Objective: To evaluate whether genetic variants in genes known to be associated with Abeta1-42 clearance contribute to the interval between ages at onset of parkinsonism and dementia in Lewy body disorders (LBD).

Background: Amyloid-beta1-42 (Abeta1-42) clearance deficits play a central role in the pathogenesis of Alzheimer disease (AD). Although Abeta1-42 pathology is also regularly observed in dementia associated with Lewy body disorders (encompassing Parkinson`s disease and dementia with Lewy bodies), the contribution of Abeta1-42 clearance deficits in these diseases is far less understood.

Methods: Single nucleotide polymorphisms (SNPs) in APOE, MME, and CST3 were analyzed in relation to demographic variables, clinical phenotypes and cerebrospinal (CSF) Abeta1-42 levels in a large cohort of 521 LBD patients (382 PDND, 102 PDD, 37 DLB).

Results: Genetic risk variants in the genes APOE, MME and CST3 are associated with reduced CSF levels of Abeta1-42 as well as a shorter interval of developing dementia. Of note, the observed differences in the interval between the onset of PD and the onset of dementia are of high clinical relevance, e.g. patients carrying two risk variants in the CST3 gene have an interval of 3 years whereas those carrying two protective variants manifest with dementia only after 7 years [table1].

Conclusions: This study suggests that genetic variants associated with Abeta1-42 clearance are involved in the pathogenesis of dementia in these disorders.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-variations-in-amyloid-beta1-42-clearance-proteins-determine-onset-of-dementia-in-parkinsons-disease-and-dementia-with-lewy-bodies/