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Original Investigation
November 2018

Association of Apolipoprotein E ε4 With Transactive Response DNA-Binding Protein 43

Author Affiliations
  • 1Department of Neurology, Mayo Clinic, Rochester, Minnesota
  • 2Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  • 3Department of Neuroscience, Mayo Clinic, Jacksonville, Florida
  • 4Department of Radiology, Mayo Clinic, Rochester, Minnesota
  • 5Department of Laboratory Medicine and Pathology, Rochester, Minnesota
JAMA Neurol. 2018;75(11):1347-1354. doi:10.1001/jamaneurol.2018.3139
Key Points

Question  Is there an association between apolipoprotein E (APOE) ε4 and transactive response DNA-binding protein 43 (TDP-43), and if so, is it mediated by β-amyloid and tau?

Findings  In this cross-sectional study of 738 older adults with an Alzheimer disease spectrum pathological diagnosis, the APOE ε4 allele was both directly (ie, independent of β-amyloid and tau) and indirectly (ie, mediated by β-amyloid and tau) associated with TDP-43.

Meaning  The APOE ε4 allele appears to be a risk factor for TDP-43 in a model that accounts for age, β-amyloid, and tau, adding to the evidence that suggests that TDP-43 is a substantial factor in Alzheimer disease.


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.