Is granulovacuolar degeneration an essential pathological component of Alzheimer’s disease? A review of the pathogenesis and histochemistry of old studies

Granulovacuolar degeneration (GVD) is a histopathological feature of Alzheimer’s disease (AD) and some non-Alzheimer neurodegenerative diseases. It is also present in the brains of non-demented older adults. GVD is characterized by the presence of intracytoplasmic granule-containing vacuoles in most hippocampal neurons. It affects the neurons in sequential arrangement throughout the brain, which allows its characterization into different stages related to the severity of the disease. The mechanism of GVD formation is still poorly understood and its relationship with Tau structures remains unclear. Immunohistochemistry and ultrastructural examination suggest that GVD is mediated by cellular autophagic mechanisms. Other potential mechanisms related to GVD include protein accumulation caused by cellular defence mechanisms or impaired cellular functions. Several proteins are used as markers of GVD. Antibodies to cytoskeletal proteins and neurofilaments, both phosphorylated and non-phosphorylated forms, are used to stain GVD, the latter of which can be used to determine the nature of the cytoskeletal abnormalities in GVD formation. A link between GVD and microtubule-associated protein of tau was also reported but remains unclear. Previous studies reported neurons containing GVDs in the hippocampus of AD sections. Other neurodegenerative diseases also randomly showed GVDs in the brain. However, these quantitative studies have not demonstrated whether GVD is an essential component of AD or non-AD dementias. In this review, we discuss our previous quantitative results of a retrospective study from 2016 and compare them with the results of older published studies to examine whether GVD is an essential feature of AD dementia or additional neurodegenerative features. We also revisit the pathogenesis and histochemistry profile of this common pathology.