TDP‐43 and tau concurrence in the entorhinal subfields in primary age‐related tauopathy and preclinical Alzheimer's disease

Phosphorylated tau (p‐tau) pathology correlates strongly with cognitive decline and is a pathological hallmark of Alzheimer's Disease (AD). In recent years, phosphorylated transactive response DNA‐binding protein (pTDP‐43) has emerged as a common comorbidity, found in up to 70% of all AD cases (Josephs et al., Acta Neuropathol, 131(4), 571–585; Josephs, Whitwell, et al., Acta Neuropathol, 127(6), 811–824). Current staging schemes for pTDP‐43 in AD and primary age‐related tauopathy (PART) track its progression throughout the brain, but the distribution of pTDP‐43 within the entorhinal cortex (EC) at the earliest stages has not been studied. Moreover, the exact nature of p‐tau and pTDP‐43 co‐localization is debated. We investigated the selective vulnerability of the entorhinal subfields to phosphorylated pTDP‐43 pathology in preclinical AD and PART postmortem tissue. Within the EC, posterior‐lateral subfields showed the highest semi‐quantitative pTDP‐43 density scores, while the anterior‐medial subfields had the lowest. On the rostrocaudal axis, pTDP‐43 scores were higher posteriorly than anteriorly (p < 0.010), peaking at the posterior‐most level (p < 0.050). Further, we showed the relationship between pTDP‐43 and p‐tau in these regions at pathology‐positive but clinically silent stages. P‐tau and pTDP‐43 presented a similar pattern of affected subregions (p < 0.0001) but differed in density magnitude (p < 0.0001). P‐tau burden was consistently higher than pTDP‐43 at every anterior–posterior level and in most EC subfields. These findings highlight pTDP‐43 burden heterogeneity within the EC and the posterior‐lateral subfields as the most vulnerable regions within stage II of the current pTDP‐43 staging schemes for AD and PART. The EC is a point of convergence for p‐tau and pTDP‐43 and identifying its most vulnerable neuronal populations will prove key for early diagnosis and disease intervention.