References of "International LBD Genomics Consortium"
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See detailEvaluation of SORL1 in Lewy Body Dementia Identifies No Significant Associations
Ray, Anindidta; Reho, Paolo; Shah, Zalak et al

in Movement Disorders (2022)

Lewy body dementia (LBD) is a clinically heterogeneous neurodegenerative disorder characterized by parkinsonism, visual hallucinations, fluctuating mental status, and rapid eye movement sleep behavior ... [more ▼]

Lewy body dementia (LBD) is a clinically heterogeneous neurodegenerative disorder characterized by parkinsonism, visual hallucinations, fluctuating mental status, and rapid eye movement sleep behavior disorder. LBD lies along a spectrum between Parkinson's disease and Alzheimer's disease, and recent evidence suggests that the genetic architectures of these age-related syndromes are intersecting. In summary, we did not find a significant enrichment of rare, damaging SORL1 mutations in our well-powered LBD cohort. Our data set is, to our knowledge, the largest genome-sequence cohort in this understudied disease. Although it is possible that an association was missed due to allelic heterogeneity, our findings indicate that caution should be exercised when interpreting SORL1 mutations in LBD, as the current evidence does not conclusively support an association with disease risk. [less ▲]

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See detailGenetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups
Kaivola, Karri; Shah, Zalak; Chia, Ruth et al

in Brain: a Journal of Neurology (2021), awab402

The APOE locus is strongly associated with risk for developing Alzheimer’s disease and dementia with Lewy bodies (DLB). In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein ... [more ▼]

The APOE locus is strongly associated with risk for developing Alzheimer’s disease and dementia with Lewy bodies (DLB). In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2,466 DLB cases versus 2,928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for DLB in patients without APOE ε4 (p = 6.58 x 10−9, OR = 3.41, 95% CI = 2.25–5.17), but not with DLB with APOE ε4 (p = 0.034, OR = 1.87, 95%, 95% CI = 1.05–3.37). We then divided 495 neuropathologically examined DLB cases into three groups based on the extent of concomitant Alzheimer’s disease co-pathology: pure DLB (n = 88), DLB with intermediate Alzheimer’s disease co-pathology (DLB + iAD, n = 66), and DLB with high Alzheimer’s disease co-pathology (DLB + AD, n = 341). In each group, we tested the association of the APOE ε4 against the 2,928 neurologically healthy controls. Our examination found that APOE ε4 was associated with DLB + AD (p = 1.29x10−32, OR = 4.25, 95% CI = 3.35–5.39) and DLB + iAD (p = 0.0011, OR = 2.31, 95% CI = 1.40–3.83), but not with pure DLB (p = 0.31, OR = 0.75, 95% CI = 0.43–1.30). In conclusion, though deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure DLB, but rather implicate GBA as the main risk gene for the pure DLB subgroup. [less ▲]

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