Tau-PET subtype modifies the association between plasma p-tau217 and memory in Alzheimer's disease

INTRODUCTION: Plasma p-tau217 is associated with Alzheimer's disease pathology and memory performance, but its implications for memory may depend on fibrillar tau topography. We examined whether tau-PET subtype modified the association between plasma p-tau217 and memory. METHODS: We analyzed 396 amyloid-positive, tau-positive participants spanning cognitively unimpaired, mild cognitive impairment, and dementia stages from six cohorts with tau-PET and plasma p-tau217; 301 had harmonized memory data. Tau-PET subtypes were derived using data-driven disease progression modelling. Primary cross-sectional models tested subtype×p-tau217 interactions for memory, adjusting for age, sex, education, APOE ϵ4 status, and cohort. Secondary and exploratory analyses examined latent global cognition, non-memory measures, and longitudinal cognitive change. RESULTS: Three tau-PET subtypes were retained: limbic-predominant, medial temporal lobe (MTL)-sparing, and posterior-predominant. Cross-sectionally, MTL-sparing participants had lower plasma p-tau217 than the other subtypes. The association between higher plasma p-tau217 and worse memory differed by subtype (interaction p =0.002) and was stronger in MTL-sparing ( B =-0.191, p <0.001) than in limbic-predominant ( B =-0.07, p =0.002) and posterior-predominant participants ( B =-0.07, p <0.001). The interaction remained significant after additional adjustment for diagnostic group ( p =0.015). This pattern also persisted after additional adjustment for PET tau burden, amyloid Centiloids, or plasma Aβ42/40﹔ none of these biomarkers showed comparable subtype modification. Subtype modification was also observed for a global cognitive composite (interaction p =0.004) and subsequent memory decline in an exploratory analysis conditioned on baseline memory (interaction p =0.016). DISCUSSION: Tau-PET subtype modified the p-tau217–memory association, suggesting that the cognitive implications of plasma p-tau217 may vary with tau topography.