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Association of Apolipoprotein E ε4 With Transactive Response DNA-Binding Protein 43.
JAMA Neurol 2018; 75(11):1347-1354JN

Abstract

Importance

Transactive response DNA-binding protein 43 (TDP-43) is associated with Alzheimer disease (AD), progressive hippocampal atrophy, and cognitive decline. The apolipoprotein E (APOE) ε4 allele is strongly associated with β-amyloid (Aβ) aggregation and risk of AD, but its association with TDP-43 is unknown.

Objective

To determine whether the APOE ε4 allele is a risk factor for TDP-43.

Design, Setting, Participants

This cross-sectional, genetic-histologic study analyzed APOE genotype, TDP-43 status (positive vs negative), Aβ status (positive vs negative), and tau neurofibrillary tangle stage (B0, Braak stage 0; B1, Braak stages I-II; B2, Braak stages III-IV; B3, Braak stage ≥ V). We fit structural equation models to map the association between APOE and TDP-43, Aβ, and tau, accounting for age and hippocampal sclerosis. We identified 751 participants with an AD pathological spectrum diagnosis and completed Aβ, tau, and TDP-43 data who were enrolled in the Mayo Clinic Alzheimer Disease Research Center, Mayo Clinic Alzheimer Disease Patient Registry, or the population based Mayo Clinic Study of Aging and died between May 12, 1999, and December 31, 2015. However, 13 were excluded from the analyses because of missing APOE data, leaving a total of 738 participants.

Main Outcomes and Measures

Transactive response DNA-binding protein 43 was the main outcome of interest. We hypothesized that the APOE ε4 allele would be significantly directly and indirectly associated with TDP-43.

Results

The 751 study participants were older (median age [interquartile range], 87 years [51-105 years]), 395 (54%) were women, and 324 (44%) were APOE ε4 carriers. The patients died between May 12, 1999, and December 31, 2015. Accounting for age, Aβ, and tau, APOE ε4 had a direct association with TDP-43 (estimate [SE], 0.31 (0.11); P = .01). The association was present among individuals with an intermediate to high likelihood of having AD (neurofibrillary tangle stage B2/B3; n = 604 [81.8%]; estimate [SE], 0.51 [0.11]; P < .001), with a similar trend for those with a low likelihood of having AD (B1; n = 134 [18.2%]; estimate [SE], 0.54 [0.32]; P = .10). We also found an indirect association of APOE ε4 with TDP-43 via Aβ and tau (estimate [SE], 0.34 [0.06]; P < .001), which was similar in magnitude to the direct association and an indirect association of APOE ε4 with hippocampal sclerosis via TDP-43 (estimate [SE], 0.65 [0.26]; P = .01).

Conclusions and Relevance

The study's findings, which mapped a system of risk factors and outcomes, showed that the APOE ε4 allele appears to be a risk factor for TDP-43 independently of Aβ in patients with AD.

Authors+Show Affiliations

Department of Neurology, Mayo Clinic, Rochester, Minnesota.Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.Department of Radiology, Mayo Clinic, Rochester, Minnesota.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.Department of Neurology, Mayo Clinic, Rochester, Minnesota.Department of Laboratory Medicine and Pathology, Rochester, Minnesota.Department of Neurology, Mayo Clinic, Rochester, Minnesota.Department of Neurology, Mayo Clinic, Rochester, Minnesota.Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.Department of Neurology, Mayo Clinic, Rochester, Minnesota.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30422173

Citation

Wennberg, Alexandra M., et al. "Association of Apolipoprotein E Ε4 With Transactive Response DNA-Binding Protein 43." JAMA Neurology, vol. 75, no. 11, 2018, pp. 1347-1354.
Wennberg AM, Tosakulwong N, Lesnick TG, et al. Association of Apolipoprotein E ε4 With Transactive Response DNA-Binding Protein 43. JAMA Neurol. 2018;75(11):1347-1354.
Wennberg, A. M., Tosakulwong, N., Lesnick, T. G., Murray, M. E., Whitwell, J. L., Liesinger, A. M., ... Josephs, K. A. (2018). Association of Apolipoprotein E ε4 With Transactive Response DNA-Binding Protein 43. JAMA Neurology, 75(11), pp. 1347-1354. doi:10.1001/jamaneurol.2018.3139.
Wennberg AM, et al. Association of Apolipoprotein E Ε4 With Transactive Response DNA-Binding Protein 43. JAMA Neurol. 2018 11 1;75(11):1347-1354. PubMed PMID: 30422173.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of Apolipoprotein E ε4 With Transactive Response DNA-Binding Protein 43. AU - Wennberg,Alexandra M, AU - Tosakulwong,Nirubol, AU - Lesnick,Timothy G, AU - Murray,Melissa E, AU - Whitwell,Jennifer L, AU - Liesinger,Amanda M, AU - Petrucelli,Leonard, AU - Boeve,Bradley F, AU - Parisi,Joseph E, AU - Knopman,David S, AU - Petersen,Ronald C, AU - Dickson,Dennis W, AU - Josephs,Keith A, PY - 2018/11/14/entrez PY - 2018/11/14/pubmed PY - 2019/10/11/medline SP - 1347 EP - 1354 JF - JAMA neurology JO - JAMA Neurol VL - 75 IS - 11 N2 - Importance: Transactive response DNA-binding protein 43 (TDP-43) is associated with Alzheimer disease (AD), progressive hippocampal atrophy, and cognitive decline. The apolipoprotein E (APOE) ε4 allele is strongly associated with β-amyloid (Aβ) aggregation and risk of AD, but its association with TDP-43 is unknown. Objective: To determine whether the APOE ε4 allele is a risk factor for TDP-43. Design, Setting, Participants: This cross-sectional, genetic-histologic study analyzed APOE genotype, TDP-43 status (positive vs negative), Aβ status (positive vs negative), and tau neurofibrillary tangle stage (B0, Braak stage 0; B1, Braak stages I-II; B2, Braak stages III-IV; B3, Braak stage ≥ V). We fit structural equation models to map the association between APOE and TDP-43, Aβ, and tau, accounting for age and hippocampal sclerosis. We identified 751 participants with an AD pathological spectrum diagnosis and completed Aβ, tau, and TDP-43 data who were enrolled in the Mayo Clinic Alzheimer Disease Research Center, Mayo Clinic Alzheimer Disease Patient Registry, or the population based Mayo Clinic Study of Aging and died between May 12, 1999, and December 31, 2015. However, 13 were excluded from the analyses because of missing APOE data, leaving a total of 738 participants. Main Outcomes and Measures: Transactive response DNA-binding protein 43 was the main outcome of interest. We hypothesized that the APOE ε4 allele would be significantly directly and indirectly associated with TDP-43. Results: The 751 study participants were older (median age [interquartile range], 87 years [51-105 years]), 395 (54%) were women, and 324 (44%) were APOE ε4 carriers. The patients died between May 12, 1999, and December 31, 2015. Accounting for age, Aβ, and tau, APOE ε4 had a direct association with TDP-43 (estimate [SE], 0.31 (0.11); P = .01). The association was present among individuals with an intermediate to high likelihood of having AD (neurofibrillary tangle stage B2/B3; n = 604 [81.8%]; estimate [SE], 0.51 [0.11]; P < .001), with a similar trend for those with a low likelihood of having AD (B1; n = 134 [18.2%]; estimate [SE], 0.54 [0.32]; P = .10). We also found an indirect association of APOE ε4 with TDP-43 via Aβ and tau (estimate [SE], 0.34 [0.06]; P < .001), which was similar in magnitude to the direct association and an indirect association of APOE ε4 with hippocampal sclerosis via TDP-43 (estimate [SE], 0.65 [0.26]; P = .01). Conclusions and Relevance: The study's findings, which mapped a system of risk factors and outcomes, showed that the APOE ε4 allele appears to be a risk factor for TDP-43 independently of Aβ in patients with AD. SN - 2168-6157 UR - https://www.unboundmedicine.com/medline/citation/30422173/Association_of_Apolipoprotein_E_ε4_With_Transactive_Response_DNA_Binding_Protein_43_ L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2018.3139 DB - PRIME DP - Unbound Medicine ER -