Abstract
Staging the severity of Alzheimer's disease pathology using biomarkers is central to early detection and therapeutic trial design. In this cross-sectional study, we standardized amyloid and tau PET data across multiple cohorts to characterize the frequency of amyloid and tau PET-based stages across the clinical continuum. We examined amyloid and tau severity in 10,396 participants (mean [SD] age, 71.9 [7.1] years) with amyloid PET imaging and a subset (n = 3,295) with tau PET imaging. Clinical stage was defined using cohort-specific criteria and categorized as cognitively unimpaired (n = 7,764), mild cognitive impairment (n = 1,480), or dementia (n = 1,152). Amyloid positivity was defined as ≥25 centiloids and amyloid severity was staged using centiloids bins (e.g., <10, 10-24, 25-49, 50-74, 75-99, ≥100). Tau PET severity was staged using a hierarchical Braak staging schema (e.g., T-, T12+, T34+, T56+), and combined with amyloid status to operationalize PET-based Alzheimer's disease biological stages (e.g., Stage A: A+T-; Stage B: A+T12+; Stage C: A+T34+; Stage D: A+T56+). The cumulative probabilities of PET-based stages were estimated using ordinal logistic regression models. In cognitively unimpaired individuals, the frequency of amyloid levels ≥10 centiloids increased with age. Similarly, amyloid levels ≥25 centiloids increased with age in mild cognitive impairment. Overall, elevated amyloid (≥25 CL) was more likely with increasing age among non-demented individuals. By contrast, this age association was attenuated in dementia where severe amyloid burden (e.g., ≥100 CL) was most common. In the tau PET subsample (n = 3,295), there was a three-way interaction between amyloid, age, and clinical impairment on likelihood of tau severity. Both higher amyloid and greater clinical impairment were associated with increased tau severity; however, the strength and direction of these associations varied with age. At lower amyloid levels, the odds of tau severity increased with older age among cognitively unimpaired and mild cognitive impairment. Conversely, at higher amyloid levels, the odds of higher tau severity (e.g., T56+) decreased with older age in mild cognitive impairment and dementia. A similar age-related pattern was observed in the frequency of biological stages (n = 1,154), where Stage D (e.g., A+T56+) was most frequent in younger individuals with dementia. These findings underscore the dual importance of amyloid and tau PET severity as biomarkers for staging and characterizing Alzheimer's disease progression. They also demonstrate the feasibility of applying PET-based staging frameworks for the diagnosis of Alzheimer's disease across multiple tracers and cohorts.