Abstract
Genetics and other data modalities indicate that microglia play a critical role in Alzheimer's disease progression, but details of the disease-driving influence of microglia are poorly understood. Microglial cells can be parsed into subtypes based on their histological appearance. One subtype of microglia, termed dystrophic microglia, is characterized structurally by fragmented processes and cytoplasmic decay, and their presence has been associated with ageing and neurodegeneration. Recent studies suggest that the interaction between tau proteins and amyloid-β might induce dystrophic changes in microglia, potentially linking amyloid-β and tau pathologies to their effects on these microglia. We developed a study of human brains to test the hypothesis that dystrophic microglia are involved in Alzheimer's disease progression. We speculated that if their presence is unique to Alzheimer's disease neuropathological change, they would be substantially more common in Alzheimer's disease neuropathological change than in neurodegenerative diseases characterized by other proteinopathies, e.g. α-synuclein or transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology. Our analyses used histologically stained sections from five human brain regions of 64 individuals across six disease states, from healthy controls to advanced Alzheimer's disease stages, including comparative conditions such as Lewy body disease and limbic-predominant age-related TDP-43 encephalopathy neuropathological change. Using stereological sampling and digital pathology, we assessed populations of ramified, hypertrophic and dystrophic microglia. We found a significant increase in dystrophic microglia in areas affected early by Alzheimer's disease neuropathological change, suggesting a disease-specific role in neuropathology. Mediation analysis and structural equation modelling suggest that dystrophic microglia might impact the regional spread of Alzheimer's disease neuropathological change. In the mediation model, tau was found to be the initiating factor leading to the development of dystrophic microglia, which was then associated with the spread of amyloid-β and tau. These results suggest that a loss of the protective role of microglia could contribute to the spread of Alzheimer's disease neuropathological change and indicate that further research into preserving microglial function might be warranted.