Dataset Information

Effects of Alzheimer's genetic risk scores and CSF biomarkers in de novo Parkinson's Disease.

ABSTRACT: Coexisting Alzheimer's disease (AD) pathology is common in Parkinson's disease (PD). However, the implications of genetic risk scores (GRS) for AD have not been elucidated in PD. In 413 de novo PD and 195 healthy controls from the Parkinson's Progression Marker Initiative database, the effects of GRS for AD (GRS-AD) and PD (GRS-PD) on the risk of PD and longitudinal CSF biomarkers and clinical outcomes were explored. Higher GRS-PD and lower baseline CSF α-synuclein were associated with an increased risk of PD. In the PD group, GRS-AD was correlated positively with CSF p-tau/Aβ and negatively with CSF α-synuclein. Higher GRS-PD was associated with faster CSF p-tau/Aβ increase, and GRS-AD and GRS-PD were interactively associated with CSF α-synuclein. In the PD group, higher GRS-AD was associated with poor visuospatial function, and baseline CSF p-tau/Aβ was associated with faster cognitive decline. Higher GRS-PD was associated with better semantic fluency and frontal-related cognition and motor function given the same levels of CSF biomarkers and dopamine transporter uptake. Taken together, our results suggest that higher GRS-AD and CSF p-tau/Aβ, reflecting AD-related pathophysiology, may be associated with cognitive decline in PD patients.

SUBMITTER: Lee YG

PROVIDER: S-EPMC9095668 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Effects of Alzheimer's genetic risk scores and CSF biomarkers in de novo Parkinson's Disease.

Lee Young-Gun YG Jeong Seong Ho SH Park Mincheol M Kang Sung Woo SW Baik Kyoungwon K Jeon Seun S Lee Phil Hyu PH Sohn Young Ho YH Ye Byoung Seok BS

NPJ Parkinson's disease 20220511 1

Coexisting Alzheimer's disease (AD) pathology is common in Parkinson's disease (PD). However, the implications of genetic risk scores (GRS) for AD have not been elucidated in PD. In 413 de novo PD and 195 healthy controls from the Parkinson's Progression Marker Initiative database, the effects of GRS for AD (GRS-AD) and PD (GRS-PD) on the risk of PD and longitudinal CSF biomarkers and clinical outcomes were explored. Higher GRS-PD and lower baseline CSF α-synuclein were associated with an increa ...[more]

PMID: 35545633

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Project description:Background: APOE is the largest genetic risk factor for sporadic Alzheimer's disease (AD), but there is a substantial polygenic component as well. Polygenic risk scores (PRS) can summarize small effects across the genome but may obscure differential risk associated with different molecular processes and pathways. Variability at the genetic level may contribute to the extensive phenotypic heterogeneity of Alzheimer's disease (AD). Here, we examine polygenic risk impacting specific pathways associated with AD and examined its relationship with clinical status and AD biomarkers of amyloid, tau, and neurodegeneration (A/T/N). Methods: A total of 1,411 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with genotyping data were included. Sets of variants identified from a pathway analysis of AD GWAS summary statistics were combined into clusters based on their assigned pathway. We constructed pathway-specific PRSs for each participant and tested their associations with diagnostic status (AD vs cognitively normal), abnormal levels of amyloid and ptau (positive vs negative), and hippocampal volume. The APOE region was excluded from all PRSs, and analyses controlled for APOE -ε4 carrier status. Results: Thirteen pathway clusters were identified relating to categories such as immune response, amyloid precursor processing, protein localization, lipid transport and binding, tyrosine kinase, and endocytosis. Eight pathway-specific PRSs were significantly associated with AD dementia diagnosis. Amyloid-positivity was associated with endocytosis and fibril formation, response misfolded protein, and regulation protein tyrosine PRSs. Ptau positivity and hippocampal volume were both related to protein localization and mitophagy PRS, and ptau positivity was additionally associated with an immune signaling PRS. A global AD PRS showed stronger associations with diagnosis and all biomarkers compared to pathway PRSs, suggesting a strong synergistic effect of all loci contributing to the global AD PRS. Conclusions: Pathway PRS may contribute to understanding separable disease processes, but do not appear to add significant power for predictive purposes. These findings demonstrate that, although genetic risk for AD is widely distributed, AD-phenotypes may be preferentially associated with risk in specific pathways. Defining genetic risk along multiple dimensions at the individual level may help clarify the etiological heterogeneity in AD.

Dataset Information

Effects of Alzheimer's genetic risk scores and CSF biomarkers in de novo Parkinson's Disease.

Publications

Effects of Alzheimer's genetic risk scores and CSF biomarkers in de novo Parkinson's Disease.

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