Wirth M, Villeneuve S, Haase CM, Madison CM, Oh H, Landau SM, Rabinovici GD, Jagust WJ. Associations between Alzheimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people. JAMA Neurol. 2013 Dec;70(12):1512-9. PubMed.
Recommends
Please login to recommend the paper.
Comments
Case Western Reserve University
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 (Pimplikar, 2009), 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 (Pimplikar et al., 2010) 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 (Petersen et al., 2013). 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 (Petersen et al., 2013), 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.
References:
Pimplikar SW. Reassessing the amyloid cascade hypothesis of Alzheimer's disease. Int J Biochem Cell Biol. 2009 Jun;41(6):1261-8. PubMed.
Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH. Amyloid-independent mechanisms in Alzheimer's disease pathogenesis. J Neurosci. 2010 Nov 10;30(45):14946-54. PubMed.
Petersen RC, Aisen P, Boeve BF, Geda YE, Ivnik RJ, Knopman DS, Mielke M, Pankratz VS, Roberts R, Rocca WA, Weigand S, Weiner M, Wiste H, Jack CR. Criteria for mild cognitive impairment due to alzheimer's disease in the community. Ann Neurol. 2013 May 20; PubMed.
View all comments by Sanjay PimplikarBanner Research Institute
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).
References:
Tomiyama T, Nagata T, Shimada H, Teraoka R, Fukushima A, Kanemitsu H, Takuma H, Kuwano R, Imagawa M, Ataka S, Wada Y, Yoshioka E, Nishizaki T, Watanabe Y, Mori H. A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia. Ann Neurol. 2008 Mar;63(3):377-87. PubMed.
Shimada H, Ataka S, Tomiyama T, Takechi H, Mori H, Miki T. Clinical course of patients with familial early-onset Alzheimer's disease potentially lacking senile plaques bearing the E693Δ mutation in amyloid precursor protein. Dement Geriatr Cogn Disord. 2011;32(1):45-54. PubMed.
View all comments by Paul ColemanMake a Comment
To make a comment you must login or register.