We aim to compare the biological staging of Alzheimer Disease using two different tau PET tracers.

The Alzheimer’s Association workgroup criteria (AA-2024) suggest four biological stages based on PET imaging. However, the application of this framework may vary depending on the tau PET tracer used. Also, the distribution of clinical stages by biological stage may differ.

We stratified 182 amyloid-positive participants from the HEAD study (Head-to-Head Harmonization of Tau Tracers in Alzheimer's Disease) that underwent both [18F]MK-6240 and Flortaucipir tau PET. Four clinical stages (normal, transitional, MCI, and dementia) were defined based on the AA-2024 criteria. Within clinical stage-2 (transitional) we assessed subgroups: subjective cognitive decline (SCD), subtle objective cognitive decline (SOCD), and mild behavioral impairment (MBI). Logistic and linear models corrected by age and sex tested association of groups with amyloid and tau pathology. The biological staging was performed using tracer-specific thresholds for regional SUVR and testing three regions of interest schemes: (i)proposed by AA-2024, (ii)Braak stages, (iii)or single anatomical regions. Cohen’s weighted-kappa (K) statistic measured clinical-biological and between-tracer agreements.

Clinical stages showed progressively increased prevalence of Aβ-positivity and higher entorhinal tau PET pathology from cognitively normal (CN) to SOCD, MCI, and dementia, in both tracers. MBI and SCD groups showed no increased Aβ or tau pathology compared to CN. For this reason, only SOCD was considered part of stage 2 for following analyses. All tested biological staging strategies showed moderate agreement (Cohen's-kappa 0.34-0.59) with clinical stages for both MK-6240 and Flortaucipir.

Our results support that AA-2024 biological and clinical stages show similar clinical-biological concordance using either Flortaucipir or MK-6240, although this can vary based on biological staging method. Only SOCD among transitional stage subgroups showed higher amyloid and tau burden compared to clinical stage 1, while SCD and MBI showed similar pathologic burden to the cognitively normal group.