Beyond the Hippocampus: Objective Memory Stages Capture Widespread Brain Aging in a Cross-Sectional Analysis of Baseline RCT Data

Background: Reliable staging of early memory decline is essential for identifying individuals at risk for Alzheimer’s disease. The Stages of Objective Memory Impairment (SOMI) framework provides a clinically scalable tool for characterizing episodic memory loss, yet its neurobiological validity remains underexplored. Recent advances in plasma biomarkers (e.g., p-tau217, p-tau181, Aβ42/40) offer emerging blood-based alternatives to CSF and PET, although their diagnostic implementation continues to evolve. Here, we examine whether SOMI stages reflect widespread brain aging, as indexed by BrainAGE, a structural MRI–based biomarker quantifying deviation from normative aging trajectories. While previous studies have linked SOMI to hippocampal atrophy and tau pathology, no study to date has examined its association with a global MRI-derived biomarker of systemic brain aging. Methods: In a well-characterized cohort of 119 older adults on the Alzheimer’s disease continuum, we evaluated whether higher SOMI stages were linked to elevated BrainAGE scores and examined whether this association remained significant after adjusting for age, sex, education, and hippocampal volume. Results: Higher SOMI stages were robustly associated with elevated BrainAGE scores, indicating accelerated neurobiological aging. This relationship remained significant after adjusting for covariates and was confirmed in sensitivity analyses. Notably, a marked discontinuity in BrainAGE emerged between SOMI stages 0–2 and 3–5, aligning with the theoretical transition from retrieval to storage impairment, long recognized as a turning point in prodromal Alzheimer’s disease. Conclusions: These findings validate SOMI as a low-cost, non-invasive behavioral marker of systemic brain health. By linking cognitive staging to global neuroimaging biomarkers, our study supports SOMI’s translational utility for large-scale screening, clinical trial stratification, and early intervention planning in Alzheimer’s disease.