A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease

AD is responsible for approximately 70% of all dementias.5 Currently, a confirmed diagnosis of AD requires the presence of plaques (deposited amyloid β Aβ peptide) and tangles (intracellular, aggregated, hyperphosphorylated, tau protein) found via postmortem neuropathological examination of the brain. Although there are many abnormalities within an AD brain, neuronal death, particularly within the hippocampus, entorhinal cortex, and frontal cortical regions, contribute to cognitive impairment. The amount and regional distribution of plaques in AD brains does not correlate well with the extent of neuronal loss or with the clinical severity of dementia.6 There have been studies suggesting a better correlation with soluble Aβ in AD brain.7 However, deposited Aβ comprises approximately 95% of total Aβ (soluble plus deposited).8 The role of Aβ in AD has been long debated; does it trigger the disease process, is there some threshold amount that is required to sustain the disease, or does deposited Aβ drive the disease forward in a continuous fashion?9 The presence of tau pathology, in the form of insoluble paired helical filaments (PHFs), correlates much better both with the areas of the brain that suffer from neurodegeneration and also with the extent of cognitive impairment.10, 11 However, the numbers of PHFs do not account for all the neuronal loss.6 Finally, brain volume remains the best pathological correlate of dementia in AD.12 There is extensive literature demonstrating that proteoglycans bind to Aβ peptide and can accelerate the transition of soluble Aβ to a β-sheet structure that is required for the formation of plaques.13, 14 Tramiprosate (3-amino-1-propanesulfonic acid) is a glycosaminoglycan mimetic that was discovered in a screen that measured the heparin-stimulated conversion of soluble Aβ40 from a random coil to the β-sheet structure that is characteristic of aggregated Aβ.15 Tramiprosate was tested for its ability to bind to soluble Aβ and thereby prevent its aggregation. Mechanistically, this would prevent the accumulation of aggregated Aβ and increase the levels of soluble Aβ in AD brain. The published data on tramiprosate are not as comprehensive as might be expected for a clinical candidate. A 20-fold molar excess of tramiprosate prevented the conversion of Aβ40 from random coil/alpha helix to β-sheet, as assessed by circular dichroism spectral analysis. No data were available for Aβ42.16 Experiments to determine the interaction between tramiprosate and Aβ were performed that tramiprosate was to bind to both Aβ40 and with a molar excess of required to a that was by However, there are data on or and the of Aβ and tramiprosate were for of and of with a of soluble in of the of this to an is not A was was and with were to the of tramiprosate to prevent Aβ of this were brain from AD this of of required to of of Aβ were Tramiprosate was to be the tested that a molar excess of Aβ and tramiprosate as been in the the in the also to a 20-fold molar tramiprosate was to the by to data are to there were and the was not it is not to determine this was with of Aβ aggregation. that the and tramiprosate was or for The levels of in the brain the of this were not a continuous of for was to brain and levels of in and tramiprosate brain levels of and The was between and in and in brain. However, the of total were and it is not data might with the that was to determine The a on the of the by plaques not and the on the of plaques A would have required a of and brain for and the for of Aβ the levels of soluble Aβ40 and were both in a by A of levels of Aβ is with some of this was not A of were that for a to increase in Aβ of tramiprosate much in in brain of both soluble and insoluble Aβ40 and data that are to for an The data some for an of tramiprosate on Aβ levels in brain, the data were that a of and performed and of and total levels would have a of the of the was not there was of The of in for and and the of Aβ for the do not data would have confirmed or the that the tramiprosate to Aβ and aggregation. the tramiprosate was and for to AD with a between and is not to determine were from the Tramiprosate not increase in a between the and were and tramiprosate be in of between and The of total Aβ in is approximately and it is that tramiprosate the 20-fold molar excess to be required to bind to Aβ in some of the in However, it was not were found in the some data that Aβ in the in the brain might be as much as that found in would that levels of tramiprosate not have been there was a in levels of to 70% of with in the AD this were in a that was to Aβ it would have been an of and of a in is as an increase in an to prevent levels to the the both to prevent and to increase or there was on Aβ40 the in data in the between Aβ40 and Tramiprosate on cognitive and clinical is the of the The on were to the was a that in and Tramiprosate was and for The were the and of The was to a in clinical volume were assessed by and as a of disease this its and there was a clinical that the analysis. some of volume that a of the data was a in in the it is that data are not available from the Tramiprosate is as an for data that the of some the of this has not been by studies have been However, were tested for ability to Aβ and and the of and this was for by an increase in the Aβ a of the are not of the in of the of of do not the of an of The on were not via of the the and was that and the and were of The tested was that would a for AD by the of in the brains of AD The published on not in for of have to and that were to bind to an not to of However, studies have that to the that a in of Aβ in of with a of of Although the of to the of has been it remains a an of of that would have as a or as an of on the The of in was not and of were for to with levels of brain and Aβ40 a there was and the were from to The brain and levels of also not increase in a The measured brain levels of were between and some the in the of levels to A in a were for between the of and was for from to The brains of the were for Aβ40 and levels and was measured of the or was in the not the The between a of on of and and a of in the that of in the to of and of and the total was the in in to to an of for The was to the to The brain was There was a in brain not to the the and of of this is and 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