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Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N, Scarpini E, Liu-Seifert H, Case M, Dean RA, Hake A, Sundell K, Poole Hoffmann V, Carlson C, Khanna R, Mintun M, DeMattos R, Selzler KJ, Siemers E. Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med. 2018 Jan 25;378(4):321-330. PubMed.
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RIKEN Center for Brain Science
In my opinion, the primary question here is, “Do the intravenously administered therapeutic antibodies ever reach brain parenchyma in humans?” The are some data from mice, but the biochemical observations do not exclude vascular binding. Human data are indirect because there are no negative controls.
In fact, immunoreactivity of anti-human IgG is a marker for brain hemorrhage. Besides, IgG is too hydrophilic and too large to cross the blood-brain barrier (BBB). Note that curcumin, 400 times smaller than IgG in molecular weight, never crosses the BBB. People in India take curcumin in every meal, and their brains are not yellowish.View all comments by Takaomi Saido
University of Minnesota
Sadly, these results are not surprising considering previous work from Dominic Walsh’s group (Mably et al., 2015) showing that m266 does not lower Aβ oligomers (AβO) and does not alleviate cognitive deficits in J20 APP transgenic animals. In addition, numerous evidences appear to support an initiator role of AβO in the cascade leading to synaptic and cognitive impairment, while tau mediates these deleterious effects, as we and others have reported (Roberson et al., 2007; Vossel et al., 2010; Amar et al., 2017).
Mably AJ, Liu W, Mc Donald JM, Dodart JC, Bard F, Lemere CA, O'Nuallain B, Walsh DM. Anti-Aβ antibodies incapable of reducing cerebral Aβ oligomers fail to attenuate spatial reference memory deficits in J20 mice. Neurobiol Dis. 2015 Oct;82:372-84. Epub 2015 Jul 26 PubMed.
Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.
Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P, Finkbeiner S, Cui B, Mucke L. Tau reduction prevents Abeta-induced defects in axonal transport. Science. 2010 Oct 8;330(6001):198. PubMed.
Amar F, Sherman MA, Rush T, Larson M, Boyle G, Chang L, Götz J, Buisson A, Lesné SE. The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. Sci Signal. 2017 May 9;10(478) PubMed. Expression of Concern.View all comments by Sylvain Lesne
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