Basic Science and Pathogenesis

Alzheimer's disease (AD) is marked by the stereotypical spread of hyperphosphorylated tau (p-tau), which closely correlates with neuronal loss and clinical decline, making it a key disease marker. While other tau posttranslational modifications (PTMs) exist in AD pathology, the prevailing model assumes they always co-occur with p-tau inclusions. However, our recent findings challenge this, showing that caspase-6-truncated tau (tr-tau), a pathological PTM generated by active caspases, is as prevalent as p-tau in neurons, yet only 40% of tr-tau-positive neurons also contain p-tau. This suggests tr-tau is a previously unrecognized AD marker and a potential therapeutic target. However, it remains unclear how early tr-tau accumulates relative to p-tau and whether their limited overlap persists in earlier disease stages. Here, we investigate tr-tau deposition patterns throughout AD progression.

We analyzed 56 cases (Table 1) spanning all AD Braak stages (0-6). We used multiplex immunofluorescence to probe tr-tau (D13, D402, TauC3) and p-tau (PHF1) species in the same slides of postmortem human brain tissue. We quantified neuronal tau pathology and colocalization in scans of entorhinal cortex (EC, a Braak 1 region) and inferior temporal gyrus (ITG, a Braak 4 region).

We detected D13 tr-tau before p-tau in EC and ITG (Figure 1A/B). Tr-tau burden was higher than p-tau burden at early Braak stages (Figure 1A/B). The EC accumulated more D13 tr-tau than the ITG in early Braak stages (Figure 1A/B). Overlap between D13 tr-tau and p-tau was minimal in both regions from early to late Braak stages, with 0% at Braak 3 in both regions and 16.7% and 16.1% at Braak 5 in EC and ITG, respectively (Figure 2).

Our findings challenge the prevailing model that tau PTMs always co-occur with p-tau inclusions in AD. We demonstrate that caspase-6-cleaved tr-tau appears earlier than p-tau in EC and ITG, with a higher burden at early Braak stages. Additionally, tr-tau and p-tau show minimal colocalization throughout disease progression, reinforcing the idea that tr-tau represents a distinct and previously overlooked pathological feature of AD. These results highlight tr-tau as a potential early marker of AD progression and a promising target for therapeutic intervention.