AbstractObjectiveThe plasma Aß40/42 ratio is a biomarker of brain amyloidosis. However, the threshold difference between amyloid positivity and negativity is only 10–20% and fluctuates with circadian rhythms, aging, andAPOE‐ε4during the decades of evolution of Alzheimer's disease.MethodsPlasma Aß40 and Aß42 levels in 1472 participants aged between 19 and 93 years in the Iwaki Health Promotion Project for 4 years were statistically analyzed.ResultsThe means and standard deviations of annual inter‐individual coefficients of variation were 5.3 ± 3.2% for Aß40, 7.8 ± 4.6% for Aß42, and 6.4 ± 4.1% for the Aß40/42 ratio. No significant age‐dependent changes were observed in inter‐individual coefficients of variation. Age‐dependent increases in Aβ42 levels were suppressed, whereas those in the Aβ40/42 ratio were enhanced inAPOE‐ε4carriers. The change points of Aß42, Aß40, and the Aß40/42 ratio were 36.4, 38.2, and 43.5 years, respectively. In the presence ofAPOE‐ε4, the Aß40/42 ratio increased in middle‐aged and elderly subjects while Aβ42 levels decreased in elderly subjects.InterpretationIndividual values for Aß40, Aß42, and the Aß40/42 ratio did not fluctuate annually or in an age‐dependent manner. If the plasma Aβ40/42 ratio changes by more than 14.7% (+2 standard deviations) relative to age‐ andAPOE‐ε4‐adjusted normal annual fluctuations, other biomarkers also need to be examined.