Using CA1 rather than the whole hippocampus to capture tau-PET Braak stage II

Tau-PET enables in-vivo staging of Alzheimer disease (AD) pathology, including early Braak stage II involvement of the hippocampus. Conventional whole-hippocampus definitions combine heterogeneous subfields and are susceptible to off-target signal that varies across tracers, limiting sensitivity, specificity, and longitudinal interpretability of early tau accumulation.

Cross-sectional and longitudinal analyses were conducted in the TRIAD (N = 456) and the ADNI (N = 497) observational cohorts with tau-PET with [¹⁸F]MK-6240 or [¹⁸F]flortaucipir and structural MRI. A CA1-specific Braak stage II region of interest was compared with a whole-hippocampus approach. Outcomes included Braak stage concordance, longitudinal stability, tau-PET progression, and biological plausibility assessed by amyloid-PET burden and extrahippocampal tau signal.

Spatial analyses localised early hippocampal tau-PET signal predominantly to the anterior CA1. Whole-hippocampus measures were more frequently influenced by off-target signal consistent with choroid plexus contamination. Participants classified as CA1-based Braak stage II showed higher amyloid-PET burden, more consistent tau accumulation in the Braak stage III region, and more stable longitudinal progression. CA1-based staging yielded fewer discordant classifications and fewer stage regressions at follow-up.

CA1-specific tau-PET quantification improves biological plausibility and longitudinal consistency of Braak stage II classification by targeting the hippocampal subfield most vulnerable to early tau pathology and mitigating off-target contamination. CA1-based Braak stage II participants showed greater coherence with the biological framework of AD than those staged using the whole hippocampus. Applicable to available PET resolution, this approach may enhance characterisation of early AD and support participant selection in trials targeting preclinical tau accumulation.