Amyloid-β: The Beginning of the End and the End of the Beginning
The paper by Head and colleagues (2008) should serve as a major warning for those hoping that removing amyloid will be effective in the treatment of Alzheimer disease (AD) or age-related cognitive impairment. So far, aside from transgenic mice engineered to overproduce amyloid, the record for amyloid immunotherapy has been one of abject failure: 1) trial suspension (human) and 2) no improvement (dogs). At minimum, these studies indicate that our current mouse models of AD are inadequate and, being amyloidocentric, naturally respond to amyloidocentric therapies. By contrast, rather than being driven by a transgene, the amyloid in aging or AD is there for a physiological or pathological reason (Nunomura et al., 2001), and removal of amyloid will not remove these precipitating factors. Moreover, we suspect that the production of amyloid, in response to a primary disease etiology, may...  Read more

Amyloid-β: The Beginning of the End and the End of the Beginning
The paper by Head and colleagues (2008) should serve as a major warning for those hoping that removing amyloid will be effective in the treatment of Alzheimer disease (AD) or age-related cognitive impairment. So far, aside from transgenic mice engineered to overproduce amyloid, the record for amyloid immunotherapy has been one of abject failure: 1) trial suspension (human) and 2) no improvement (dogs). At minimum, these studies indicate that our current mouse models of AD are inadequate and, being amyloidocentric, naturally respond to amyloidocentric therapies. By contrast, rather than being driven by a transgene, the amyloid in aging or AD is there for a physiological or pathological reason (Nunomura et al., 2001), and removal of amyloid will not remove these precipitating factors. Moreover, we suspect that the production of amyloid, in response to a primary disease etiology, may serve a beneficial function such that the removal of amyloid would be detrimental and exacerbate any underlying pathological processes (Perry et al., 2000; Rottkamp et al., 2002; Smith et al., 2002; Castellani et al., 2006; Lee et al., 2006a). We previously noted the existence of amyloid spin doctors (Castellani et al., 2007) and wonder whether the ever-increasing inconsistencies in the amyloid hypothesis (Lee et al., 2006b), together with recent therapeutic failures, will finally lead to the realization that it is time to stop spinning. Perhaps the time has come for this to be the beginning of the end for amyloid and the end of the beginning in our quest to understand and treat this disease.

References:
Castellani R, Lee HG, Perry G, Smith MA, Zhu X (2007) ARF Comment: Amyloid spin doctors.

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

Head E, Pop V, Vasilevko V, Hill M, Saing T, Sarsoza F, Nistor M, Christie LA, Milton S, Glabe C, Barrett E, Cribbs D (2008) A Two-Year Study with Fibrillar {beta}-Amyloid (A{beta}) Immunization in Aged Canines: Effects on Cognitive Function and Brain A{beta}. J Neurosci 28, 3555-3566. Abstract

Lee HG, Zhu X, Nunomura A, Perry G, Smith MA (2006a) Amyloid-beta vaccination: testing the amyloid hypothesis?: heads we win, tails you lose! Am J Pathol 169, 738-739. Abstract

Lee HG, Zhu X, Nunomura A, Perry G, Smith MA (2006b) Amyloid beta: the alternate hypothesis. Curr Alzheimer Res 3, 75-80. Abstract

Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60, 759-767. Abstract

Perry G, Nunomura A, Raina AK, Smith MA (2000) Amyloid-beta junkies. Lancet 355, 757. Abstract

Rottkamp CA, Atwood CS, Joseph JA, Nunomura A, Perry G, Smith MA (2002) The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease. Peptides 23, 1333-1341. Abstract

Smith MA, Joseph JA, Atwood CS, Perry G (2002) Dangers of the amyloid-beta vaccination. Acta Neuropathol (Berl) 104, 110. Abstract

View all comments by Rudy Castellani
View all comments by Hyoung-gon Lee
View all comments by Akihiko Nunomura
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View all comments by Xiongwei Zhu

The intimate association of vascular disease and AD suggests that in many patients with early signs of dementia, amyloid disruption therapy may be complicated by impaired perfusion and drainage. Such conditions may explain the outcomes observed following the first human vaccination trial in which senile plaques were disrupted, but the amyloid remnants did not exit the brain. That makes the data of Nikolic et al. exciting, as these experiments suggest another means to actually eliminate and/or effectively alleviate the effects of toxic Aβ molecules.

Successful disruption of amyloid plaques will mitigate and perhaps eliminate the cascade of consequential destruction associated with these deposits. But great uncertainties remain regarding the ultimate risks posed by the chronic...  Read more

The intimate association of vascular disease and AD suggests that in many patients with early signs of dementia, amyloid disruption therapy may be complicated by impaired perfusion and drainage. Such conditions may explain the outcomes observed following the first human vaccination trial in which senile plaques were disrupted, but the amyloid remnants did not exit the brain. That makes the data of Nikolic et al. exciting, as these experiments suggest another means to actually eliminate and/or effectively alleviate the effects of toxic Aβ molecules.

Successful disruption of amyloid plaques will mitigate and perhaps eliminate the cascade of consequential destruction associated with these deposits. But great uncertainties remain regarding the ultimate risks posed by the chronic disturbance of the immobilized amyloid sequestered within plaques. The relative stress resilience of animal model and human neurons may be quite different, making the extrapolation of laboratory results to clinical outcomes such as improvements in cognitive status a challenging endeavor.

We cannot yet delineate precise pathological role(s) of Aβ in AD dementia, nor can we assign with certainty a normal-state function for this evolutionarily conserved molecule. Inducing or infusing high titers of antibody in the periphery to effect a CNS compartment change is still in an experimental stage. Present immunization trials employing this stratagem must be supported by further analyses beyond antibody titers and plaque removal.

View all comments by Tyler A. Kokjohn
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