Assessment of APOE in atypical parkinsonism syndromes
Introduction
The prevalence of age-related neurodegenerative diseases is a growing public health concern (World Health Organization, 2006). There exists a critical, unmet need for unraveling the genetic architectures that underlie neurodegenerative disorders. Identifying and validating pathogenic molecular defects can inform targets for drug-discovery efforts and disease-modifying interventions. Atypical parkinsonism syndromes are a diverse group of progressive neurological disorders characterized by the presence of parkinsonism in addition to clinical features considered atypical for Parkinson's disease (PD), such as early falls and/or early cognitive impairment (Scholz and Bras, 2015). The accurate clinical diagnosis of atypical parkinsonism disorders remains a major challenge as a result of broad phenotypic variability and the overlap with mimic syndromes.
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are characterized pathologically by the presence of neuronal and glial tau-positive inclusions, while multiple system atrophy (MSA) and Lewy body dementia (LBD) are defined by abnormal accumulation of aggregated α-synuclein as glial cytoplasmic inclusions and as neuronal Lewy bodies, respectively (Irwin et al., 2015; Spillantini and Goedert, 2016). Interestingly, AD co-pathology is observed in approximately 65 to 90% of LBD patients, placing LBD along a clinicopathological continuum between PD and AD (Dugger et al., 2014; Harding and Halliday, 2001; Merdes et al., 2003; Schneider et al., 2012).
Advances in modern genomic technologies have been key to the systematic dissection of the molecular etiology of neurodegenerative diseases. These efforts have revealed overlapping risk loci among atypical parkinsonism syndromes and other neurodegenerative diseases clearly suggesting that these diseases are etiologically related. Dysregulation of lipid metabolism/homeostasis has been ascertained as a contributor of degenerative disorders (Bleasel et al., 2014; Sultana et al., 2013). The ε4 allele of apolipoprotein E (APOE), a well-established lipid metabolism and cholesterol transport gene, is known to be a major genetic risk determinant for sporadic, late-onset AD and LBD (Corder et al., 1993; Liu et al., 2013). Allelic dose effects for this gene have been observed among AD cases: a single copy of the ε4 allele imparts a three-fold risk of developing disease, while subjects with an ε4/ε4 genotype demonstrate an approximate eight-fold increase in disease risk (Corder et al., 1993; Liu et al., 2013). The ε4 allele is also associated with a significantly decreased age at disease onset and decreased survival in a dose-dependent manner (Christensen et al., 2006; Corder et al., 1993; Schächter et al., 1994). On the other hand, the APOE ε2 allele has been reported to have a protective effect in late-onset AD. Despite this, the role of the ε2 allele in LBD and other atypical parkinsonism disorders remains unclear (Berge et al., 2014; Corder et al., 1994; Lovati et al., 2010; Van Cauwenberghe et al., 2016). To address this question, we investigated the allele frequencies of APOE in four pathologically-confirmed cohorts of atypical parkinsonism in addition to AD and PD patients. We compared our findings to neurologically healthy controls.
Section snippets
Study subjects
Brain tissue and/or blood samples were obtained from eighteen North American and European research centers and brain banks (Supplementary Table 1). All participants gave written, informed consent for post mortem brain or blood donation. A total of 1910 neurodegenerative disease patients of European ancestry and 591 neurologically healthy controls over the age of 50 were included (Table 1). The neurodegenerative disease cases included: AD (n = 571), PD (n = 348), LBD (total n = 525; dementia
Results
We demonstrated that APOE ε4 carriers (genotypes: ε2/ε4, ε3/ε4, and ε4/ε4) had a statistically significant increased risk of developing AD (OR: 4.13, 95% CI: 3.23–5.26, p = 3.67 × 10−30) and LBD (OR: 2.94, 95% CI: 2.34–3.71, p = 6.60 × 10−20). Both of these results surpassed the Bonferroni threshold for multiple comparisons (Table 2). In contrast, carriers of the APOE ε2 allele, as defined by ε2/ε2 and ε2/ε3 genotypes, had a significantly decreased risk of developing AD (OR: 0.21, 95% CI:
Discussion and conclusions
The APOE ε4 allele has been widely and consistently implicated in the pathogenesis of AD and LBD (Galasko et al., 1994; Robinson et al., 2018; Singleton et al., 2002; St Clair et al., 1994; Tsuang et al., 2013). The main objective of this study was to determine the frequency and risk of disease associated with the APOE ε4 and ε2 alleles in pathologically-confirmed atypical parkinsonism subjects compared to neurologically healthy individuals. We confirmed the well-known effect of APOE on AD and
Acknowledgments
We would like to thank the NIH Neuro Brain Bank for contributing tissue samples; this study was supported in part by grants from the National Institutes of Health: U19-AG03365, P50 NS38377, and P50-AG005146. Tissue samples for genotyping were provided by the Johns Hopkins Morris K. Udall Center of Excellence for Parkinson's Disease Research (NIH P50 NS38377) and the Johns Hopkins Alzheimer's Disease Research Center. We are grateful for the support of the entire BIOCARD study team at Johns
Authors’ roles
Research Project: A. Conception (SWS), B. Organization (SWS), C. Sample Contributors (GES, TGB, MP, ACR, EM, CMM, LP, AP, SR, MRC, DGH, MA, TMD, LSR, HH, OP, JT), D. Execution (MSS, CB, SA, SWS). Statistical Analysis: A. Design (MSS, CB, SWS) B. Execution (MSS), C. Review and Critique (MSS, CB, SWS). Manuscript: A. Writing of the first draft (MSS), B. Review and Critique (CB, SA, GES, TGB, MP, ACR, EM, CMM, LP, AP, SR, MRC, DGH, MA, TMD, LSR, HH, OP, JT, SWS).
Disclosure statement
The authors report no conflicts of interest.
Funding
This study was supported in part by the Intramural Research Program of the NIH National Institute of Neurological Disorders and Stroke and the National Institute on Aging (project numbers: ZIA-NS003154, Z01-AG000949).
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