Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies

Abstract

Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson’s and Alzheimer’s diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.

LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance

“…Therefore, further validation of LIMP-2 mutations on a larger cohort of patients with PD will be required. A recent report describing a significant association of the SCARB2 locus with dementia with LBs supports our findings of synucleinopathy in murine brain lacking LIMP-2 (19).…”

The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder

“…These and previous results ,Saunders-Pullman, et al, 2015 further suggest that RBD may have a distinct genetic background; it is associated with GBA mutations , but unlike PD it is not associated with LRRK2 mutations ,Saunders-Pullman, et al, 2015, and unlike DLB it is not associated with the APOE 4 allele. Thus far, GBA, SCARB2, and potentially SNCA overlap between RBD, PD and DLB (Figure 1) (Bras, et al, 2014. Whether RBD has additional, unique genetic factors that were not identified in PD or DLB cohorts is still to be determined.…”

“…Therefore, there are two possible explanations for the lack of association between the APOE 4 allele and conversion to DLB in our cohort. First, as previously suggested (Bras, et al, 2014), it is possible that the association of the APOE 4 allele with DLB is due to the component of DLB patients who also have a tauopathy, and that the association of RBD with DLB is with those who have more pure synucleinopathy.…”

Epigenetic considerations of the APOE gene

“…alzgene.org/). Besides AD and CVD, genetic studies have also connected APOE and its ε2/ε3/ε4 alleles to multiple physiological conditions and disorders, including aging (18,19), diabetes (20), dysbetalipoproteinemia (21), frontotemporal dementia (22), fragile X-associated ataxia (23), glomerulopathy (24), Lewy body dementia (25), metabolic syndrome (26), retinal-related disorders (27) disease (28), posttraumatic stress disorder (29), primary progressive aphasia (30), schizophrenia (31), stroke (32), traumatic brain injury (33), and vascular dementia (34).…”