Characterizing A‐T+ PET participants across the Alzheimer’s disease spectrum in the ADNI cohort

Abstract Background For individuals on the Alzheimer’s disease trajectory, amyloid positivity generally precedes tau positivity, as defined by PET biomarkers. However, multiple studies report amyloid‐negative tau‐positive PET (A‐T+) participants, whose clinical implications remain unclear. Here, utilizing the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, we examined how A‐T+ participants differ from other A/T profiles based on cognition, fluid biomarkers, and neuropathology—we also investigated the longitudinal trajectories of A‐T+ participants. Method We studied 806 participants from the ADNI cohort who underwent an initial amyloid ( 18 F‐Florbetaben, FBB, or 18 F‐Florbetapir, FBP) and tau ( 18 F‐Flortaucipir, FTP) PET‐scan. The amyloid‐positivity thresholds for FBB and FBP were SUVR = 1.08 and SUVR = 1.11, respectively. Tau‐positivity was set as 2SD above the mean of Aβ‐PET negative CU participants in a neocortical ROI (SUVR = 1.24). The A‐T+ participants were then compared to other A/T biomarker groups in terms of clinical diagnoses, CSF/plasma Aβ and ptau, and hippocampal volume. Using a similar approach, we assessed the concordance of A‐T+ participants using CSF Aβ42 (981 pg/mL) and phosphorylated tau 181 (24.3 pg/mL) instead. Finally, we assessed the cognitive and biomarker trajectories of PET A‐T+ participants. Result Twelve participants were classified as PET A‐T+. Of eleven PET A‐T+ participants with CSF biomarker data, only two (18%) were also CSF A‐T+ (A‐T‐ = 4, A+T‐ = 2, A+T+ = 3). Across all outcomes, A‐T+ (PET or CSF) participants fared similarly to A‐T‐ participants ( Figures 1 and 2 ). Overall, PET A‐T+ exhibited benign longitudinal trajectories ( Figure 3 ). However, one participant, classified as PET A‐T+ but CSF A+T+, displayed concomitant precipitous declines across all cognitive domains, which coincided with an acceleration in neocortical tau burden. Conclusion While displaying pathological levels of cerebral tau, PET A‐T+ participants are highly similarly to PET A‐T‐ participants. Additionally, there is minimal overlap between PET A‐T+ and CSF A‐T+ participants, emphasizing the fact that PET and CSF biomarkers are not interchangeable. While A‐T+ may reflect participants with primary age‐related tauopathy (PART), in which amyloidosis is not the primary driver of tau accumulation, some A‐T+ participants might also have amyloidosis levels that are not yet detectable with PET.