In early mild cognitive impairment, astrocytes may be the primary responsibility for this, but, in moderate or severe cognitive impairment such as AD, amounts of accompanied neurons death or apoptosis may also directly activate microglia, as microglia are more sensitive to pathogens/damage and trigger more reactive astrocytes via inflammatory signals, which can be amplified not only by the self-feedback loop of HMGB1 but also by the unique anatomy structure of astrocytes. Here, HMGB1 is linked to Cognitive impairment.