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Boosting TREM2 in AD: Alzheimer's disease (AD) is a devastating neurodegenerative disorder, and clinical trials using anti-amyloid treatments have failed. New therapeutic targets are therefore required. Recent genetic studies have revealed a major role for microglia in disease progression. Loss-of-function mutations in TREM2 dramatically increase the risk for late onset AD, therefore boosting that TREM2 function may be a useful therapeutic strategy. Ewers et al. examined whether increased TREM2 is protective in patients with AD. They found that higher concentrations of soluble TREM2 in cerebrospinal fluid were associated with reduced memory decline and hippocampal shrinkage in patients with AD. Thus, therapeutic strategies that boost TREM2 signaling may be beneficial in AD. Loss of function of TREM2, a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer's disease (AD). We therefore examined whether soluble TREM2 (sTREM2) concentrations in cerebrospinal fluid (CSF) were associated with reduced rates of cognitive decline and clinical progression in subjects with AD or mild cognitive impairment (MCI). We measured sTREM2 in CSF samples from 385 elderly subjects, including cognitively normal controls, individuals with MCI, and subjects with AD dementia (follow-up period: mean, 4 years; range 1.5 to 11.5 years). In subjects with AD defined by evidence of CSF Aβ1–42 (amyloid β-peptide 1 to 42; A+) and CSF p-tau181 (tau phosphorylated on amino acid residue 181; T+), higher sTREM2 concentrations in CSF at baseline were associated with attenuated decline in memory and cognition. When analyzed in clinical subgroups, an association between higher CSF sTREM2 concentrations and subsequent reduced memory decline was consistently observed in individuals with MCI or AD dementia, who were positive for CSF Aβ1–42 and CSF p-tau181 (A+T+). Regarding clinical progression, a higher ratio of CSF sTREM2 to CSF p-tau181 concentrations predicted slower conversion from cognitively normal to symptomatic stages or from MCI to AD dementia in the subjects who were positive for CSF Aβ1–42 and CSF p-tau181. These results suggest that sTREM2 is associated with attenuated cognitive and clinical decline, a finding with important implications for future clinical trials targeting the innate immune response in AD. [ABSTRACT FROM AUTHOR]