Association of hemoglobin A1C with TDP-43 pathology: Supplemental materials

Objective. We tested the hypothesis that an inverse association exists
between diabetes mellitus (DM) and hemoglobin A1C (A1C) with Transactive
response DNA binding protein 43 (TDP-43) levels in older adults. Methods.
We leveraged antemortem and postmortem data of decedents from three
community-based clinical-pathological studies. DM status, A1C levels, and
medications for DM were documented annually. TDP-43 cytoplasmic
inclusions, evaluated in 6 brain regions using immunohistochemistry, were
used to obtain a semiquantitative TDP-43 score (0-5) in each region, and
scores were averaged across regions to obtain a TDP-43 severity score. We
used linear regressions to test the association of DM and A1C with the
TDP-43 severity score. Results. On average, participants (n=817) were 90
years old at the time of death, three fourth were women, and one fourth
had DM. The mean A1C was 6.0% (SD=0.6). TDP-43 was observed in 54% of
participants, and the mean TDP-43 score was 0.7 (range 0-4.5). A higher
level of A1C was associated with a lower TDP-43 score (estimate=-0.156,
S.E.=0.060, p=0.009) while DM had a borderline inverse association with
the TDP-43 score (estimate=-0.163, S.E.=0.087, p=0.060). The association
of higher levels of A1C with lower TDP-43 scores persisted after further
adjustment by Apolipoprotein ε4, vascular risk factors, stroke, and
hypoglycemic medications. Exclusion of the oldest old participants did not
change the results. Conclusion. Overall, the results suggest that a high
level of A1C is associated with less TDP-43 proteinopathy in older persons
while the relationship of DM with TDP-43 needs further study.