Clinical pathways for cognitively unimpaired individuals with Alzheimer's disease neuropathological change

The recent approval of disease-modifying therapies for symptomatic Alzheimer's disease is a major advance for a condition with few therapeutic options. Anti-amyloid monoclonal antibodies have shown clinically meaningful benefits in slowing cognitive decline. Clinical trials in symptomatic Alzheimer's disease suggest that anti-amyloid therapies might provide the greatest benefit in subgroups who have low baseline levels of Alzheimer's disease pathology; ongoing prevention trials are evaluating these therapies in cognitively unimpaired individuals who have biomarker evidence of Alzheimer's disease neuropathological change (ADNC). However, the possibility of biomarker testing and treatment in cognitively unimpaired people raises key questions about ethics and the consequences that follow from a positive test or an uncertain result (ie, the so-called downstream effects on patients and health systems). Furthermore, test accuracy might be questioned when ADNC has a low prevalence in the population being tested and in the case of intermediate-range biomarker concentrations that might not reliably indicate true ADNC or be false positives. If anti-amyloid therapies prove beneficial for cognitively unimpaired people with ADNC and become part of routine practice, several key knowledge gaps must be addressed to support safe, scalable, real-world implementation of Alzheimer's disease treatment.