5 Genes May Underlie Lewy Body Dementia, With Overlap in Parkinson’s and Alzheimer’s

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by Joana Carvalho |

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Five genes appear to be involved in the onset and development of Lewy body dementia (LBD), a neurodegenerative disorder characterized by toxic protein clumps, known as Lewy bodies, inside brain cells, a study by a branch of the National Institutes of Health reported.

Some of these genes are also associated with Parkinson’s and Alzheimer’s, reinforcing the likelihood of ties between LBD and these two neurodegenerative diseases.

“Lewy body dementia is a devastating brain disorder for which we have no effective treatments. Patients often appear to suffer the worst of both Alzheimer’s and Parkinson’s diseases,” Sonja Scholz, MD, PhD, an investigator with the National Institute of Neurological Disorders and Stroke (NINDS) in the U.S. and the study’s senior author, said in a press release.

“Our results support the idea that this may be because Lewy body dementia is caused by a spectrum of problems that can be seen in both disorders,” Scholz said. “We hope that these results will act as a blueprint for understanding the disease and developing new treatments.”

Her team’s study, “Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture,” published in the journal Nature Genetics.

LBD, Parkinson’s, and Alzheimer’s are all  caused by the buildup of toxic protein clumps — alpha-synuclein aggregation in the case of LBD and Parkinson’s, and beta-amyloid and tau in the case of Alzheimer’s — inside nerve cells, which progressively kills these cells.

At an early stage, people with Lewy body dementia can experience hallucinations, mood swings, and other cognitive and behavioral problems commonly seen in people with Alzheimer’s.

Parkinson’s patients, as this diseases advances, also develop the mental and cognitive problems more typically associated with LBD or Alzheimer’s, the study noted.

“These neuropathological observations have led to the hypothesis, as yet unproven, that LBD lies on a disease continuum between Parkinson’s disease and Alzheimer’s disease,” its researchers wrote.

Several studies have proposed that certain genes are involved in the onset and development of LBD. These include SNCA, the gene that provides instructions to make alpha-synuclein, the main protein found in Lewy bodies, and several APOE gene variants also known to play a key role in Alzheimer’s.

“Compared to other neurodegenerative disorders, very little is known about the genetic forces behind Lewy body dementia. To get a better understanding we wanted to study the genetic architecture of Lewy body dementia,” said Bryan Traynor, MD, PhD, a senior investigator at the National Institute on Aging and study co-author.

Researchers examined and compared the genome — the DNA sequence of all human genes — of 2,981 LBD patients to that of 4,931 healthy individuals, matched with patients by age and serving as controls. (All involved were of European ancestry, and samples were collected from 44 sites, 17 in Europe and 27 across North America.)

Initial analyses revealed the DNA sequences of five genes — SNCA, APOE, GBA, BIN1, and TMEM175 — often differed between these two groups, suggesting these genes might figure in LBD.

While two of these genes (BIN1 and TMEM175) were never previously associated with Lewy body dementia, the other three had  been identified as possible genetic causes in previous studies. Importantly, some were also previously associated with Parkinson’s and Alzheimer’s, reinforcing again the idea of a connection among the three disorders.

Investigators confirmed these findings in a genome study of a second group of 970 LBD patients, compared with genomic analysis of 8,928 controls.

“These results provide a list of five genes that we strongly suspect play a role in Lewy body dementia,” Traynor said.

Evidence also supported certain variants of GBA, a gene that provides instructions to make an enzyme needed to breakdown sugary fats — and is a known risk factor for Parkinson’s — were likely also implicated in LBD.

To further explore the ties between LBD, Parkinson’s, and Alzheimer’s, researchers used the genetic data collected from LBD patients and combined it with genetic data from previous studies in Parkinson’s and Alzheimer’s patients. The aim here was to calculate the risk of Alzheimer’s or Parkinson’s being also diagnosed in people with Lewy body dementia.

LBD patients had a genetic profile that made them 66% more likely to develop Alzheimer’s, and 20% more likely to develop Parkinson’s, results showed. These risk scores remained significant even after adjusting for genes known to substantially contribute to Alzheimer’s (APOE variants) and to Parkinson’s (GBA, SNCA, and LRRK2).

No overlap risk was seen, however, between the genetic profiles of patients with Alzheimer’s and those with Parkinson’s, “implying that Alzheimer’s disease and Parkinson’s disease risk variants are independently associated with LBD risk.”

According to the team, the discovery of the intricate relationships between these neurodegenerative disorders “paves the way for precision medicine and has implications for prioritization of targets for therapeutic development.”

“Determining shared molecular genetic relationships among complex neurodegenerative diseases paves the way for precision medicine and has implications for prioritization of targets for therapeutic development,” the researchers wrote.

To support future work into LBD and similar disorders, the researches are sharing their data with the scientific community through an online database.

“These genomes constitute, to our knowledge, the largest sequencing effort in LBD to date and are designed to accelerate the pace of discovery in dementia,” they added.

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