To the Editor Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell surface receptor of microglia, and its stimulation enhances the phagocytic activity of microglia and modulates inflammatory signaling. The activation of TREM2 in response to the presence of amyloid β (Aβ) plaques and tau tangles plays a crucial role in the pathogenesis of Alzheimer disease (AD).¹ A soluble form of TREM2 (sTREM2) promotes microglial activation with stimulation of phagocytic activity and neuronal survival. sTREM2 may exert stage-specific proinflammatory or anti-inflammatory effects. Wagemann and colleagues² have recently reported that prolonged treatment with gantenerumab, an anti-Aβ monoclonal antibody, did not significantly slow cognitive decline compared with placebo in individuals with dominantly inherited AD but increased cerebrospinal (CSF) levels of soluble levels of sTREM2 at 2 and 4 years compared with baseline. The authors emphasized the potential beneficial effects of an increase in CSF sTREM2 as reflecting increased microglial phagocytosis and plaque clearance. However, there have been contradictory findings regarding the potential detrimental or protective effects of microglial activation and TREM2-related microglial responses in AD. Although several studies reported increased CSF sTREM2 levels in different clinical stages of AD, the exact association between AD hallmarks such as Aβ and tau pathology remains unclear. Aβ binding to complement component C1q can activate the classical complement pathway, resulting in excessive microglial phagocytosis of synapses. This complement-dependent pathway and excessive microglial activation lead to synaptic loss and are associated with cognitive dysfunction in AD.³ A protracted nonphysiological drug-induced and excessive microglia phagocytic activation, might lead to excessive elimination of functional neurons and synapses expressing subtle AD pathologies including phosphorylated tau as well as attenuation of potential beneficial effects of a reduction in brain plaques on cognition. Indeed, anti-Aβ monoclonal antibodies have been consistently associated with extensive brain atrophy whose mechanisms remains poorly understood.⁴ Excessive phagocytosis of normal neuronal synapses by microglia may represent a critical factor contributing to cognitive decline in AD. Therefore, to clarify the potential impact of the gantenerumab-induced elevations in CSF sTREM2, it would be important for the authors to provide data on the relationship between individual sTREM2 levels and positron emission tomography amyloid burden and other AD biomarkers. Additionally, the relationship of increased CSF sTREM2 to magnetic resonance imaging indices of gray matter and white matter atrophy and to cognitive outcome measures needs to be described.