CSF colony-stimulating factor 1 and its receptor mediate the association of amyloid-β with tau pathology and predict Alzheimer’s disease progression: a longitudinal ADNI study

Microglial responses are increasingly recognized as important modulators of Alzheimer’s disease (AD) progression. The colony-stimulating factor 1 (CSF1) and CSF1 receptor (CSF1R) axis is essential for microglial survival and functional adaptation, yet its relationships with AD pathology and clinical progression in humans remain unclear. This study included 706 participants from the Alzheimer’s Disease Neuroimaging Initiative with CSF measurements of CSF1 and CSF1R. We systematically examined their cross-sectional and longitudinal associations with cognition, dementia risk, AD biomarkers, microglial activity, brain volume, and metabolism. Additionally, subgroup analyses based on A/T(N) classification were conducted to evaluate their relationships with pathological status, and receiver operating characteristic (ROC) analyses were performed to assess their discriminative performance. Mediation analyses were further used to investigate potential pathways linking amyloid burden, CSF1 and CSF1R-related microglial responses, tau pathology, and cognition. Higher CSF1 and CSF1R levels were associated with greater tau-related pathology and elevated microglia-related markers, including soluble Triggering Receptor Expressed on Myeloid Cells-2 (sTREM2). Higher baseline CSF1 was further associated with subsequent cognitive decline, increased incident dementia risk (HR = 1.325, 95% CI, 1.142–1.537), tau-related biomarker progression, and regional brain atrophy. These associations with dementia risk remained significant after excluding participants who developed dementia within the first 2 years of follow-up. CSF1 and CSF1R showed limited ability to discriminate amyloid positivity but greater performance for TN status. CSF1 alone yielded an area under the curve (AUC) of 0.743 for distinguishing TN− from TN+, which increased to 0.856 when combined with amyloid-PET and to 0.865 when further combined with sTREM2. Mediation analyses identified significant indirect pathways linking amyloid burden to tau pathology through serial pathways involving CSF1 or CSF1R and sTREM2-related microglial responses. CSF1 and CSF1R, as markers related to microglial proliferation, are closely associated with tau pathology and AD progression. Following amyloid deposition, they may act together with the microglial activation marker sTREM2 in biological processes linking amyloid-β (Aβ) pathology to downstream tau abnormalities and neurodegeneration. CSF1 may serve as a promising biomarker for monitoring disease progression, assessing disease risk, and supporting clinical evaluation in AD.