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

Abstract

Strong genetic evidence supports an imbalance between production and clearance of amyloid β-protein (Aβ) 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 Aβ 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 Aβ 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.

Fig 1. Aβ can trigger AD.

(A) Proteolytic processing of APP by β-secretase and γ-secretase leads to the generation of Aβ protein. Red asterisks: mutations that cause familial AD; green asterisk: a protective mutation. Insert: typical amyloid plaques and neurofibrillary tangles of AD pathology. (B) One way to depict the amyloid cascade. Individual steps in the cascade may evoke distinct microglial responses. Aβ, amyloid β-protein; AD, Alzheimer disease; APP, amyloid precursor protein.

Fig 2. Pathology of early-onset and late-onset AD.

Similar Aβ protein and tau pathology in a tissue sample from a patient with “sporadic” late-onset AD and an individual with a mutation in PS1, encoding presenilin-1, which causes early-onset familial AD. Shown is the gyrus parahippocampalis immunostained with the antibodies 4G8, which labels Aβ, and AT8, which labels ptau. Figure kindly provided by Dr. Thomas Arzberger (Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Munich). Aβ, amyloid β-protein; AD, Alzheimer disease; ptau, phospho-tau.

Fig 3. Relationship of plaque lowering and less cognitive decline across anti-Aβ antibody trials.

Graphical relationship between amyloid-lowering effect (abscissa) of various anti-Aβ antibodies (“compounds”) in individual completed therapeutic trials and their effects on clinical outcome on the CDR-SB test (ordinate). The trend line moving toward the lower left corner across these trials signifies the relationship. (Obtained from reference [74]). Aβ, amyloid β-protein; CDR-SB, Clinical Dementia Rating-Sum of Boxes; PET, positron emission tomography.