Tau-PET and CSF MTBR-tau243 comparisons validate increased tau aggregation in females

Background Females consistently demonstrate greater tau Positron Emission Tomography (PET) tracer signal. Although interpreted as reflecting greater Alzheimer disease (AD) pathology, it’s unclear whether differences arise from biological mechanisms or methodological factors. Microtubule binding region tau species containing residue 243 (MTBR-tau243) in cerebrospinal fluid (CSF) is a biomarker of aggregated tau but avoids PET limitations such as off-target binding. Comparing tau-PET and CSF MTBR-tau243, including sex interactions, can help elucidate the origin of sex differences in tau. Purpose Conduct a cross-sectional analysis of CSF MTBR-tau243 and tau-PET by sex in the Swedish BioFINDER-2 (BioFINDER-2) Study and Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight-ADRC). Methods Participants had CSF MTBR-tau243, tau-PET, and Aβ status defined by the CSF Aβ42/40 ratio. Tau-PET was measured using [ 18 F]Flortaucipir (Knight-ADRC, N = 219) and [ 18 F]RO948 (BioFINDER-2, N = 446). We tested the interaction between sex and CSF MTBR-tau243 on tau-PET burden in a temporal meta region-of-interest (ROI) across all participants and in Aβ-positive participants. Results In both cohorts, CSF MTBR-tau243 was associated with tau-PET temporal meta-ROI burden (BioFINDER-2: β = 1.1, p = < 0.0001 and Knight-ADRC: β = 0.7, p = < 0.0001), and this association did not differ by sex (BioFINDER-2 β = 0.04, p = 0.6 and Knight-ADRC: β = 0.009, p = 0.9). Among Aβ-positive subgroups, results remained consistent for the main effect (BioFINDER-2: β = 1.1, p = < 0.0001 and Knight-ADRC: β = 0.7, p = < 0.0001) and interaction (BioFINDER-2: β = 0.04, p = 0.7 and Knight-ADRC: β = 0.06, p = 0.6). Conclusion The lack of sex moderating the association between tau-PET and CSF MTBR-tau243 indicates that higher tau-PET signal in females reflects greater susceptibility to tau pathology rather than a methodological artifact.