Low-dose CT for MRI-free Quantification of Tau PET in Alzheimer’s Disease: a Multicentre, Cross-Sectional, Comparison Study

Background Tau PET quantification typically requires structural MRI for reference-region definition, normalisation, and segmentation, which imposes a logistical and operational burden. In this study, we evaluated whether low-dose CT can serve as a reliable MRI alternative for tau PET quantification when MRI is unavailable. Methods In this multicentre, cross-sectional study comparing methods, we developed a PET–CT pipeline using low-dose CT as the sole anatomical reference for tau PET quantification. Participants were recruited from six sites in the multicentre Head-to-head Harmonisation of tau PET tracers (HEAD) study (NCT05361382). The cohort comprised cognitively unimpaired young adults (<28 years), cognitively unimpaired middle-aged adults (50–65 years), cognitively unimpaired older adults (>65 years), and participants with mild cognitive impairment or dementia. Participants underwent [18F]MK6240 and [18F]flortaucipir PET–CT, T1-weighted MRI, and amyloid PET. Standardised uptake value ratios were calculated for three Alzheimer’s disease-relevant composite regions and 34 individual brain regions using a template-based cerebellar reference and compared with PET–MR pipelines using template-based or FreeSurfer subject-space segmentation. Agreement was assessed using linear regression, intraclass correlation coefficients, Bland–Altman analysis, equivalence testing (two one-sided tests), and Cohen’s kappa (κ) for binary positivity concordance. Findings 387 participants were included, with recruitment spanning from Nov 11, 2022, to July 7, 2025 (205 [53%] women, 182 [47%] men; six [2%] aged 19–25 years, 130 [34%] aged 50–65 years, and 251 [65%] aged 66–89 years). CT-derived standardised uptake value ratios showed near-perfect linear correspondence with the template-based PET–MR pipeline for MK6240 (R2=0·959–0·975) and flortaucipir (0·925–0·964), with high absolute agreement (intraclass correlation coefficient 0·976–0·985 for MK6240 and 0·955–0·978 for flortaucipir). Against the FreeSurfer subject-space pipeline, correspondence remained strong for MK6240 (R2=0·952–0·971) and flortaucipir (0·909–0·949). Mean R2 across 34 brain regions was 0·917 (SD 0·049) for MK6240 and 0·874 (0·057) for flortaucipir. Tau-positivity concordance was high (92–97%; κ 0·802–0·895; all p<0·001), with discordant cases near the classification threshold. Associations with amyloid burden and memory were preserved across pipelines (Steiger’s test, all p>0·05). Equivalence was formally confirmed by two one-sided tests (all p<0·001). Interpretation CT-only processing enables robust tau PET quantification, comparable to standard MRI-based pipelines, including computationally intensive FreeSurfer-based approaches. This method was validated across different radiotracers and represents a reliable alternative when MRI is unavailable or contraindicated. Because low-dose CT is routinely acquired during PET–CT sessions, this approach enables quantification of legacy datasets without MRI, broadens participant inclusion in clinical trials, and can reduce imaging costs in settings where MRI is not clinically indicated. Funding National Institute on Aging.