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Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated.
Brain. 2018 07 01; 141(7):2181-2193.B

Abstract

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-β, α-synuclein and TDP-43.

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Authors+Show Affiliations

Robinson JL
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Lee EB
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Xie SX
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Biostatistics and Epidemiology, and Informatics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Rennert L
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Biostatistics and Epidemiology, and Informatics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Suh E
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Bredenberg C
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Caswell C
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Biostatistics and Epidemiology, and Informatics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Van Deerlin VM
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Yan N
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. University-town Hospital of Chongqing Medical University, China.
Yousef A
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Hurtig HI
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Siderowf A
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Grossman M
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Frontotemporal Degeneration Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
McMillan CT
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Frontotemporal Degeneration Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Miller B
Memory and Aging Center, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
Duda JE
Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Parkinson's Disease Research, Education and Clinical Center, Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.
Irwin DJ
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Frontotemporal Degeneration Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Wolk D
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Frontotemporal Degeneration Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Memory Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Elman L
Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
McCluskey L
Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Chen-Plotkin A
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Weintraub D
Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
Arnold SE
Translational Neurology Head of the Interdisciplinary Brain Center at Massachusetts General Hospital, Harvard Medical School.
Brettschneider J
Neurological Clinic of the Caritas Clinic of Saarbrücken St. Theresia, Germany.
Lee VM
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Trojanowski JQ
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

MeSH

AgedAlzheimer DiseaseAmyotrophic Lateral SclerosisApolipoprotein E4DNA-Binding ProteinsFemaleHumansInclusion BodiesLewy BodiesLewy Body DiseaseMaleMiddle AgedMultiple System AtrophyNeurodegenerative DiseasesPick Disease of the BrainPrevalenceSupranuclear Palsy, ProgressiveTDP-43 ProteinopathiesTauopathiesalpha-Synucleintau Proteins

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29878075

Citation

Robinson, John L., et al. "Neurodegenerative Disease Concomitant Proteinopathies Are Prevalent, Age-related and APOE4-associated." Brain : a Journal of Neurology, vol. 141, no. 7, 2018, pp. 2181-2193.
Robinson JL, Lee EB, Xie SX, et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain. 2018;141(7):2181-2193.
Robinson, J. L., Lee, E. B., Xie, S. X., Rennert, L., Suh, E., Bredenberg, C., Caswell, C., Van Deerlin, V. M., Yan, N., Yousef, A., Hurtig, H. I., Siderowf, A., Grossman, M., McMillan, C. T., Miller, B., Duda, J. E., Irwin, D. J., Wolk, D., Elman, L., ... Trojanowski, J. Q. (2018). Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain : a Journal of Neurology, 141(7), 2181-2193. https://doi.org/10.1093/brain/awy146
Robinson JL, et al. Neurodegenerative Disease Concomitant Proteinopathies Are Prevalent, Age-related and APOE4-associated. Brain. 2018 07 1;141(7):2181-2193. PubMed PMID: 29878075.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. AU - Robinson,John L, AU - Lee,Edward B, AU - Xie,Sharon X, AU - Rennert,Lior, AU - Suh,EunRan, AU - Bredenberg,Colin, AU - Caswell,Carrie, AU - Van Deerlin,Vivianna M, AU - Yan,Ning, AU - Yousef,Ahmed, AU - Hurtig,Howard I, AU - Siderowf,Andrew, AU - Grossman,Murray, AU - McMillan,Corey T, AU - Miller,Bruce, AU - Duda,John E, AU - Irwin,David J, AU - Wolk,David, AU - Elman,Lauren, AU - McCluskey,Leo, AU - Chen-Plotkin,Alice, AU - Weintraub,Daniel, AU - Arnold,Steven E, AU - Brettschneider,Johannes, AU - Lee,Virginia M-Y, AU - Trojanowski,John Q, PY - 2017/12/01/received PY - 2018/04/06/accepted PY - 2018/6/8/pubmed PY - 2019/7/18/medline PY - 2018/6/8/entrez SP - 2181 EP - 2193 JF - Brain : a journal of neurology JO - Brain VL - 141 IS - 7 N2 - Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-β, α-synuclein and TDP-43. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/29878075/Neurodegenerative_disease_concomitant_proteinopathies_are_prevalent_age_related_and_APOE4_associated_ DB - PRIME DP - Unbound Medicine ER -