OBJECTIVE: Active or passive immunization of Alzheimer's disease (AD) patients leads to targeting of beta-amyloid plaques by immunoglobulins (IgG) and their subsequent removal by microglia. Here, we investigate whether naturally occurring autoantibodies to beta-amyloid contribute to beta-amyloid plaque removal in nonimmunized AD patients. METHODS: We generated an AD tissue microarray with 2,325 tissue specimens from 3 defined central nervous system regions of 48 AD patients and 48 age-matched control patients. Absolute quantification of beta-amyloid, beta-amyloid plaque-bound IgG, and phagocytic, resting, and activated microglia and microhemorrhages was done using a standardized, highly reproducible scoring system. RESULTS: The majority of neuritic plaques are decorated by IgG. AD patients with prominently IgG-labeled neuritic plaques have a significantly reduced plaque burden and an increase in phagocytic microglia, yet no increase in microhemorrhages. INTERPRETATION: Autoantibodies directed against beta-amyloid are common in AD patients and may contribute in controlling plaque burden.