Measuring oxygen extraction fraction (OEF) in brain aging and AD: a scoping review of observational studies

Background Oxygen extraction fraction (OEF) reflects the cerebral balance between oxygen delivery and consumption, making it a candidate biomarker for brain metabolism. In aging and Alzheimer’s disease (AD), including its prodromal stage, mild cognitive impairment (MCI), OEF offers insight into pathophysiological changes that may relate to cognitive and functional outcomes. Objective This scoping review maps and evaluates OEF as a research biomarker for brain aging and Alzheimer’s disease, synthesising evidence from MRI-based observational and preclinical studies published between 2014 and 2026. A scoping approach was adopted because the research question is broad by design and eligibility criteria were refined iteratively as evidence emerged, rather than fixed a priori as required for a conventional systematic review. Studies in other neurological conditions incidentally captured by the search (multiple sclerosis, normal pressure hydrocephalus, sickle-cell disease, RVCL-S) are outside this review’s scope and are addressed only narratively. Methods This review followed the PRISMA extension for Scoping Reviews (PRISMA-ScR; [1]), which, unlike PRISMA for systematic reviews, does not require prospective protocol registration; this review was accordingly not registered. A comprehensive search of six databases (PubMed, Google Scholar, ProQuest, IEEE Xplore, ScienceDirect, MEDLINE) covering January 2014 to September 2026 yielded 1,364 records. After removing 131 duplicates and screening, 21 studies met eligibility criteria; of these, 16 (12 human observational, 4 preclinical) addressed brain aging, MCI, or AD and form the primary synthesis reported here. Full search strings for all six databases are reported in Supplementary Table S1. Study quality was assessed with the Newcastle-Ottawa Scale (NOS) for the 12 human observational studies and the SYRCLE risk-of-bias tool for the 4 animal studies. No meta-analysis was performed owing to methodological heterogeneity. Findings OEF changed with age and in AD/MCI, but the direction and regional pattern were inconsistent across studies and imaging techniques: several studies reported reduced OEF (particularly with tissue-based techniques in AD), others reported OEF increases with age (particularly with venous techniques such as TRUST and AS-aTRUPC), and others found no significant OEF difference alongside clear reductions in cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO₂). Multi-modal studies linked regional OEF alterations to microvascular pathology such as white matter hyperintensities. Substantial heterogeneity in imaging modality, brain region, and analysis pipeline precluded pooled quantitative synthesis. Conclusions OEF is a biologically motivated candidate measure of cerebral oxygen metabolism in aging and AD, but the direction of its association with either process is not yet established. The evidence base remains small, predominantly cross-sectional (fifteen of sixteen core studies), and technique-heterogeneous; only one study used a longitudinal design, and none were interventional. This evidence does not yet support biomarker-level claims for OEF; methodological standardisation and longitudinal validation are needed before its research, or clinical utility can be properly assessed.