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

Alzheimer's disease shows prolonged prodromal stability before accelerating decline, yet molecular markers resolving this heterogeneity are limited. We asked whether astrocytic prostaglandin D2 synthase (PTGDS) marks a statistically resolved metabolic inflection during this transition.

We analysed 1.24 million single nuclei retained after quality control from the Seattle Alzheimer's Disease Brain Cell Atlas middle temporal gyrus dataset (84 donors), ordered along a continuous pseudo-progression score, using donor-level quadratic and segmented regression with donor bootstrap resampling and leave-one-donor-out refitting. Findings were then examined in independent bulk brain proteomics (ROSMAP and Banner cohorts), in cerebrospinal fluid proteomics from the Alzheimer's Disease Neuroimaging Initiative on two orthogonal platforms, in a reversible zebrafish model of mild cognitive impairment, and in an amyloid-beta mouse model.

PTGDS followed a biphasic astrocytic trajectory with a statistically resolved donor-level inflection (quadratic term -2.27, p = 0.006; vertex at pseudo-progression score 0.47, bootstrap 95% confidence interval 0.32 to 0.53). The same directional change was reproduced in ROSMAP and Banner brain proteomics (Alzheimer's disease versus control p = 3.4 × 10-3), and the biphasic pattern reconciles previously conflicting cerebrospinal fluid reports as stage-dependent. In cerebrospinal fluid, downstream neurofilament light tracked cognitive decline strongly and lipocalin-2 weakly, whereas PTGDS itself was tissue-restricted and not a stand-alone predictor.

The atlas provides pseudo-time rather than longitudinal sampling, so causality is not established. Coverage is restricted to one cortical region, donor coverage across the pseudo-progression range is uneven with a single donor in the lowest bin, lipocalin-2 transcript detection was sparse, zebrafish validation covered only the early compensatory phase, and the pharmacological arm was not tested after the inflection.

These data position astrocytic PTGDS as a candidate stage marker, not a causal driver, of the compensatory-to-vulnerable shift in prodromal Alzheimer's disease, with potential relevance to stage-stratified patient selection. We propose, but do not establish, that attenuation of PTGDS after the inflection accompanies lipocalin-2-linked inflammation and suppression of nerve growth factor receptor.