Association of Apolipoprotein e ϵ4 with Transactive Response DNA-Binding Protein 43

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.