Fig. 7.

Selected findings and context of the current study. Data were analyzed from participants in 13 high quality community- and population-based cohorts comprising over 6000 individuals followed longitudinally to autopsy. As such, the findings (with appropriate caveats) have broad implications. In participants that had none or minimal ADNC, a substantial proportion (~ 25%) had LATE-NC. This indicates that there are ADNC-independent TDP-43 pathology-driving mechanisms, which probably include gene variants in TMEM106B and GRN [26, 87, 96]. LATE-NC also was associated with more severe PART pathology (and vice versa), indicating pathologic synergy between LATE-NC and PART. Approximately 2/3rd of subjects in advanced age showed moderate or severe ADNC at brain autopsy, in concordance with the published literature [15]. In these individuals, there was a relatively high frequency of LATE-NC: approximately 50% of participants with moderate to severe ADNC had LATE-NC. The “mixed” ADNC-LATE-NC may be driven by pleiotropic genetic factors (e.g., APOE ε4 allele [114]) and there may also be pathologic synergies downstream from genetics. For example, intracellular tauopathy may promote TDP-43 pathology in the same cell [44, 103, 111]. The neuron shown here is stained with immunofluorescence in the hippocampal dentate gyrus, and is immunolabeled green (tau), and red (phospho-TDP-43) with overlap depicted in white [103]