Associations of plasma biomarkers and amyloid positron emission tomography with regional tau burden in Alzheimer’s disease

Purpose Amyloid positron emission tomography (PET) and plasma biomarkers are clinically established; however, their topographical relationship with regional tau burden remains unclear. We investigated whether amyloid PET and plasma biomarkers are associated with regional tau pathology, measured using second-generation tracer florzolotau ( 18 F) PET, across the Alzheimer’s disease (AD) continuum. Materials and methods This cross-sectional study enrolled participants who underwent biomarker assessment between September 2018 and May 2022. The primary outcome was the voxel-wise spatial correlation of florzolotau ( 18 F) standardised uptake value ratio with amyloid PET centiloid and plasma biomarkers, assessed using age- and sex-adjusted whole-brain and region-of-interest (ROI) linear regression analyses, including multivariate models adjusted for amyloid PET centiloid. Results The study included 92 individuals (mean age, 71 [standard deviation, 8.8] years; 46 men), comprising 40 amyloid-negative healthy controls, 10 patients with preclinical AD, 21 with mild cognitive impairment due to AD, and 21 with AD dementia. In initial analyses, regional tau uptake correlated widely with plasma amyloid-beta 42/40 (Aβ42/40) ratio, p-tau, and glial fibrillary acidic protein (GFAP). However, following multivariate adjustment for global amyloid burden, correlations for Aβ42/40 and GFAP were completely abolished. In contrast, plasma p-tau217, p-tau181, and neurofilament light chain (NfL) maintained significant amyloid-independent correlations with temporoparietal tau uptake, with p-tau217 uniquely retaining robust and extensive associations across the cortex. Conclusion Plasma p-tau217 is strongly associated with the spatial distribution and severity of tau burden independent of global amyloid burden. Measuring plasma p-tau217 holds significant potential for patient stratification and monitoring in the era of disease-modifying therapies. Trial registration UMIN Clinical Trials Registry (UMIN000032027), registered 31 March 2018, prospectively registered (URL https//center6.umin.ac.jp/cgiopenbin/ctr_e/ctr_view.cgi? recptno=UMIN000032027). Japan Registry of Clinical Trials (jRCTs031180225), prospectively registered (URL https//jrct.niph.go.jp/enlatestdetail/jRCTs031180225).