Paul Aisen is justified in asserting that “…the results do not refute the amyloid hypothesis,” and a similar line of reasoning was put forth at each of the previous setbacks. The amyloid hypothesis, which has been extensively scrutinized and has produced the most visible therapeutic target, has morphed from “plaques are bad” to “Aβ42 is bad”’ to “soluble oligomers are bad” to “Aβ dimers are bad,” to name a few manifestations. Yet a dispassionate look at the literature tells us that something is not right with this picture. Up to 30-40 percent of non-demented subjects have ample plaques by PIB scanning, flurbiprofen,...  Read more

Paul Aisen is justified in asserting that “…the results do not refute the amyloid hypothesis,” and a similar line of reasoning was put forth at each of the previous setbacks. The amyloid hypothesis, which has been extensively scrutinized and has produced the most visible therapeutic target, has morphed from “plaques are bad” to “Aβ42 is bad”’ to “soluble oligomers are bad” to “Aβ dimers are bad,” to name a few manifestations. Yet a dispassionate look at the literature tells us that something is not right with this picture. Up to 30-40 percent of non-demented subjects have ample plaques by PIB scanning, flurbiprofen, which reduces Aβ42 and increases Aβ38, is ineffective, tramiprosate is supposed to act by preventing oligomerization, and the Aβ vaccines have not delivered the expected results.

There are still a number of “amyloid-directed” clinical trials in the pipeline, and we hope that some of them will turn into an effective therapy. The amyloid hypothesis has been the “engine” behind much of the basic and translational AD research, and these setbacks should not diminish its past contributions to the field. Nonetheless, there is no shame in taking a deep breath and opening up to the possibility that maybe we need to revise our strategy. Wishful thinking and contorting to hold on to a favorite—but perhaps wrong—idea is seldom helpful.

View all comments by Sanjay W. Pimplikar

1911 to 2008: The Dismal Progress of Knowledge in Alzheimer’s Disease Research
In a study of senile plaques in brains of the demented and non-demented, Fuller in 1911 noted the presence of plaques in both groups, as well as in a young tabetic without cerebral cortical signs (1). He further summarizes the work of other investigators, in which senile plaques were found in brains of patients with senile dementia, as well as neurologically intact patients dying from other causes. In a review of the issue of clinical-pathological correlation by Huebner (cited in the Fuller paper), performed to help resolve medico-legal issues surrounding brain changes and competency, Huebner notes “the presence of (senile) plaques in the brain is not characteristic of any special (neurological condition)”; that the subject had at least reached the fifth decade is the most that could be medico-legally advocated. In a rather prescient remark, Fuller writes “while many interesting details...  Read more

1911 to 2008: The Dismal Progress of Knowledge in Alzheimer’s Disease Research
In a study of senile plaques in brains of the demented and non-demented, Fuller in 1911 noted the presence of plaques in both groups, as well as in a young tabetic without cerebral cortical signs (1). He further summarizes the work of other investigators, in which senile plaques were found in brains of patients with senile dementia, as well as neurologically intact patients dying from other causes. In a review of the issue of clinical-pathological correlation by Huebner (cited in the Fuller paper), performed to help resolve medico-legal issues surrounding brain changes and competency, Huebner notes “the presence of (senile) plaques in the brain is not characteristic of any special (neurological condition)”; that the subject had at least reached the fifth decade is the most that could be medico-legally advocated. In a rather prescient remark, Fuller writes “while many interesting details concerning (senile) plaques of the brain have been established, the last word, perhaps, has not been said. As to the origin and nature of these (senile) plaques opinions differ, some even taking on the character of polemics.”

Welcome to 1911.

So here we are now in 2008, surprised to find evidence of amyloid-β with Pittsburgh Compound B in non-demented subjects, and surprised by the continued failure of anti-amyloid-based therapies.

It bears remembering that the now 25-year-old Brownian-like motion that surrounds the amyloid cascade hypothesis is rooted in a causal association between plaques, or variations thereof (e.g., low n Aβ-mers), and human disease (2,3). Absent such an association (which has long been the case), the cascade represents effect rather than cause (4), and the cascade hypothesis an expensive and even harmful distraction. Therefore, while many interesting details of the amyloid cascade have been established, the last word, perhaps, has not been said. As to the origin and nature of neurodegeneration in AD, opinions differ, but the reticence to accept empirical truths (“Though disappointing, the results do not refute the amyloid hypothesis”) takes on the character of polemics.

Welcome to 2008.

References:
1. Fuller SC. A study of the miliary plaques in the brains of the aged. American Journal of Insanity. 1911;LXVIII:147-219.

2. Castellani RJ, Lee HG, Zhu X, Nunomura A, Perry G, Smith MA. Neuropathology of Alzheimer disease: pathognomonic but not pathogenic. Acta Neuropathol. 2006;111:503-509. Abstract

3. Castellani RJ, Lee HG, Zhu X, Perry G, Smith MA. Alzheimer disease pathology as a host response. J Neuropathol Exp Neurol. 2008;67:523-531. Abstract

4. Smith MA, Casadesus G, Joseph JA, Perry G. Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med. 2002;33:1194-1199. Abstract

View all comments by Rudy Castellani
View all comments by Hyoung-gon Lee
View all comments by George Perry
View all comments by Mark A. Smith
View all comments by Xiongwei Zhu

The tragedy is that the principal idea of modulation of APP processing deserves to be tested, but, because of how the Flurizan rationale has been communicated, other tests, with perhaps more deserving compounds, may be obstructed.

View all comments by Hanno Roder