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INTRODUCTION The role of neuroinflammation in preclinical Alzheimer's disease (AD) remains unclear. METHODS We assessed changes in microglial and astrocytic biomarkers in a well‐characterized cohort of 211 cognitively unimpaired individuals. Structural equation modeling was used to simultaneously assess all relationships among microglial and astrocytic responses and AD pathological events. RESULTS Plasma glial fibrillary acidic protein (GFAP) and cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were increased in preclinical AD. Plasma GFAP showed an inverse bidirectional relationship with CSF amyloid beta (Aβ)42/40. CSF sTREM2 directly influenced CSF phosphorylated tau‐181 (p‐tau181) and neurogranin, and correlated with CSF S100 calcium‐binding protein beta (S100β). CSF chitinase‐3‐like protein 1 (YKL‐40) mediated the association between CSF p‐tau181 and total tau (t‐tau), whereas CSF S100β and neurofilament light showed mutual influence. DISCUSSION Our findings suggest that microglial and astrocyte reactivity, measured through fluid biomarkers, occur early and impact the amyloid cascade on the preclinical Alzheimer´s continuum. Specifically, GFAP influences amyloid accumulation, sTREM2 promotes tau pathology, and YKL‐40 and S100β contribute to the progression of downstream neurodegenerative changes. Highlights Preclinical Alzheimer's disease (AD) showed increased levels of plasma glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) compared to cerebrospinal fluid (CSF) in healthy subjects. Higher plasma GFAP levels was directly associated with lower CSF amyloid beta (Aβ)42/Aβ40. Higher CSF sTREM2 concentrations increased CSF phosphorylated tau‐181. Chitinase‐3‐like protein 1 (YKL‐40) mediated tau‐induced neurodegeneration. S100 calcium‐binding protein beta (S100β) was directly linked to higher neurofilament light (NfL) and showed a mutual relationship with sTREM2.

Background Plasma biomarkers for Alzheimer's disease (AD) are a promising tool for accessible and accurate biological diagnostics. However, data in clinical practice are needed to better understand their diagnostic and prognostic ability in memory unit patients. Methods We analyzed plasma phosphorylated tau at threonine 217 (p-tau217) and neuroflament light chain (NfL) levels and AD cerebrospinal fluid (CSF) biomarkers in a group of 493 subjects using the Lumipulse G600II platform. The sample includes 340 patients from our memory unit (142 dementia, 186 mild cognitive impairment, and 12 with subjective complaints) and 153 cognitively unimpaired volunteers. We have correlated plasma and CSF biomarkers; we have analyzed plasma biomarker levels as a function of clinical diagnosis, cognitive status and amyloid status. We have also studied the ability of p-tau217 to discriminate between amyloid-positive and -negative subjects according to CSF using receiver operating characteristic curves. Results Plasma p-tau217 correlated significantly with CSF Aβ42/Aβ40 (Rho = -0.75; p -value < 0.001), p-tau181 ( r  = 0.66; p -value < 0.001), and t-tau ( r  = 0.59; p -value < 0.001). Plasma NfL correlated with CSF NfL ( r  = 0.48; p -value < 0.001). By clinical diagnosis, plasma p-tau217 levels showed to be higher in AD patients than in healthy controls (difference = 0.63 pg/ml; p -value < 0.001), FTD (difference = 0.60 pg/ml; p -value < 0.001), and nondegenerative dementias (difference = 0.61 pg/ml; p -value < 0.001). Plasma p-tau217 showed an area under the curve of 0.95 to discriminate between A + and A- subjects (95%CI 0.93–0.97). Conclusion Plasma p-tau217 shows excellent results for detecting amyloid pathology at brain level in a clinical setting with an AUC of 0.95. It is a highly specific marker of AD and increases progressively along the disease continuum . Using plasma p-tau217 as an initial diagnostic tool with cut-offs at sensitivities and specificities of 95 or 97.5% could save between 57.4–84.8% of LP/PETs with diagnostic accuracies of 95–97%. Plasma NfL increases progressively at different cognitive stages.