A biphasic astrocytic PTGDS trajectory marks a metabolic vulnerability stage in prodromal Alzheimer’s disease

Abstract Alzheimer’s disease shows prolonged prodromal stability before accelerating decline, yet molecular markers resolving this heterogeneity are limited. Using pseudo-progression analysis of 1.3 million SEA-AD single nuclei (84 donors), we identify a reproducible biphasic astrocytic trajectory anchored to prostaglandin D2 synthase (PTGDS), with a statistically resolved donor-level inflection (quadratic β₂ = −2.27, p = 0.006; vertex CPS 0.47). The same directional change is independently reproduced in external brain proteomics (ROSMAP and Banner; AD versus control p = 3.4 × 10⁻³), and the biphasic pattern reconciles previously conflicting CSF reports as stage-dependent. In ADNI CSF, downstream NEFL tracks cognitive decline strongly and LCN2 weakly, whereas PTGDS itself is tissue-restricted and not a stand-alone predictor. We propose, but do not establish, that post-inflection PTGDS attenuation accompanies LCN2-linked inflammation and NGFR suppression. These data position astrocytic PTGDS as a candidate stage marker, not a causal driver, of the compensatory-to-vulnerable shift in the aging brain — the astrocytic PTGDS inflection (CPS 0.47).