Temporal Ordering of Astrocytic and Lipid-Handling Biomarkers Relative to Phosphorylated Tau in Genetically At-Risk Alzheimer's Disease: A Systematic Review and Structured Synthesis

Abstract

This record contains the preprint and supporting materials for a prospectively registered systematic review evaluating whether astrocytic or lipid-handling biomarkers precede phosphorylated tau (p-tau) in populations at genetic risk for Alzheimer’s disease. The review was registered on OSF, with a documented pre-selection comparator amendment. Searches conducted through 28 August 2026 identified 25 eligible reports representing 19 independent studies. Nine studies provided 14 classifiable target-biomarker–p-tau timing comparisons. At study level, a candidate marker preceded p-tau in one study, appeared near-contemporaneously in two, and p-tau was earlier in six. Among studies assessing p-tau217 or p-tau231, p-tau was earlier in three and near-contemporaneous in one. No eligible lipid-handling study reported a paired longitudinal p-tau trajectory. Meta-analysis was not performed because of clinical and methodological heterogeneity, study dependence, missing paired uncertainty, and the absence of a pool containing at least three compatible independent studies. The available evidence does not identify a validated astrocytic or lipid-handling biomarker that consistently precedes p-tau. Therefore, it does not currently justify replacing tau-directed research. Instead, the review identifies an important evidence gap and supports longitudinal, head-to-head studies testing whether astrocyte-specific lipid signatures predict incident p-tau217 or p-tau231 beyond genotype, estimated years to onset, amyloid status, and baseline p-tau. This record includes the manuscript, PRISMA materials, figures, and the auditable supplementary data workbook. This version is a preprint and has not undergone peer review. OSF registration: https://doi.org/10.17605/OSF.IO/54GEFProtocol version 4.1: https://doi.org/10.5281/zenodo.22111898