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Published in final edited form as: Neurobiol Dis. 2019 Feb 21;127:142–146. doi: 10.1016/j.nbd.2019.02.016

Assessment of APOE in Atypical Parkinsonism Syndromes

Marya S Sabir 1, Cornelis Blauwendraat 1, Sarah Ahmed 1, Geidy E Serrano 2, Thomas G Beach 2, Matthew Perkins 3, Ann C Rice 4, Eliezer Masliah 5, Christopher M Morris 6, Lasse Pihlstrom 7, Alexander Pantelyat 8, Susan M Resnick 9, Mark R Cookson 5, Dena G Hernandez 5, Marilyn Albert 8, Ted M Dawson 8,10,11,12, Liana S Rosenthal 8, Henry Houlden 13, Olga Pletnikova 14, Juan Troncoso 14, Sonja W Scholz 1,8,†
PMCID: PMC6588472  NIHMSID: NIHMS1523253  PMID: 30798004

Abstract

Atypical parkinsonism syndromes are a heterogeneous group of neurodegenerative disorders that include corticobasal degeneration (CBD), Lewy body dementia (LBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). The APOE ε4 allele is a well-established risk factor for Alzheimer’s disease; however, the role of APOE in atypical parkinsonism syndromes remains controversial. To examine the associations of APOE ε4 and ε2 alleles with risk of developing these syndromes, a total of 991 pathologically-confirmed atypical parkinsonism cases were genotyped using the Illumina NeuroChip array. We also performed genotyping and logistic regression analyses to examine APOE frequency and associated risk in patients with Alzheimer’s disease (n=571) and Parkinson’s disease (n=348). APOE genotypes were compared to those from neurologic ally healthy controls (n=591). We demonstrate that APOE ε4 and ε2 carriers have a significantly increased and decreased risk, respectively, of developing Alzheimer’s disease (ε4: OR: 4.13, 95% CI: 3.23-5.26, p = 3.67 × 10−30; ε2: OR: 0.21, 95% CI: 0.13-0.34; p = 5.39 × 10−10) and LBD (ε4: OR: 2.94, 95% CI: 2.34-3.71, p = 6.60 × 10−20; ε2: OR = OR: 0.39, 95% CI: 0.26-59; p = 6.88 × 10−6). No significant associations with risk for CBD, MSA, or PSP were observed. We also show that APOE ε4 decreases survival in a dose-dependent manner in Alzheimer’s disease and LBD. Taken together, this study does not provide evidence to implicate a role of APOE in the neuropathogenesis of CBD, MSA, or PSP. However, we confirm association of the APOE ε4 allele with increased risk for LBD, and importantly demonstrate that APOE ε2 reduces risk of this disease.

Keywords: APOE, atypical parkinsonism, Lewy body dementia, progressive supranuclear palsy, multiple system atrophy

1. INTRODUCTION

The prevalence of age-related neurodegenerative diseases is a growing public health concern.1 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.2 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.3,4 Interestingly, AD co-pathology is observed in approximately 65 to 90% of LBD patients, placing LBD along a clinicopathological continuum between PD and AD.5,6,7,8

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.9,10 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.11,12 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.11,12 The ε4 allele is also associated with a significantly decreased age at disease onset and decreased survival in a dose-dependent manner.11,13,14 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.15–18 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.

2. MATERIAL AND METHODS

2.1. 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 1,910 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 with Lewy bodies (n=468) and Parkinson’s disease dementia (n=57)), MSA(n=223), PSP (n=202), and CBD (n=41). All cases were diagnosed using consensus pathologic criteria.19–24

Table 1:

Cohort characteristics and distribution of APOE genotypes in study populations

Controls AD PD CBD LBD MSA PSP
N 591 571 348 41 525 223 202
Mean Age ± SD (years)a 71.7 ± 11.0 81.8 ± 10.1 78.2 ± 9.4 74.8 ± 9.3 77.5 ± 8.2 66.1 ± 10.8 78.1 ± 9.7
Age range (years)a (50, 105) (41, 103) (19, 107) (51, 96) (49, 99) (20, 90) (55, 102)
No. Male (%) 318 (53.8) 221 (38.7) 234 (67.2) 18 (43.9) 338 (64.4) 109 (48.9) 113 (55.9)
No. Female (%) 273 (46.2) 350 (61.3) 114 (32.8) 23 (56.1) 187 (35.6) 114 (51.1) 89 (44.1)
No. Pathologically-confirmed 218 (36.9) 571 (100) 348 (100) 41 (100) 525 (100) 223 (100) 202 (100)
No. Clinically-defined 373 (63.1)b N/A N/A N/A N/A N/A N/A
No. with ε2/ε2 (%) 5 (0.8) 0 (0) 0 (0) 0 (0) 2 (0.4) 0 (0) 3 (1.5)
No. with ε2/ε3 (%) 83 (14.0) 29 (5.1) 54 (15.5) 4 (9.8) 35 (6.7) 25 (11.2) 20 (9.9)
No. with ε2/ε4 (%) 14 (2.4) 11 (1.9) 6 (1.7) 1 (2.4) 14 (2.7) 6 (2.7) 5 (2.5)
No. with ε3/ε3 (%) 368 (62.3) 208 (36.4) 203 (58.3) 28 (68.3) 239 (45.5) 141 (63.2) 138 (68.3)
No. with ε3/ε4 (%) 104 (17.6) 252 (44.1) 82 (23.6) 6 (14.6) 187 (35.6) 48 (21.5) 33 (16.3)
No. with ε4/ε4 (%) 17 (2.9) 71 (12.4) 3 (0.9) 2 (4.9) 48 (9.1) 3 (1.3) 3 (1.5)
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a

Age was defined as age at death for pathologically-confirmed samples and age at specimen collection for clinically-defined control samples. Age information was available for 590/591 controls, 568/571 AD samples, 342/348 PD samples, 41/41 CBD samples, 523/525 LBD samples, 101/223 MSA samples, and 202/202 PSP samples.

b

DNA from clinically defined control samples was extracted from blood as opposed to brain tissue from all other cohorts.

Abbreviations: AD, Alzheimer’s disease; PD, Parkinson’s disease; CBD, corticobasal degeneration; LBD, Lewy body dementia; MSA, multiple system atrophy; PSP, progressive supranuclear palsy; SD, standard deviation; N/A, not applicable.

2.2. NeuroChip Array Genotyping and Quality Control

Genomic DNA was extracted from frozen brain tissue or blood using standard phenol-chloroform extraction techniques. Genotyping was performed using the NeuroChip (Illumina, San Diego, CA, USA), a versatile microarray that is comprised of a tagging backbone (n=306,670 variants) and 179,467 variants of custom “neuro” content.25 NeuroChip genotyping was conducted following the manufacturer’s protocol as described elsewhere.25 The data were exported from GenomeStudio using the Illumina-to-PLINK module 2.1.4 and imported into PLINK version 1.90.26 Quality control procedures were performed, and only samples with call rates > 95%, lack of contamination (i.e. passing heterozygosity threshold of < 0.15), concordance between reported and genotypic sex, relatedness based on PIHAT metric < 0.125, and European ancestry individuals based on the 1000 Genomes Project were included in the study.27

2.3. APOE Allele Genotyping

Genotype calls of two APOE single nucleotide polymorphisms, rs429358 and rs7412, were used to determine the APOE status of each sample. The combination of genotypes for rs429358 (C/T) and rs7412 (C/T) defines the three allelic variants of APOE: epsilon 2 (ε2), epsilon 3 (ε3), and epsilon 4 (ε4). These three allelic variants produce six genotypes, ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, and ε4/ε4. Validation of accurate APOE genotype calls using NeuroChip compared to standard Taqman genotyping has been previously described.25

2.4. Statistical Analysis

Association of APOE ε2 and ε4 alleles with risk of neurodegenerative disease (i.e.; AD, PD, CBD, LBD, MSA, and PSP) compared to controls was evaluated using PLINK version 1.90 logistic regression models, adjusted for sex and age (i.e. age at death for pathologically-confirmed samples or age at specimen collection for clinically-defined control samples). Survival analyses were performed for each cohort using log-rank tests as implemented in the R “survival” and “survminer” packages. Only samples for which age of death information was available were included in these analyses (217/218 controls, 568/571 Alzheimer’s disease cases, 523/525 LBD cases, 101/223 MSA cases, 202/202 PSP cases, 41/41 CBD cases).

3. 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: 0.13-0.34; p = 5.39 × 10−10) or LBD (OR: 0.39, 95% CI: 0.26-0.59; p = 6.88 × 10−6) (Table 2). There were no significant associations of APOE ε4 and ε2 with altered risk of developing CBD, MSA, PSP, or PD (Table 2, Supplementary Table 2). Additionally, a dose-response association between increasing APOE ε4 allele dose and reduced survival was observed in AD (p < 0.0001) and LBD (p = 0.0022); the association with PSP did not surpass the Bonferroni threshold (Supplementary Figure 1).

Table 2:

Association of APOE ε4 and ε2 with risk of neurodegenerative diseases

Cohort N APOE ε4 carriers
 APOE ε2 carriers
N. samples (%)a OR (95% CI) p value No. samples (%)b OR (95% CI)c p value
Controls 591 135 (22.8) 1.00 (Reference) N/A 102 (17.3) 1.00 (Reference) N/A
AD 571 334 (58.5) 4.13 (3.23, 5.26) 3.67 × 10−30 40 (7.0) 0.21 (0.13, 0.34) 5.39 × 10−10
PD 348 91 (26.1) 1.18 (0.88, 1.59) 0.27 60 (17.2) 0.88 (0.60, 1.29) 0.52
CBD 41 9 (22.0) 1.10 (0.59, 2.04) 0.76 5 (12.2) 0.57 (0.20, 1.60) 0.29
LBD 525 249 (47.4) 2.94 (2.34, 3.71) 6.60 × 10−20 51 (9.7) 0.39 (0.26, 0.59) 6.88 × 10−6
MSA 223 57 (25.6) 1.11 (0.74, 1.67) 0.62 31 (13.9) 0.80 (0.43, 1.49) 0.48
PSP 202 41 (20.3) 0.95 (0.66, 1.35) 0.77 28 (13.9) 0.72 (0.45, 1.14) 0.16
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ORs, 95% CIs, and p value results from logistic regression models adjusted for sex and age at death for pathologically-confirmed samples or age at collection for clinically-defined control samples.

a

ε4 allele carriers included individuals with genotypes ε2/ε4, ε3/ε4, and ε4/ε4.

b

ε2 allele carriers included individuals with genotypes ε2/ε2, ε2/ε3 and ε2/ε4.

c

When calculating the OR, individuals with the ε2/ε4 genotype were excluded from the ε2 relative risk analyses since ε2 is predicted to be protective and ε4 is shown to be a risk factor.

Abbreviations: AD, Alzheimer’s disease; PD, Parkinson’s disease; CBD, corticobasal degeneration; LBD, Lewy body dementia; MSA, multiple system atrophy; PSP, progressive supranuclear palsy; OR, odds ratio; CI, confidence interval; N/A, not applicable.

4. DISCUSSION AND CONCLUSIONS

The APOE ε4 allele has been widely and consistently implicated in the pathogenesis of AD and LBD.28–32 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 LBD risk. In addition, we also compared autopsy-confirmed AD and PD cohorts to controls. We found that APOE ε4 carrier status is significantly associated with increased risk of developing AD and LBD, while APOE ε2 carriers have a decreased relative risk of developing these degenerative dementias. A prior study of APOE ε2 in clinically-diagnosed DLB patients also demonstrated a protective ε2 effect.17 Recently, Dickson et al. reported that APOE ε4 is associated with greater severity of Lewy body pathology independent of Alzheimer’s disease pathology.33 Interestingly, another recent study demonstrated similar decreases in methylation at the APOE locus in post mortem brain tissues of neuropathological pure LBD and AD suggesting that this epigenetic alteration may also be contributing to disease risk.34

Our data indicate that APOE is not a risk factor for PD nor MSA or for the tauopathies CBD and PSP. Our results confirmed previous studies of APOE in PD and MSA.35–40 A genome-wide association study (GWAS) performed on a small cohort of CBD also found no association of APOE with CBD.41 Recently, a study of 134 CBD cases found no significant associations of ε2 or ε4 with disease risk.42 The role of APOE variants in risk of developing PSP has been controversial.37,38,43,44,45,46 A higher frequency of APOE, ε2 allele, but not ε4 allele, in PSP was found in a Japanese cohort.47 The first PSP GWAS, including 1,150 autopsy-confirmed cases, demonstrated that the ε4 frequency is reduced in PSP.48 A recent study by Zhao and colleagues of a series of 994 PSP patients found that APOE ε2 ε2 carriers have a significantly increased risk of developing disease (OR=4.41).42 Similarly, our study shows a higher frequency of APOE ε2/ε2 carriers in PSP (1.5%) versus controls (0.8%), but no significant association of the ε2 allele with risk of disease. Additionally, possession of the APOE ε4 allele has not been shown to affect age of disease onset in MSA or PSP.37

A notable strength of this study is the use of large, pathologically-proven cohorts of atypical parkinsonism syndrome patients. This approach effectively eliminates diagnostic uncertainty due to heterogeneous clinical presentations and possible presence of mimic syndromes.

There are a number of limitations to this study. First, age information was not available for 134 subjects and most of the patients (122/134) were within the MSA cohort. Second, although our CBD cohort consisted of only 41 subjects, previous non-GWAS studies investigating APOE allele frequencies in CBD have been limited to 18 patients or fewer.43,49,50,51 We acknowledge that our CBD cohort has only low power for identifying significant associations, and thus the results of the APOE analysis in this cohort should be interpreted with caution. Additionally, it is possible that our clinically-defined controls (n=373/591 subjects) may develop a neurodegenerative disease later in their life. To counter this limitation, logistic regression analyses performed with inclusion of only pathologically-confirmed controls mirrored the results in Table 2.

Taken together, our findings did not implicate APOE ε4 as a major genetic risk determinant for atypical parkinsonism syndromes, including CBD, MSA, and PSP. In contrast, we replicate association of the APOE ε4 allele and risk for LBD, and importantly demonstrate that possession of the ε2 allele is associated with a lower relative risk. Additional functional studies are required to elucidate the biological mechanism underlying this effect. Our findings support the notion of overlapping pathogenetic mechanisms between AD and LBD. Further investigation of other genetic loci associated with the spectrum of neurodegenerative diseases, particularly of AD- and PD-related loci, is essential for improving the diagnostic, prognostic, preventative and therapeutic management of atypical parkinsonism syndromes.

Supplementary Material

1
2

HIGHLIGHTS.

  • APOE ε4 increases while APOE ε2 decreases relative risk of developing AD and LBD.

  • APOE does not alter risk of developing CBD, MSA, or PSP.

  • APOE ε4 decreases survival in a dose-dependent manner in AD and LBD.

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 Hopkins University. Additionally, we acknowledge the contributions of the Geriatric Psychiatry Branch (GPB) in the intramural program of NIMH who initiated the BIOCARD study. We would like to thank the NIA Baltimore Longitudinal Study of Aging for contributing tissue samples to the Johns Hopkins Alzheimer’s Disease Research Center. DNA panels from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds) were used in this study, as well as clinical data. We thank the following brain banks for providing brain tissues: Banner Sun Health Research Institute, New York Brain Bank, Newcastle Brain Tissue Resource, Human Brain and Spinal Fluid Resource Center, Netherlands Brain Bank Amsterdam, Mount Sinai Brain Bank, Harvard Brain Bank, Duke University Brain Bank, Virginia Commonwealth University Brain Bank, and the Georgetown University Brain Bank. We also thank the following research centers for providing patient samples: Michigan Brain Bank (5P30 AG053760 University of Michigan Alzheimer’s Disease Core Center), University College London Institute of Neurology, University of Maryland, University of California – San Diego, and University of Miami. We are grateful to members of the North American Brain Expression Consortium for contributing DNA samples. The authors thank the patients and families who have donated DNA samples and brain tissue for scientific research. The research 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).

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).

Footnotes

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DISCLOSURE STATEMENT

The authors report no conflicts of interest.

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NIHMS1523253-supplement-1.docx (27.3KB, docx)
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NIHMS1523253-supplement-2.docx (101.8KB, docx)

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