If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline?

Strong genetic evidence supports an imbalance between production and clearance of amyloid beta-protein (A beta) in people with Alzheimer disease (AD). Microglia that are potentially involved in alternative mechanisms are actually integral to the amyloid cascade. Fluid biomarkers and brain imaging place accumulation of A beta at the beginning of molecular and clinical changes in the disease. So why have clinical trials of anti-amyloid therapies not provided clear-cut benefits to patients with AD? Can anti-amyloid therapies robustly decrease A beta in the human brain, and if so, could this lowering be too little, too late? These central questions in research on AD are being urgently addressed.

Automated summary

Strong genetic evidence supports an imbalance between production and clearance of amyloid beta-protein (Aβ) in people with Alzheimer disease (AD). Microglia, potentially involved in alternative mechanisms, are integral to the amyloid cascade. Fluid biomarkers and brain imaging indicate that Aβ accumulation occurs at the beginning of molecular and clinical changes in the disease. Despite this, clinical trials of anti-amyloid therapies have not shown clear benefits for patients with AD. Key questions about whether anti-amyloid therapies can effectively decrease Aβ in the human brain and if it is already too late are urgently being addressed in AD research.