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Cited by 206Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

Prevalence and clinical phenotype of quadruple misfolded proteins in older adults

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Karanth, Shama, Nelson, Peter T., Katsumata, Yuriko, Kryscio, Richard J., Schmitt, Frederick A., Fardo, David W., Cykowski, Matthew D., Jicha, Gregory A. +2 more·2020·JAMA Neurology
DOI 10.1001/jamaneurol.2020.1741PMC PMC7309572
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Abstract

Importance: Quadruple misfolded proteins (tau neurofibrillary tangles, amyloid-β [Aβ], α-synuclein, and transactive response DNA-binding protein 43 [TDP-43]) in the same brain are relatively common in aging. However, the clinical presentation, associated factors, frequency in community-based cohorts, genetic characteristics, and cognitive trajectories associated with the quadruple misfolded proteins phenotype are not well understood. Objective: To describe the quadruple misfolded proteins phenotype, including the trajectories of global cognition, in an autopsy cohort. Design, Setting, and Participants: This retrospective cohort study used brain autopsy data from the University of Kentucky Alzheimer Disease Center (UK-ADC) Brain Bank. Participants were deceased individuals who were enrolled in a longitudinal community-based cohort study of aging and dementia in central Kentucky conducted by the UK-ADC. Included participants were enrolled in the UK-ADC cohort between January 1, 1989, and December 31, 2017; aged 55 years or older at baseline; and followed up for a mean duration of 10.4 years. The participants had Alzheimer disease pathology (tau and Aβ), α-synuclein, and TDP-43 data, along with Braak neurofibrillary tangle stage I to VI. Data analysis was conducted between February 1, 2019, and September 30, 2019. Main Outcomes and Measures: Frequency of quadruple misfolded proteins was estimated, and proteinopathy group characteristics and associations with global cognition were evaluated. Multinomial logistic regression was used to estimate the association of proteinopathy group with participant characteristics, including age at death, sex, and apolipoprotein ε4 (APOE ε4) allele. Generalized estimating equations were used to estimate the probability of obtaining Mini-Mental State Examination (MMSE) scores within the normal cognition (27-30 points) and severe impairment (≤13 points) ranges during the 12 years before death. Results: The final sample included 375 individuals (mean [SD] age at death, 86.9 [8.0] years); 232 women [61.9%]). Quadruple misfolded proteins were detected in 41 of 214 individuals with dementia (19.2%). Overall, 46 individuals (12.3%) had quadruple misfolded proteins, whereas 143 individuals (38.1%) had 3 proteinopathies. Dementia frequency was highest among those with quadruple misfolded proteins (41 [89.1%]), and participants with quadruple misfolded proteins had the lowest final mean (SD) MMSE scores of 13.4 (9.8) points. Adjusting for age at death and sex, the APOE ε4 allele was associated with higher odds of quadruple misfolded proteins (adjusted odds ratio, 2.55; 95% CI, 1.16- 5.62; P = .02). The quadruple misfolded proteins group had both the lowest probability of obtaining MMSE scores in the normal cognition range, even 12 years before death, and the highest probability of having MMSE scores in the severe impairment range. Conclusions and Relevance: Quadruple misfolded proteins appear to be a common substrate for cognitive impairment and to be associated with an aggressive course of disease that typically ends with severe dementia. The prevalence of comorbid α-synuclein and TDP-43 with Alzheimer disease pathology (tau and Aβ) may complicate efforts to identify therapies to treat and prevent Alzheimer disease.

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  • Carriers of the APOEε4 allele have increased odds of a multi-proteinopathy, whereas carrying the APOEε2 allele reduces these odds, relative to APOEε3 homozygosis.

    “Carriers of the APOEε4 allele have increased odds of a multi-proteinopathy, whereas carrying the APOEε2 allele reduces these odds, relative to APOEε3 homozygosis60,61.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [60]

    The Results report higher odds of quadruple misfolded proteins among APOE ε4 carriers (adjusted OR 2.55). However, the Covariates section models ε4 carriage rather than ε2 carriage, and the Statistical Analysis section uses a tau-and-Aβ proteinopathy group—not APOE ε3 homozygotes—as the outcome reference. The paper therefore does not support the claimed reduction for ε2 or the stated genotype comparison. (LLM, conf=0.88)

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  • 50-60% of Alzheimer's-type dementia is estimated to be attributable to copathologies including α-synucleinopathy, vascular pathology, non-Alzheimer's disease tauopathies, and TDP-43 pathology.

    “50–60% of Alzheimer’s-type dementia (dementia defined clinically as Alzheimer’s disease) is estimated to be attributable to these copathologies.40,42–45”

    From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [44]

  • Alzheimer's disease can be associated with other brain pathologies, including α-synucleinopathy, vascular pathology, non-Alzheimer's disease tauopathies, and TDP-43 pathology.

    “Alzheimer’s disease can be associated with other brain pathologies, including α-synucleinopathy,56 vascular pathology, non-Alzheimer’s disease tauopathies, and TDP-43 pathology.40,42–44”

    From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [44]

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Authors
Karanth, S., Nelson, P. T., Katsumata, Y., Kryscio, R. J., Schmitt, F. A., Fardo, D. W., Cykowski, M. D., Jicha, G. A., Van Eldik, L. J., & Abner, E. L.
Affiliations
  • University of Kentucky (US)
  • Houston Methodist (US)
  • Sanders-Brown Center on Aging, University of Kentucky, Lexington
Corresponding author
Abner, Erin L.
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2020-10-01
Volume
77
Issue
10
Pages
1299
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2020.1741
PMC
PMC7309572
OpenAlex
W3035869254
Cited by
206
References
60
Citations by year
2026: 25 · 2025: 33 · 2024: 46 · 2023: 33 · 2022: 38 · 2021: 24 · 2020: 7
FWCI
18.61
Type
journal article
Language
en
Open access
Locations
  • JAMA Neurology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Eli Lilly and Company
  • Eisai
  • National Institutes of Health (5r01ag038651-10)
  • National Institute on Aging (AG-028383, R01‐AG038651, P30AG028383, P01AG003949, R56AG057191, P30AG072946)
  • National Heart, Lung, and Blood Institute
  • National Institute on Drug Abuse
  • National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
neurofibrillary tangles, amyloid-beta, alpha-synuclein, TDP-43, proteinopathies, dementia, Alzheimer's disease, cognitive trajectories, APOE ε4, older adults, autopsy brain tissue, clinical phenotype, central Kentucky
MeSH terms
Aged, Aged, 80 and over, DNA-Binding Proteins, Female, Follow-Up Studies, Humans, Male, Phenotype, Retrospective Studies, Cohort Studies, Prevalence, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, alpha-Synuclein, Proteostasis Deficiencies

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