Increased frequency of argyrophilic grain disease in Alzheimer disease with 4R tau-specific immunohistochemistry

Argyrophilic grain disease (AGD) is a medial temporal 4R tauopathy with filamentous inclusions in dendrospinal portions of neurons. AGD is often associated with mild Alzheimer-type pathology, but it is difficult to detect AGD in the setting of advanced Alzheimer disease (AD). The frequency of AGD in AD has been difficult to determine because of masking of grains by neurofibrillary lesions. To address this issue, medial temporal lobe sections from AD brains were immunostained with a 4R tau-specific antibody, ET3, which permitted detection of grains even in the setting of advanced neurofibrillary degeneration. AGD was found in 61 of 239 AD cases (26%). The frequency of AGD in AD in this study is higher than in previous studies that relied on less selective staining methods, such as the Gallyas silver stain or immunostaining with phospho-tau antibodies. The frequency of AGD in AD did not correlate with Braak stage or with the density of neurofibrillary tangles and senile plaques in the limbic lobe; however, AD cases with AGD were significantly older than cases without AGD. The MAPTH1 frequency tended to be higher in AD cases with AGD than in those without AGD, but there were no differences in APOE epsilon 4 carrier state. These findings suggest advanced age and possibly MAPTH1 are risk factors for AGD, even in the setting of concurrent AD, in which neurofibrillary degeneration is associated with accumulation of both 3R and 4R tau.