Wennberg AM, et al. - In this cross-sectional, genetic-histologic study, researchers intended to determine if the apolipoprotein E (APOE) ε4 allele is a risk factor for transactive response DNA-binding protein 43 (TDP-43). In patients with Alzheimer disease (AD), the APOE ε4 allele seems to be a risk factor for TDP-43 independently of β-amyloid (Aβ).

Methods

• For this investigation, researchers 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).
• They map the association between APOE and TDP-43, Aβ and tau with age and hippocampal sclerosis in structural equation models.
• They identified 751 study participants (with an AD pathological spectrum diagnosis and completed Aβ, tau, and TDP-43 data) who were enlisted 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 due to the lack of APOE data and 738 participants were left.
• The main outcome of interest was transactive response DNA-binding protein 43.
• They assumed that the APOE ε4 allele would be significantly directly and indirectly related to TDP-43.

Results

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