012 in Neurology and was funded by grants from the Department of Veterans Affairs and the National Institutes of Health.