Abstract
Background. Parkinson's disease (PD) and Alzheimer's disease (AD) share pathological features, including amyloid-beta pathology. Amyloid-beta peptide is generated by sequential proteolysis of amyloid precursor protein (APP), and genetic variations in the processing pathway genes have been found to increase the risk of AD; however, the contribution in PD is unknown. Methods. The aim of this study was to investigate whether candidate polymorphisms in five genes (ADAM10, BACE1, BACE2, PSEN2, and CLU) involved in the APP processing pathway affect PD risk in a population-based cohort of patients with incident PD and control subjects from the Norwegian ParkWest study. Results. We found an association of rs638405 in BACE1 with increased risk of PD, thus providing a novel link, at the genetic level, between amyloid-beta pathology and PD.
Highlights
Parkinson’s disease (PD) and Alzheimer’s disease (AD) are the two most common age-related neurodegenerative diseases
The BACE1 rs638405 major allele has been associated with increased risk for late-onset AD (LOAD), and several studies have observed that this effect is enhanced in ApoE-ε4 carriers [7, 8, 21, 22]
We tested for a possible link between rs638405 and ApoE-ε4 in our cohort and found that ApoE-ε4 did not add to the effect of rs638405 on PD risk
Summary
Parkinson’s disease (PD) and Alzheimer’s disease (AD) are the two most common age-related neurodegenerative diseases. In addition to Lewy body pathology, typical AD related morphological changes, including amyloid-beta (Aβ) pathology, have been proposed to be involved in the pathogenesis of PD dementia. According to the amyloid cascade hypothesis, an imbalance between Aβ production and clearance plays a critical role in AD pathogenesis Genetic variations in both APP and the genes encoding enzymes of the APP processing pathway are linked to modified risk of AD [6,7,8], elevated APP production [6], and changes in CSF Aβ levels [9,10,11]. In light of the occurrence of Aβ pathology in PD, we sought to determine if genetic variations within five genes involved in APP processing and clearance (ADAM10, BACE1, BACE2, PSEN2, and CLU1) are risk factors for PD in an unselected, population-based cohort of patients with incident PD and age-matched controls. We found an association of rs638405 in BACE1 with increased risk of PD, providing a novel link, at the genetic level, between amyloid-beta pathology and PD
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