Genetic risk for PD-related cognitive impairment and it disease mechanisms

University Of Washington, Seattle WA

Investigators

Linked publications & trials

Abstract

PROJECT 1 (MONTINE): Abstract Genetic risk for PD-related cognitive impairment and its disease mechanisms The inaugural PANUC award was funded to pursue the association of three candidate genes with cognitive impairment and dementia in PD: APOE ?4 allele and variants in SNCA and MAPT; to these we added GBA and LRRK2 mutations. With our collaborators, we demonstrated that cognitive impairment and dementia are significantly more common among PD patients who carry APOE ?4 or GBA variants, less common in patients with LRRK2 mutations, and not associated with variants in MAPT or SNCA. In this project our approach will be to bring insight to disease mechanisms by determining the corresponding molecular pathology. During the current PANUC award, we and others used standard histopathologic criteria for Lewy bodies (LB) or Alzheimer's disease (AD). Unfortunately, this approach has led to unexpected and conflicting results for GBA variants and APOE ?4 in PDD in part because some studies were limited by low number of cases or inconsistent attention to genetic risk. Specific Aim 1 proposes to fill these gaps in knowledge by regional quantification of neurotoxic proteins and synaptic degeneration using a novel technique developed by our laboratory coupled with a large, multisite autopsy cohort assembled by PANUC. Specific Aim 2 reflects that although successful with our candidate gene approach during the inaugural PANUC award, we propose to expand gene discovery for cognitive impairment and dementia in PD by evaluating additional candidate genomic regions recently identified by the PDCGC, and by determining genetic influences on longitudinal change in cognition measured prospectively using consensus assessments.