Anti-Amyloid Agents: A Self-Fulfilling prophecy

The introduction of anti-amyloid antibodies has ushered in a new era in the treatment of Alzheimer’s disease (AD), coinciding with the revision of its diagnostic criteria, which now focus on the biological definition of AD, with amyloid beta at its core. However, despite being fully aligned with these criteria—and therefore with how we define the disease—amyloid-targeting therapies have not yielded the expected results. How can a treatment targeting the very core of the disease be ineffective? Perhaps because AD, as we have defined it, is not actually the disease that afflicts millions of patients worldwide. Patients with conditions related to AD, such as apolipoprotein ε4 allele (APOE4) homozygotes, patients receiving anticoagulant therapy for atrial fibrillation, and those with microhemorrhages, are excluded from treatment. Several other pathogenetic mechanisms continue to arise, including neuroinflammation, cerebrovascular disease, and metal ion dysregulation. At the same time, Alzheimer’s pathology frequently coexists with other brain pathologies in AD patients, the roles and interactions of which remain largely unknown. Thus, AD should be redefined as a multifactorial neurodegenerative disorder, in which various processes contribute to amyloid accumulation or independently drive neurodegeneration.