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However, whether microglial reactivity is detrimental or neuroprotective for Alzheimer disease (AD) is still debatable.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We identified 663 participants with baseline \u03b2\u2010amyloid (A\u03b2) positron emission tomography (PET) and CSF biomarker data, including phosphorylated tau181 (p\u2010Tau<jats:sub>181<\/jats:sub>), soluble TREM2 (sTREM2), PGRN, and growth\u2010associated protein\u201043 (GAP\u201043). Among them, 254 participants had concurrent longitudinal CSF biomarkers. We used multivariate regression analysis to study the associations of CSF microglial biomarkers with A\u03b2 PET, CSF p\u2010Tau<jats:sub>181<\/jats:sub>, and CSF GAP\u201043 cross\u2010sectionally and longitudinally. A Chinese aging cohort's independent CSF samples (n\u2009=\u200965) were analyzed as a validation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Higher baseline levels of CSF microglial biomarkers were related to faster rates of CSF sTREM2 increase and CSF PGRN decrease. Elevated CSF p\u2010Tau<jats:sub>181<\/jats:sub> was associated with higher levels of CSF microglial biomarkers and faster rates of CSF sTREM2 increase and CSF PGRN decrease. In both cohorts, higher A\u03b2 burden was associated with attenuated CSF p\u2010Tau<jats:sub>181<\/jats:sub> effects on CSF microglial biomarker increases. Independent of A\u03b2 PET and CSF p\u2010Tau<jats:sub>181<\/jats:sub> pathologies, higher levels of CSF sTREM2 but not CSF PGRN were related to elevated CSF GAP\u201043 levels and faster rates of CSF GAP\u201043 increase.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These findings suggest that higher A\u03b2 burden may attenuate the p\u2010Tau\u2010associated microglial responses, and TREM2\u2010related microglial reactivity may independently correlate with GAP\u201043\u2010related presynaptic loss. This study highlights the two\u2010edged role of microglial reactivity in AD and other neurodegenerative diseases. 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