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.