Klunk WE, Perani D.
Amyloid and neurodegeneration: Converging and diverging paths.
Neurology. 2013 Nov 12;81(20):1728-9.
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The significance of these findings, which now validate the phenomenon of SNAP, cannot be overstated. In 2009, based on the data then available, I suggested that amyloid is not the cause of AD, but a cause of AD (1), and that amyloid-independent mechanisms must also be at work. Later, together with Drs. Nixon, Robakis, Shen, and Tsai, I presented multiple, amyloid-independent mechanisms of neurodegeneration that could be operative in AD (2) and, therefore, potential drug targets. The current observations that older, cognitively normal individuals and patients diagnosed with MCI/AD exhibit neurodegeneration in the absence of amyloid plaques (see Aug 2013 news) can be seen as a clinical validation of the “amyloid-independent” pathogenesis of AD (3). There is now enough clinical evidence to conclude that amyloid is neither sufficient (based on cognitively normal PiB-positive individuals) nor necessary (MCI/AD patients with SNAP) to cause AD (there is no clinical evidence that oligomeric Aβ, invisible to PiB imaging, is responsible for AD and the preclinical studies on Aβ oligomers are wrought with artifacts, see Oct 2011 Webinar).
Such a conclusion, uncomfortable as it might seem, has important implications for AD drug trials. Despite the multiple failures of amyloid-focused drugs in MCI/AD patients, leaders in the field have doubled down on the amyloid-centric approach and a significant amount of the financial resources of the NIH have been directed toward long-term trials in asymptomatic individuals (see Sep 2013 news story). On one hand, the knowledge that neurodegeneration in AD patients (or future AD patients) with SNAP could be due to amyloid-independent mechanisms should increase the success of amyloid-focused drugs by excluding such patients. On the other hand, since the SNAP cohort of AD patients is estimated to be between 17 and 29 percent (3), between 1 million and 1.5 million Americans with AD will need alternative therapeutic intervention.
If nothing else, these two papers once again underscore the urgent need to evaluate AD pathogenesis through an amyloid-independent framework and the fact that resources are required to rigorously test alternative pathogenic mechanisms and therapies based on such hypotheses. We must look beyond amyloid and diversify our AD drug target repertoire.
I suggest that the E693delta (Osaka) mutation in APP may be pertinent to the SNAP cases (e.g., Tomiyama et al., 2008; Shimada et al., 2011).