Multiple Cortical to Striatal Accumulation Trajectories of {beta}-Amyloid: Do All Roads Lead to Rome?

Alzheimer disease (AD) is conceptualized as an overlapping and sequential continuum of multiple biological processes that slowly progress in the human brain. These include upstream accumulation of β-amyloid (Aβ) oligomers and Aβ plaques, putatively leading to downstream accumulation of tau protein, synapse loss, neuroinflammation, neurodegeneration, and cognitive and clinical dysfunction. Variation has consistently been observed in the age at onset, pattern of pathology, and clinical presentation of the disease.1 Such diversity underscores the complexity that has made the search for interventions for AD challenging and, thus far, unsuccessful. Although it is important to critically evaluate all potential factors that influence negative outcomes in AD therapeutic trials, as in other fields of medicine,2 person-specific disease expression is likely among the key reasons for failure in late-stage clinical trials. Identifying and characterizing systematic population variation in disease expression may facilitate therapies tailored towards specific disease presentations, which may themselves possess distinct underlying etiologies and respond differentially to intervention strategies.

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