Parkinson’s disease, Lewy body dementia, and Alzheimer’s disease are considered part of the same disease spectrum because their symptoms and brain pathologies often overlap. But genetic data backing up this theory has been sparse. Now, a whole-genome-sequencing based, genome-wide association study puts some meat on its bones. In the February 15 Nature Genetics, researchers led by Sonja Scholz at the National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, report five LBD risk loci. Three—GBA, APOE, and SNCA—were known; two—BIN1 and TMEM175—are new to LBD research. APOE and BIN1 are AD risk genes, as well, whereas variants in GBA, SNCA, and TMEM175 increase risk for PD. A larger sample will be needed to confirm the two new LBD risk loci, researchers said.
- WGS identifies five LBD loci—two are new.
- Three are known PD genes, two are AD genes.
- People who carried AD variants died sooner; people with PD variants developed LBD at a younger age.
“Neuropathological features of multiple dementias co-existing in a person is known; these results suggest that does not occur by chance,” Philippe Amouyel, Institut Pasteur de Lille, France, wrote to Alzforum (full comment below). Julie Williams at Cardiff University, Wales, U.K., agreed. “This is pretty hard evidence that there are shared factors contributing to these three diseases,” she told Alzforum.
Memory loss and worsening cognition loom large in AD, LBD, and sometimes late-stage PD. People with PD lose motor function early on, and people with later-stage LBD do, as well. As for neuropathology, coexisting Lewy bodies, amyloid plaques, and neurofibrillary tau tangles bridge PD and AD in some people with LBD (Sep 2016 news; Kon et al., 2020). “Stitching the three diseases together on a spectrum accounts for the clinical similarities,” said Clifton Dalgard, Uniformed Services University, Bethesda. Dalgard was a senior author on the study, along with Scholz, Bryan Traynor and Raphael Gibbs at the National Institute on Aging, Bethesda, Owen Ross at the Mayo Clinic, Jacksonville, Florida, and Adriano Chiò at the University of Turin, Italy.
LBDs encompass both dementia with Lewy bodies (DLB), which tends to present initially with cognitive symptoms, and Parkinson’s disease dementia (PDD), which begins as a movement disorder. A previous GWAS, led by Rita Guerreiro and Jose Bras, then at University College, London, linked GBA, APOE, and SNCA variants to DLB (Dec 2017 news; Dec 2015 news). In this new, whole-genome-sequencing (WGS) study, researchers combined DLB and PDD cases under the blanket term LBD. This was controversial: Several researchers were concerned that pooling the two may muddy the results.
Searching for Commonalities. Lewy body dementia GWAS hits were combined with expression data to identify risk variants, calculate genetic risk scores, and examine faulty pathways that underlie LBD, AD, and PD. [Courtesy of Chia et al., Nature Genetics, 2021.]
For this study, researchers combined samples from 2,981 people with clinically diagnosed LBD and from 2,173 healthy people of European ancestry from 27 sites in North America and 17 in Europe. Adding genome data from 1,016 volunteers of European ancestry from the NIA cohorts and the Accelerating Medicine Partnership–Parkinson’s Disease Initiative and 1,202 over age 80 in the Wellderly cohort (Erikson et al., 2016) generated a total of 4,391 controls available for analysis. LBDs are difficult to diagnose clinically due to their overlapping symptoms with other dementias. To get around that, the researchers selected for pathologically confirmed LBD cases, which accounted for 69 percent of the total.
Co-first authors Ruth Chia at NIA and Marya Sabir at NINDS sequenced each participant’s entire genome, ultimately analyzing 2,591 LBD cases and 4,027 controls. Whole-genome sequencing allows researchers to tease out both common and rare variants. “This allows us to detect associations with disease that we may have otherwise missed,” Dalgard explained.
The researchers then correlated variants with an LBD diagnosis, using a cutoff P value of less than 5 × 10−8. Only five risk loci prevailed (see image below).
Next, Chia and colleagues cross-checked the associations against an additional 970 LBD and 8,928 controls chosen from a previous cohort from Scholz and colleagues that included 468 DLB cases, 57 PDD cases, and 591 controls, and from the previous DLB GWAS cohort, which included 1,743 DLB cases and 4,454 controls (Sabir et al., 2019; Guerreiro et al., 2017). Among these samples, Chia found that only the associations between LBD and APOE and SNCA held. However, in a meta-analysis of the combined discovery and replication cohorts, all five loci strongly associated with LBD.
Next, the researchers searched for rare variants found in fewer than 1 percent of cases. Only GBA came up, meaning that both common and rare variants in this gene are linked to the disease (see image below).
High Five. Multiple common variants (red dots) at five loci survived statistical analysis in an LBD GWAS (top). Known LBD risk genes are green, new ones are black. GBA also associated with LBD in a search for rare variants (bottom). [Courtesy of Chia et al., Nature Genetics, 2021.]
All five genes previously have been tied to other neurodegenerative diseases. ApoE and BIN1, which encodes an endosomal trafficking protein, are two of the strongest risk genes for late-onset AD. GBA, encoding lysosomal enzyme β-glucocerebrosidase; TMEM175, encoding a lysosomal potassium channel; and the α-synuclein gene SNCA are PD risk genes. There was no genetic synergy between AD and PD risk, meaning that disease alleles independently affected LBD risk.
The five identified genes appear to point to the lysosomal pathway as a nexus for LBD pathology. ApoE and GBA variants mishandle lipids, impairing their metabolism and clearance from lysosomes (Lee et al., 2021). TMEM175 stabilizes lysosomes and reduces buildup of phosphorylated α-synuclein (Jinn et al., 2017). In people, the rs6733839 Bin1 SNP, the variant identified in the current study, regulates microglial function (Nov 2019 news). In rat neurons, lack of Bin1 revs up endocytosis and promotes tau misfolding and aggregation (Oct 2016 news). In mice, Bin1 deficiency impairs synaptic transmission and spatial memory (Mar 2020 news).
“Neurodegenerative disease risk genes commonly impair essential cellular pathways, such as protein degradation and endosomal trafficking, that are crucial in many age-related diseases,” Scholz noted. Dalgard agreed. “Both BIN1 and TMEM175 are involved with either eating up protein trash in the brain or processing trash that has been eaten up,” he told Alzforum.
Chia, Sabir, and colleagues wondered if having the BIN1 or TMEM175 variant correlated with amyloid plaque or neurofibrillary tangle load. They counted plaques in 700 of the LBD cases using the CERAD criteria, and tangles in 1,459 cases using postmortem Braak staging. There was no association for the TMEM175 variant; however, people who carried the rs6733839-T BIN1 SNP had more tangles than those without the variant. “An association between BIN1 and tangles in the brain was also reported for AD cases, which seems to reinforce the role of this interaction in dementia,” wrote Jean-Charles Lambert, Institut Pasteur de Lille, France (full comment below).
To dig deeper into how the five loci were driving LBD risk, the researchers turned to expression data. They used co-localization statistics called Coloc to ask if higher risk and altered gene expression could both be traced back to the same variant (Giambartolomei et al., 2014). They examined expression quantitative trait loci (eQTL) data from two datasets. eQTLGen draws on blood-expression data from 31,684 healthy people, and PsychENCODE catalogs brain eQTLs from 1,387 healthy people and those with autism, bipolar disorder, and schizophrenia. Only eQTLs at the TMEM175 and the SNCA loci emerged; each regulated their respective gene’s expression in the blood and brain. Curiously, the SNCA eQTL regulates an antisense transcript that the authors found to be specifically expressed in neurons. The authors believe the LBD variant increases SNCA antisense expression, suppressing α-synuclein production. “This insight may open up a new therapeutic avenue for modifying disease risk by fine-tuning SNCA expression,” Scholz wrote to Alzforum.
To probe the variants for effects on cognition, the scientists calculated a polygenic risk score based on the five WGS hits and 117 others that fell just under the cutoff of statistical significance. In the 214 cases for whom the authors had Clinical Dementia Rating scores, they saw that those with the highest risk scores had the most severe dementia.
Previously, researchers had found that Parkinson’s patients who had many genetic risk factors for AD were more likely to develop aggressive PD with dementia than those without AD genetic risk (Sandor et al., 2021). Here, Chia found that people who had a higher AD risk score died sooner after their LBD diagnosis, and at a younger age. "Genetic risk factors for Alzheimer's result in quicker decline in both Parkinson's and now Lewy body dementia," Williams told Alzforum. "We need to know more about these mechanisms of action because they span across different dementias."
Grouping the LBD-linked variants into molecular pathways, Chia, Sabir, and colleagues found that most of the five definite and 117 possible variants were involved in Aβ and endocytosis regulation, tau binding, and protein-lipid complexes (see image at right).
Knowing pathways that are affected in multiple forms of dementia can inform clinical trial design and facilitate drug repurposing. “We hope shared gene variants and disease pathways could be targeted by disease-modifying therapies,” Scholz said. Other agree. “Including subgroups of LBD patients in AD and PD drug trials would uncover if they can also benefit,” Amouyel wrote. “If you have preventative measures that can help brain tissue recycle trash better, then we could prevent all three diseases at once,” Dalgard added.
Chia and colleagues deposited their GWAS data on NCBI’s database of Genotypes and Phenotypes.—Chelsea Weidman Burke
- Tau Deepens Cognitive Trouble in Lewy Body Diseases
- First Genome-Wide Association Study of Dementia with Lewy Bodies
- Genetics of DLB: Setting Up to Fill a Mostly Empty Canvas
- Cell-Specific Enhancer Atlas Centers AD Risk in Microglia. Again.
- Lack of BIN1 Sows Tau Trouble for Neurons
- Alzheimer’s Gene BIN1 Promotes Synaptic Transmission
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