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Background: Amyloid‐β (Aβ) PET is commonly used for studying the earliest phases of Alzheimer's disease (AD) in cognitively unimpaired (CU) individuals. In this group, the expected changes in Aβ pathology are small, which emphasizes the importance of selecting a method with the highest possible precision for measuring these changes. This study compared several methods for quantifying Aβ pathology longitudinally in mostly CU individuals from the AMYPAD‐PNHS cohort. Method: Participants were scanned with either [18F]flutemetamol (baseline N = 360, follow‐up N = 243) or [18F]florbetaben (N = 66 baseline, N = 49 follow‐up), according to a dual‐time window protocol(Table 1). A subset of participants had ≥2 timepoints available (N = 206, N = 43, respectively). SUVRs were calculated, and parametric modelling was performed using RPM, SRTM2, RLogan, MRTM0, MRTM and MRTM2 using PPET software to generate parametric BPND or DVR images for a global cortical region, all with cerebellar cortex as reference tissue. Annual percentage change (APC) was calculated and compared between methods using an ANOVA. To check for changes in Aβ pathology over time, a linear mixed effects model was used. Bland‐Altman analyses were used to explore agreement between SUVR, and the outcome parameter from the parametric methods. All analyses were run per tracer, separately for visual Aβ‐positive and Aβ‐negative individuals, with a p‐value threshold of p<0.05. Result: For both tracers, there were no differences in APC between methods. However, method‐dependent differences in interquartile range of the APC were observed(Figure 1,2). For [18F]flutemetamol, only the Aβ‐negative group showed a significant change in Aβ pathology for SUVR and SRTM2 (both ‐0.004/year). For [18F]florbetaben, only the Aβ‐positive group showed a significant change in Aβ pathology for all methods except MRTM2 (range: +0.020‐0.032/year). No significant bias was observed between APC in SUVR and the other methods for either tracer or Aβ‐group. Conclusion: There were no significant differences in APC between methods, despite method‐dependent variability. In the [18F]flutemetamol‐cohort, two methods showed a minimal decrease in Aβ pathology in the Aβ‐negative‐group, possibly related to measurement variability, which requires further investigation. In the [18F]florbetaben‐cohort, which included more participants with a very mild cognitive impairment, a significant increase in Aβ pathology was observed in the Aβ‐positive‐group, except for MRTM2. [ABSTRACT FROM AUTHOR]