The path to treating multiple-etiology dementia: Combining vascular risk control and disease-modifying neurodegenerative therapies

Multiple-etiology dementia (MED), typically characterized by coexisting vascular and neurodegenerative pathology, is the most common cause of late-life cognitive impairment. Autopsy and biomarker studies demonstrate frequent overlap between cerebral small vessel disease, stroke-related injury, amyloid-β deposition, and tau pathology, yet therapeutic development has largely proceeded within single pathway silos. Randomized trials support vascular risk reduction and multidomain lifestyle interventions as strategies that modestly improve cognitive trajectories. Separately, phase 3 trials of anti-amyloid monoclonal antibodies have established proof of principle that targeting amyloid-β can modestly slow clinical decline in early Alzheimer's disease. However, patients with mixed vascular and neurodegenerative disease are often excluded from these trials, limiting generalizability to real-world populations. We propose an integrated research roadmap for MED that prioritizes biomarker-enriched cohorts, combination vascular and neurodegenerative therapies, and pragmatic trials. A unified brain health framework that addresses both pathologic domains simultaneously offers the most plausible strategy to reduce the growing global burden of MED.