Argyrophilic grain disease (AGD) is a recently recognized disorder whose relationship to dementia as well as genetic or biochemical features remain incompletely characterized in part due to diagnostic difficulties engendered by concomitant pathologies. In the present study, we reviewed a consecutive series of over 300 brains referred for evaluation of dementia for presence of argyrophilic grains (AGs). AGs were found in the hippocampal region and amygdala, and were accompanied by coiled bodies in the underlying white matter and ballooned neurons in the limbic lobe. Ballooned neurons were also found in the limbic lobe in a number of cases of advanced Alzheimer's disease (AD) that did not have AGs, supporting the lack of diagnostic significance of ballooned neurons confined to limbic lobe. The frequency of AGD in this series of dementia brains was 4.9% and was similar to the frequency in other autopsy series of nondemented cases, supporting the notion that there is no obligatory relationship between AGD and dementia. In the present series, ApoE epsilon4 allele frequency of AGD was dependent on concurrent AD, with AGD cases lacking AD similar to controls and cases with concurrent AD similar to AD. This suggests that AGD is an independent disease process from AD.