Astrocytic and Lipid-Handling Biomarkers Preceding Tau Pathology in Genetically At-Risk Alzheimer's Disease: Protocol for a Systematic Review of Biomarker Trajectories Stratified by Estimated Years to Symptom Onset

Abstract

Autosomal dominant and sporadic Alzheimer’s disease converge on an almost indistinguishable phenotype despite radically different genomic origins, and carriers of high-risk variants exist who never develop clinical disease. Both observations point to a second necessary event beyond genetic burden: a trigger. This protocol specifies a systematic review testing whether that trigger lies in astrocytic lipid handling. The hypothesis predicts a falsifiable ordinal sequence — astrocytic lipid flux, then amyloid deposition, then tau phosphorylation, then hypometabolism, then symptoms — and is refuted if lipid measures deviate after amyloid or phosphorylated tau. Because pathology precedes symptoms by ten to twenty years, stratification is by estimated years to symptom onset (EYO) rather than chronological age. Outcomes are organised in two strata: astrocytic markers (GFAP, YKL-40, S100B, 11C-DED PET), which provide the temporal backbone, and lipid-handling markers (ApoE lipidation, oxysterols, ABCA1, LXR–SREBP, lipidomics and lipid-related proteomics), which provide mechanistic specificity. Scoping searches established that the relevant lipid literature is indexed as proteomics and resilience research rather than as lipidomics, and the search strategy is calibrated accordingly. The protocol declares single-reviewer extraction with three compensating safeguards, and states in advance that elevated GFAP is compatible both with the hypothesis under test and with alternative accounts.