Tau burden across Braak stages is associated with regionally specific amyloid accumulation

Abstract Alzheimer’s disease is defined by the abnormal accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles, the two hallmark proteinopathies detectable via molecular imaging. Aβ deposition typically begins in neocortical regions and is hypothesized to constitute a permissive condition for the subsequent spread of tau. Tau pathology is known to spread systematically through select brain regions, typically described as Braak stages (I-VI), reflecting the spatiotemporal trajectory of tau distribution with disease progression. Evaluating the associations between regional Aβ accumulation and the spatial distribution of tau remains an important question in understanding disease progression. This study examined the associations between regional Aβ and tau burden, measured by positron emission tomography (PET), in 192 participants without dementia (178 cognitively unimpaired, 14 with mild cognitive impairment MCI, ) in the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) cohort (age range: 32–88 years; mean age: 68 years; 58% female), of whom 52 were Aβ positive. Aβ burden was assessed using standardized uptake value ratios (SUVR) obtained from several cortical areas the medial orbitofrontal cortex (OFC), lateral OFC, precuneus, posterior cingulate, anterior cingulate, parietal, temporal, and superior frontal regions, using 11C-PIB PET. Tau burden was quantified using 18F-MK6240 PET, within regions of interest defined as Braak stages I–VI. Elastic net regression was employed to delineate the association of regional Aβ burden and tau PET accumulation across Braak stages, covarying for age, sex, education, and apolipoprotein E (APOE) ɛ4 carrier status. Aβ burden in the medial OFC showed the strongest association with tau burden in Braak stages I–II. For Braak stage III, tau deposition was most strongly associated with Aβ burden in both the medial OFC and precuneus, while in later Braak stages (IV–V), the precuneus showed the strongest association with tau deposition. These region-specific associations remained robust in sensitivity analyses excluding participants with MCI, underscoring the consistency of these findings. Together, these results show regional differences in Aβ-tau associations, with medial OFC Aβ burden being strongly associated with early tau pathology accumulation, while precuneus Aβ burden is associated with tau in later stages. These findings suggest that localized amyloid burden measures may enhance early detection of clinically significant amyloid changes and show utility in understanding Aβ-tau dynamics.