We report a neuropathologic study of a case with features of Gerstmann-Straüssler syndrome (GSS) that is remarkable for the large number of neurofibrillary tangles (NFTs) throughout the neuraxis. The patient had a family history of spinocerebellar ataxia, but without dementia in other affected members. Our case meets the cardinal features of GSS as a rare familial degenerative disease characterized by clinically, spinocerebellar ataxia accompanied by progressive dementia, and pathologically, multiple system atrophy combined with widespread amyloid plaque deposition in the cerebral and cerebellar cortex. However, most pathologic studies stress the absence of NFTs in GSS. The nosology of this case is difficult to resolve because of profuse NFTs and morphologic differences between our and comparison Alzheimer's disease (AD) cases, the most prominent being spongiform changes. This case is remarkable because it combines features of a number of CNS degenerative diseases, including multiple system atrophy, AD, spongiform encephalopathies, and cerebrovascular amyloidosis.