{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T03:56:47Z","timestamp":1791863807077,"version":"4.3.4"},"reference-count":72,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>The role of neuroinflammation in preclinical Alzheimer's disease (AD) remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We assessed changes in microglial and astrocytic biomarkers in a well\u2010characterized 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>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 (A\u03b2)42\/40. CSF sTREM2 directly influenced CSF phosphorylated tau\u2010181 (p\u2010tau181) and neurogranin, and correlated with CSF S100 calcium\u2010binding protein beta (S100\u03b2). CSF chitinase\u20103\u2010like protein 1 (YKL\u201040) mediated the association between CSF p\u2010tau181 and total tau (t\u2010tau), whereas CSF S100\u03b2 and neurofilament light showed mutual influence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Our findings suggest that microglial and astrocyte reactivity, measured through fluid biomarkers, occur early and impact the amyloid cascade on the preclinical Alzheimer\u00b4s continuum. Specifically, GFAP influences amyloid accumulation, sTREM2 promotes tau pathology, and YKL\u201040 and S100\u03b2 contribute to the progression of downstream neurodegenerative changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>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.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Higher plasma GFAP levels was directly associated with lower CSF amyloid beta (A\u03b2)42\/A\u03b240.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Higher CSF sTREM2 concentrations increased CSF phosphorylated tau\u2010181.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Chitinase\u20103\u2010like protein 1 (YKL\u201040) mediated tau\u2010induced neurodegeneration.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>S100 calcium\u2010binding protein beta (S100\u03b2) was directly linked to higher neurofilament light (NfL) and showed a mutual relationship with sTREM2.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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