Unravelling Alzheimer's Disease: It's Not the Whole Story, but Aβ Still Matters

In late 2016, we solicited a series of reviews covering the variety of processes that appeared to be involved in the pathogenesis of neurodegenerative disorders, particularly Alzheimer's disease (AD). These essays have appeared at regular intervals in The FASEB Journal. My instructions to the researchers were simply not to emphasize Aβ per se because there had been many reviews both supporting and questioning the etiologic role of Aβ in the late-onset, sporadic form of AD, and reciting either of those scientific positions would be redundant. My colleagues responded admirably, and I believe that their contributions have significantly informed readers' awareness of the current state of knowledge of AD. I have written my epilogue from the perspective of an investigator interested in the role of protein aggregation in human disease and as a physician who may be charged with making a diagnosis and prescribing treatment for a patient. We do not yet have etiology-based therapies of AD, but we continue to gain insight into the mechanisms responsible for synaptic loss and the consequent functional deterioration. A silver therapeutic bullet does not seem to be in the offing. It is more likely that an iterative approach will lead to the development of a group of treatments that are AD specific or applicable to various features of the entire class of neurodegenerative disorders. How and when those therapies succeed or fail will, in turn, provide additional insights into disease pathogenesis, which will inform the development of succeeding generations of therapeutics.-Buxbaum, J. N. Unravelling Alzheimer's disease: it's not the whole story, but Aβ still matters.