Toward Precision Diagnosis of Late-Life Mood Disorders: A Neuropathology-Informed Framework and Research Agenda

Late-onset mood disorders frequently emerge in the context of aging-related brain changes, medical comorbidity, and cognitive vulnerability, complicating diagnosis and treatment. Symptom-based criteria alone lack biological specificity in older adults, contributing to diagnostic heterogeneity and variable outcomes. Converging neuropathological, neuroimaging, and circulating biomarker evidence suggests that vascular injury, chronic neuroinflammation, and early neurodegeneration may contribute to a meaningful subset of late-onset depressive and bipolar syndromes.

This perspective synthesizes current evidence and proposes a neuropathology-informed framework integrating accessible biomarkers (including white matter hyperintensities, C-reactive protein, and neurofilament light chain) into staged clinical and research pathways.

We emphasize that current evidence is largely observational and that randomized trials testing biomarker-guided care are needed before routine implementation. A phased research and infrastructure-building agenda is outlined, alongside ethical considerations including equity, diagnostic uncertainty, and the potential harms of premature adoption.

This framework offers a hypothesis-generating path toward precision geriatric psychiatry while underscoring the need for rigorous validation.