In Alzheimer disease (AD) research and care, novel biomarkers that measure amyloid-β (Aβ) and phosphorylated tau (P-tau)–the principal components of amyloid plaques and neurofibrillary tangles–have facilitated early detection and biomarker-supported diagnosis. Therapeutics that modify the biology of AD are being tested in clinical trials, leveraging biomarkers so that investigators select the right patients, evaluate target engagement, and gauge the effects of therapy on AD pathophysiology. The first class of therapies to reach the clinic in this modern era of AD drug development are Aβ-targeting monoclonal antibodies, which bind different species in the Aβ aggregation cascade. This treatment approach is grounded in the “amyloid hypothesis,” which postulates that Aβ aggregation triggers a cascade of pathophysiologic events, including synaptic and network dysfunction, neuroinflammation, and aggregation and spread of P-tau tangles. The spread of tangles is associated with synaptic loss and neurodegeneration, culminating in cognitive decline and dementia. By binding Aβ aggregates, monoclonal antibodies facilitate Aβ clearance from the brain, potentially mitigating both direct and downstream deleterious effects of Aβ and hence slowing cognitive decline.
Source: JAMA Online First