Anti-Amyloid Agents: A Self-Fulfilling prophecy

Area of Science:

• Neurology
• Neuroscience
• Pathology

Background:

• Recent Alzheimer's disease (AD) diagnostic criteria center on amyloid beta, aligning with anti-amyloid antibody therapies.
• Despite this alignment, amyloid-targeting treatments have shown limited efficacy in clinical practice.
• This discrepancy suggests current definitions of AD may be incomplete.

Purpose of the Study:

• To investigate the reasons behind the limited efficacy of amyloid-targeting therapies in Alzheimer's disease.
• To propose a redefinition of Alzheimer's disease based on its complex multifactorial nature.
• To highlight the need to consider co-existing pathologies and diverse pathogenetic mechanisms.

Main Methods:

• Review of current Alzheimer's disease diagnostic criteria and therapeutic strategies.
• Analysis of patient populations excluded from anti-amyloid antibody trials.
• Examination of emerging pathogenetic mechanisms beyond amyloid accumulation, such as neuroinflammation and cerebrovascular disease.

Main Results:

• Amyloid-targeting therapies are ineffective in patients with specific conditions like APOE4 homozygosity or anticoagulant use.
• Neuroinflammation, cerebrovascular disease, and metal ion dysregulation are significant contributing factors.
• Alzheimer's pathology often coexists with other brain pathologies, complicating disease mechanisms.

Conclusions:

• Alzheimer's disease should be redefined as a multifactorial neurodegenerative disorder.
• Effective treatment requires addressing multiple pathogenetic pathways, not solely amyloid accumulation.
• Future therapeutic strategies must account for the heterogeneity and complexity of AD.