Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Oct 1;77(10):1299-1307.
doi: 10.1001/jamaneurol.2020.1741.

Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults

Shama Karanth  1   2 , Peter T Nelson  2   3 , Yuriko Katsumata  2   4 , Richard J Kryscio  2   4   5 , Frederick A Schmitt  2   6 , David W Fardo  2   4 , Matthew D Cykowski  7 , Gregory A Jicha  2   6 , Linda J Van Eldik  2   8 , Erin L Abner  1   2   4
Affiliations

Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults

Shama Karanth et al. JAMA Neurol. .

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Schmitt reported receiving grants from the National Institute on Aging (NIA) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development during the conduct of the study. Dr Fardo reported receiving grants from the NIA, the National Institute on Drug Abuse, and the National Heart, Lung, and Blood Institute. Dr Jicha reported receiving grants from the National Institute of Health during the conduct of the study and grants from Alltech, Biohaven, Eisai, Lilly, Novartis, and Suven outside the submitted work. Dr Van Eldik reported receiving grants from the NIA National Institute of Neurological Disorders and Stroke, and the Alzheimer Drug Discovery Foundation during the conduct of the study. Dr. Kryscio reported receiving support from the NIA, the National Institute on Neurological Diseases and Stroke, and the National Center for Translational Sciences. Dr Abner reported receiving grants from the NIA during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Distribution of Proteinopathy Groups Among Participants With Dementia and Participants With Mild Cognitive Impairment (MCI) Proximate to Death
Aβ indicates amyloid-β; αSyn, α-synuclein; QMP, quadruple misfolded protein; and TDP-43, transactive response DNA-binding protein 43.
Figure 2.
Figure 2.. Hypothesized Patterns of Late-Life Cognitive Decline Associated With Specific Proteinopathies
Quadruple misfolded protein (QMP) is distinguished by early decline in cognition (A), fast transition through mild cognitive impairment of approximately 1.7 years (B), and long duration of severely abnormal cognition (C). Aβ indicates amyloid-β; ADNC, Alzheimer disease neuropathological change; αSyn, α-synuclein; LATE-NC, limbic-predominant, age-related TDP-43 encephalopathy neuropathological change; and TDP-43, transactive response DNA-binding protein 43.
Figure 3.
Figure 3.. Mean Estimated Probabilities of Obtaining Normal or Severely Impaired Mini-Mental State Examination (MMSE) Score Ranges in the 12 Years Before Death
Aβ indicates amyloid-β; αSyn, α-synuclein; QMP, quadruple misfolded protein; and TDP-43, transactive response DNA-binding protein 43.
See this image and copyright information in PMC

References

    1. Montine TJ, Phelps CH, Beach TG, et al. ; National Institute on Aging; Alzheimer’s Association . National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol. 2012;123(1):1-11. doi:10.1007/s00401-011-0910-3 - DOI - PMC - PubMed
    1. Higashi S, Iseki E, Yamamoto R, et al. . Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res. 2007;1184:284-294. doi:10.1016/j.brainres.2007.09.048 - DOI - PubMed
    1. McAleese KE, Walker L, Erskine D, Thomas AJ, McKeith IG, Attems J. TDP-43 pathology in Alzheimer’s disease, dementia with Lewy bodies and ageing. Brain Pathol. 2017;27(4):472-479. doi:10.1111/bpa.12424 - DOI - PMC - PubMed
    1. 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. doi:10.1093/brain/awy146 - DOI - PMC - PubMed
    1. McKeith IG, Dickson DW, Lowe J, et al. ; Consortium on DLB . Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65(12):1863-1872. doi:10.1212/01.wnl.0000187889.17253.b1 - DOI - PubMed

Publication types

MeSH terms