A Clearance-Repair-Activation Framework for Alzheimer's Disease: A Perspective and Validation Roadmap

Alzheimer's disease (AD) is a heterogeneous clinicobiological syndrome involving impaired protein clearance, neuroinflammation, synaptic and cellular injury, network dysfunction, and progressive functional decline. Amyloid-directed antibodies provide an evidence-based treatment backbone for selected patients with early symptomatic AD, but adjunctive strategies may be needed to address other disease mechanisms. This Perspective proposes a clearance-repair-activation framework for hypothesis-driven research. Clearance includes established pharmacological treatment and risk management as well as investigational drainage approaches; lymphaticovenous anastomosis (LVA) and deep cervical lymphaticovenous anastomosis (dcLVA) are considered only as research options within this broader domain. Repair includes neural stem-cell (NSC), induced pluripotent stem-cell-derived, engineered-cell, and secretome-based strategies, for which AD evidence remains predominantly preclinical. Activation encompasses invasive and non-invasive stimulation, sensory entrainment, neurofeedback, brain-computer interface (BCI) monitoring, and cognitive rehabilitation; BCI is positioned mainly as an experimental monitoring and adaptive rehabilitation platform. We define falsifiable links between clearance and repair readiness and between repair markers and activation responsiveness, consider adaptive and parallel alternatives to fixed sequencing, and integrate disease stage, heterogeneity, regulation, and combination-trial design. Informatics is limited to trial infrastructure and safety governance. The validation roadmap specifies success criteria, stop rules, interaction testing, clinically meaningful outcomes, and long-term surveillance.