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Brain. 2018 Jul 1;141(7):2181-2193. doi: 10.1093/brain/awy146.

Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated.

Robinson JL1,2,3,4, Lee EB1,2,3,4, Xie SX1,2,3,4,5, Rennert L1,2,3,4,5, Suh E1,2,3,4, Bredenberg C1,2,3,4, Caswell C1,2,3,4,5, Van Deerlin VM1,2,3,4, Yan N1,2,3,4,6, Yousef A1,2,3,4, Hurtig HI1,2,3,7, Siderowf A1,2,3,7, Grossman M1,2,3,7,8, McMillan CT7,8, Miller B9, Duda JE3,10, Irwin DJ1,2,3,7,8, Wolk D1,2,3,7,8,11, Elman L3,7, McCluskey L3,7, Chen-Plotkin A1,2,3,7, Weintraub D2,3,12, Arnold SE13, Brettschneider J14, Lee VM1,2,3,4,7, Trojanowski JQ1,2,3,4,7.

Author information

1
Penn Alzheimer's Disease Core Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
2
Penn Udall Center of Excellence in Parkinson's Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
3
Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
4
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
5
Department of Biostatistics and Epidemiology, and Informatics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
6
University-town Hospital of Chongqing Medical University, China.
7
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
8
Penn Frontotemporal Degeneration Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
9
Memory and Aging Center, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
10
Parkinson's Disease Research, Education and Clinical Center, Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.
11
Penn Memory Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
12
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
13
Translational Neurology Head of the Interdisciplinary Brain Center at Massachusetts General Hospital, Harvard Medical School.
14
Neurological Clinic of the Caritas Clinic of Saarbrücken St. Theresia, Germany.

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.

PMID:
29878075
PMCID:
PMC6022546
DOI:
10.1093/brain/awy146
[Indexed for MEDLINE]
Free PMC Article

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