The role of microglia in Alzheimer’s disease (AD) pathogenesis remains unknown. Although many studies maintain that chronic microglial activation in the AD brain is detrimental and contributes to neurodegeneration, anti-infl ammatory drugs show little promise for AD treatment or prevention. Studies provide support for the microglial dysfunction hypothesis, which postulates that the neurofi brillary degeneration of AD is the result of declining microglial neuroprotection resulting from aging-related microglial senescence and degeneration. I will report histopathological fi ndings from humans covering the spectrum from none to severe AD pathology, including patients with Down syndrome, showing that degenerating neuronal structures positive for tau, invariably colocalized with severely dystrophic rather than with activated microglial cells. Using Braak staging of AD neuropathology, I will demonstrate that microglial dystrophy precedes the spread of tau pathology. Amyloid deposits devoid of tau-positive structures are found to be colocalized with non-activated, ramifi ed microglia, suggesting that amyloid does not trigger microglial activation. The fi ndings indicate that when microglial activation does occur in the absence of an identifi able acute CNS insult, it is likely to be the result of systemic infectious disease. These fi ndings strongly argue against the belief that neuroinfl ammatory changes contribute to AD dementia. They may profoundly infl uence future treatment approaches.
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