CoChat
Sign Up
Cited by 28Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Assessment of APOE in atypical parkinsonism syndromes

Open access
Sabir, Marya S., Blauwendraat, Cornelis, Ahmed, Sarah, Serrano, Geidy E., Beach, Thomas G., Perkins, Matthew, Rice, Ann C., Masliah, Eliezer +13 more·2019·Neurobiology of Disease
DOI 10.1016/j.nbd.2019.02.016PMC PMC6588472
Open this paper in CoChat — free account

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 neurologically 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: 0.26-0.59; 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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.nbd.2019.02.016

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • No association has been found between the APOE genotype and a primary neuropathological diagnosis of multiple system atrophy.

    “By contrast, no association has been found between the APOE genotype and a primary neuropathological diagnosis of multiple system atrophy67,74.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [67]

  • Another study failed to find an association between the APOEε2 allele and neuropathologically confirmed primary tauopathy.

    “However, another study failed to find such association67 and in a third study the significance of the association was lost when adjusting for AD neuropathological changes49, suggesting a spurious association owing to the strength of the APOEε4–AD link.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [67]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 46

  1. [2]Scholz S, Bras J. Genetics Underlying Atypical Parkinsonism and Related Neurodegenerative Disorders. Int J Mol Sci. 2015; 16(10): 24629– 24655. 26501269 PMC4632769
  2. [3]Irwin DJ, Cairns NJ, Grossman M, Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. Acta Neuropathol. 2015; 129(4): 469– 491. 25549971 PMC4369168
  3. [4]Spillantini MG, Goedert M. Synucleinopathies: past, present and future. Neuropathol Appl Neurobiol. 2016; 42(1): 3– 5. 26819143
  4. [5]Merdes AR, Hansen LA, Jeste DV, Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies. Neurology. 2003; 60(10): 1586– 1590. 12771246
  5. [6]Harding AJ, Halliday GM. Cortical Lewy body pathology in the diagnosis of dementia. Acta Neuropathol. 2001; 102(4): 355– 363. 11603811
  6. [7]Dugger BN, Adler CH, Shill HA, Concomitant pathologies among a spectrum of parkinsonian disorders. Parkinsonism Relat Disord. 2014; 20(5): 525– 529. 24637124 PMC4028418
  7. [8]Schneider JA, Arvanitakis Z, Yu L, Boyle PA, Leurgans SE, Bennett DA. Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies. Brain. 2012; 135(Pt 10) 3005– 3014. 23065790 PMC3470712
  8. [9]Sultana R, Perluigi M, Allan Butterfield D. Lipid peroxidation triggers neurodegeneration: a redox proteomics view into the Alzheimer disease brain. Free Radic Biol Med. 2013; 62: 157– 169. 23044265 PMC3573239
  9. [10]Bleasel JM, Wong JH, Halliday GM, Kim WS. Lipid dysfunction and pathogenesis of multiple system atrophy. Acta Neuropathol Commun. 2014; 2: 15. 24502382 PMC3922275
  10. [11]Corder EH, Saunders AM, Strittmatter WJ, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993; 261(5123): 921– 923. 8346443
  11. [12]Liu C-C, Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013; 9(2): 106– 118. 23296339 PMC3726719
  12. [14]Christensen K, Johnson TE, Vaupel JW. The quest for genetic determinants of human longevity: challenges and insights. Nat Rev Genet. 2006; 7(6): 436– 448. 16708071 PMC2726954
  13. [16]Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med. 2016; 18(5): 421– 430. 26312828 PMC4857183
  14. [17]Berge G, Sando SB, Rongve A, Aarsland D, White LR. Apolipoprotein E 2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort. J Neurol Neurosurg Psychiatry. 2014; 85(11) 1227– 1231. 24639435 PMC4215279
  15. [18]Lovati C, Galimberti D, Albani D, APOE ε2 and ε4 influence the susceptibility for Alzheimer’s disease but not other dementias. Int J Mol Epidemiol Genet. 2010; 1(3): 193– 200. 21537391 PMC3076771
  16. [19]Hyman BT, Phelps CH, Beach TG, National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012; 8(1): 1– 13. 22265587 PMC3266529
  17. [20]Dickson DW, Braak H, Duda JE, Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol. 2009; 8(12): 1150– 1157. 19909913
  18. [21]McKeith IG. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB International Workshop. J Alzheimers Dis. 2006; 9(3 Suppl): 417– 423. 16914880
  19. [22]Gilman S, Wenning GK, Low PA, Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008; 71(9): 670– 676. 18725592 PMC2676993
  20. [23]Hauw JJ, Daniel SE, Dickson D, Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology. 1994; 44(11): 2015– 2019. 7969952
  21. [24]Dickson DW, Bergeron C, Chin SS, Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropcithol Exp Neurol. 2002; 61(11): 935– 946. 12430710
  22. [25]Blauwendraat C, Faghri F, Pihlstrom L, NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases. Neurobiol Aging. 2017; 57: 247.e9– e247.e13. PMC5534378 28602509
  23. [26]Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015; 4: 7. 25722852 PMC4342193
  24. [27]1000 Genomes Project Consortium, Auton A, Brooks LD, A global reference for human genetic variation. Nature. 2015; 526(7571): 68– 74. 26432245 PMC4750478
  25. [28]Galasko D, Saitoh T, Xia Y, The apolipoprotein E allele epsi;4 is overrepresented in patients with the Lewy body variant of Alzheimer’s disease. Neurology. 1994; 44(10) 1950– 1950. 7936253
  26. [29]Tsuang D, Leverenz JB, Lopez OL, APOE ϵ4 Increases Risk for Dementia in Pure Synucleinopathies. JAMA Neurol. 2013; 70(2): 223. 23407718 PMC3580799
  27. [30]St Clair D, Norrman J, Perry R, Yates C, Wilcock G, Brookes A. Apolipoprotein E ϵ4 allele frequency in patients with Lewy body dementia, Alzheimer’s disease and age-matched controls. Neurosci Lett. 1994; 176(1): 45– 46. 7970234
  28. [31]Singleton AB, Wharton A, O’Brien KK, Clinical and neuropathological correlates of apolipoprotein E genotype in dementia with Lewy bodies. Dement Geriatr Cogn Disord. 2002; 14(4): 167– 175. 12411758
  29. [32]Robinson JL, Lee EB, Xie SX, Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain. 2018; 141(7): 2181– 2193. 29878075 PMC6022546
  30. [33]Dickson DW, Heckman MG, Murray ME, APOE ε4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology. 2018; 91(12): e1182– e1195. 30143564 PMC6161556
  31. [34]Tulloch J, Leong L, Chen S, APOE DNA methylation is altered in Lewy body dementia. Alzheimers Dement. 2018; 14(7): 889– 894. 29544979 PMC6050144
  32. [35]Federoff M, Jimenez-Rolando B, Nalls MA, Singleton AB. A large study reveals no association between APOE and Parkinson’s disease. Neurobiol Dis. 2012; 46(2): 389– 392. 22349451 PMC3323723
  33. [36]Ogaki K, Martens YA, Heckman MG, Multiple system atrophy and apolipoprotein E. Mov Disord. 2018; 33(4): 647– 650. 29442376 PMC5889322
  34. [37]Morris HR, Schrag A, Nath U, Effect of ApoE and tau on age of onset of progressive supranuclear palsy and multiple system atrophy. Neurosci Lett. 2001; 312(2): 118– 120. 11595348
  35. [38]Morris HR, Vaughan JR, Datta SR, Multiple system atrophy/progressive supranuclear palsy: alpha-Synuclein, synphilin, tau, and APOE. Neurology. 2000; 55(12): 1918– 1920. 11134398
  36. [39]Toji H, Kawakami H, Kawarai T, No association between apolipoprotein E alleles and olivopontocerebellar atrophy. J Neurol Sci. 1998; 158(1): 110– 112. 9667788
  37. [40]Sailer A, Scholz SW, Nalls MA, A genome-wide association study in multiple system atrophy. Neurology. 2016; 87(15): 1591– 1598. 27629089 PMC5067544
  38. [43]Pickering-Brown SM, Owen F, Isaacs A, Apolipoprotein E ϵ4 Allele Has No Effect on Age at Onset or Duration of Disease in Cases of Frontotemporal Dementia with Pick- or Microvacuolar-Type Histology. Exp Neurol. 2000; 163(2): 452– 456. 10833320
  39. [44]Baba Y, Putzke JD, Tsuboi Y, Effect of MAPT and APOE on prognosis of progressive supranuclear palsy. Neurosci Lett. 2006; 405(1–2): 116– 119. 16839689
  40. [45]Anouti A, Schmidt K, Lyons KE, Normal distribution of apolipoprotein E alleles in progressive supranuclear palsy. Neurology. 1996; 46(4): 1156– 1157. 8780111
  41. [46]Tabaton M, Rolleri M, Masturzo P, Apolipoprotein E element 4 allele frequency is not increased in progressive supranuclear palsy. Neurology. 1995; 45(9): 1764– 1765. 7675243
  42. [47]Sawa A, Amano N, Yamada N, Apolipoprotein E in progressive supranuclear palsy in Japan. Mol Psychiatry. 1997; 2(4) 341– 342. 9246676
  43. [48]Höglinger GU, Melhem NM, Dickson DW, Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. 2011; 43(7): 699– 705. 21685912 PMC3125476
  44. [49]Borroni B, Perani D, Archetti S, Functional correlates of Apolipoprotein E genotype in Frontotemporal Lobar Degeneration. BMC Neurol. 2006; 631. PMC1569858 16930470
  45. [50]Josephs KA, Tsuboi Y, Cookson N, Watt H, Dickson DW. Apolipoprotein E ε4 Is a Determinant for Alzheimer-Type Pathologic Features in Tauopathies, Synucleinopathies, and Frontotemporal Degeneration. Arch Neurol. 2004; 61(10): 1579. 15477512
  46. [51]Schneider JA, Watts RL, Gearing M, Brewer RP, Mirra SS. Corticobasal degeneration: neuropathologic and clinical heterogeneity. Neurology. 1997; 48(4): 959– 969. 9109885

Cited by

Sorted by citations

Authors
Sabir, M. S., Blauwendraat, C., Ahmed, S., Serrano, G. E., Beach, T. G., Perkins, M., Rice, A. C., Masliah, E., Morris, C. M., Pihlstrom, L., Pantelyat, A., Resnick, S. M., Cookson, M. R., Hernandez, D. G., Albert, M., Dawson, T. M., Rosenthal, L. S., Houlden, H., Pletnikova, O., Troncoso, J., & Scholz, S. W.
Affiliations
  • National Institutes of Health (US)
  • Banner Sun Health Research Institute (US)
  • University of Michigan (US)
  • Virginia Commonwealth University (US)
  • Newcastle University (GB)
  • Johns Hopkins University (US)
  • National Institute on Aging (US)
  • UCL Queen Square Institute of Neurology (GB)
Corresponding author
Scholz, Sonja W.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2019-07
Volume
127
Pages
142-146
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2019.02.016
PMC
PMC6588472
OpenAlex
W2917751334
Cited by
28
References
4
Citations by year
2026: 3 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 2
FWCI
2.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
APOE ε4, APOE ε2, atypical parkinsonism, dementia with Lewy bodies, corticobasal degeneration, multiple system atrophy, progressive supranuclear palsy, Alzheimer's disease, Parkinson's disease, genetic risk factors, survival, neuropathogenesis
MeSH terms
Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Apolipoproteins E, Brain, Dementia, Female, Genotype, Humans, Male, Middle Aged, Parkinson Disease, Supranuclear Palsy, Progressive, Multiple System Atrophy, Lewy Body Disease

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review