Alzheimer's disease is the most common cause of dementia It is associated with genetic risk factors and at least three autosomal dominant mutations. Community pathologists are frequently asked by families to evaluate autopsy material for Alzheimer's disease. Neuropathologic diagnosis is based on technically difficult silver impregnation stains that may not be readily available to community-based pathologists. Because immunohistochemical techniques are more widely accessible, we evaluated the practical utility of using a single immunohistochemical stain for diagnosing Alzheimer's disease. The ubiquitin antigen was selected because of its presence in morphologically distinct deposits characteristic of several neurodegenerative diseases. Paraffin blocks were obtained from the Bryan Alzheimer's Disease Research Center Brain Bank, a repository of approximately 900 brains. Tissues from 16 individuals who exhibited the entire range of Alzheimer's-type neuropathology were selected. Ubiquitin immunostains, evaluated blindly and independently by four pathologists ranging from first-year resident trainee to experienced neuropathologist, reliably stained both neuritic plaques and neurofibrillary tangles essential for diagnosing and staging Alzheimer's disease. Nondemented controls with early Alzheimer's-type changes were easily distinguished from cases of definitive Alzheimer's disease. The stains also highlighted characteristic inclusions of Parkinson's disease or Lewy body dementia Ubiquitin immunohistochemistry is a reliable, reproducible, and readily available diagnostic aid for distinguishing Alzheimer's disease from other causes of dementia.