Objective To investigate the occurrence rates and changing role of plasma antibodies to Aβs in normal aging and their enlightenment to the pathogenesis of Alzheimer's disease.Methods Paraffin serial sections from Tg2576 mouse brains were immunostained with 205 plasma samples from healthy cases aged from 1 to 91 years old to make a specific tissue amyloid plaque immunoreactivity analysis, and subsequently, immunoprecipitation of plasma with synthetic Aβ peptides and formic acid soluble amyloid Aβ fractions (FAβ) was employed to clarify the immunospecialties of autoantibodies to Aβs. Results Plasma autoantibodies to Aβs were found to be naturally present in all age periods, even in childhood and juvenile, the total occurrence rate was 35.6%, and they showed a special age-related U-typed trend during aging. Conclusions Plasma autoantibodies to Aβ can occur before amyloid plaques in brains, and with no relationship with brain Aβ burden.