Re-Addressing Dementia by Network Medicine and Mechanism-Based Molecular Endotypes

Alzheimer's disease (AD) and other forms of dementia are together a leading cause of disability and death in the aging global population, imposing a high personal, societal, and economic burden. They are also among the most prominent examples of failed drug developments. Indeed, after more than 40 AD trials of anti-amyloid interventions, reduction of amyloid-ß (Aß) has never translated into clinically relevant benefits, and in several cases yielded harm. The fundamental problem is the century-old, brain-centric phenotype-based definitions of diseases that ignore causal mechanisms and comorbidities. In this hypothesis article, we discuss how such current outdated nosology of dementia is a key roadblock to precision medicine and articulate how Network Medicine enables the substitution of clinicopathologic phenotypes with molecular endotypes and propose a new framework to achieve precision and curative medicine for patients with neurodegenerative disorders.