Amyloid-beta vaccination for Alzheimer's dementia - Authors' reply

Nicoll, James, Boche, Delphine and Holmes, Clive (2008) Amyloid-beta vaccination for Alzheimer's dementia - Authors' reply. Evidence-Based Complementary and Alternative Medicine, 372 (9647), 1381-1382. (doi:10.1016/S0140-6736(08)61580-9).

Abstract

In the light of our observations, we have considerable sympathy for the view proposed by Jordan Holtzman that abnormal protein accumulation in Alzheimer's disease might be the product of an upstream abnormality of protein processing and that, although amyloid ? accumulates as a consequence, its presence is merely an epiphenomenon and thus other paradigms should be explored.

Holtzman, and also Peter St George-Hyslop and John Morris,1 consider the effect of our observations on the amyloid hypothesis. In our view it is important to distinguish between the amyloid hypothesis and the amyloid-? hypothesis. The term amyloid usually refers to proteins forming aggregates large enough to be histologically detectable with amyloid stains. Although, by pathological definition, amyloid ? is always present, in fact there is little direct evidence that it has a causal role in the pathogenesis of the common sporadic Alzheimer's disease, as opposed to the extremely rare familial disease. In our view, our observation that patients with little or no amyloid ? forming aggregates large enough to be detectable by immunohistochemistry continue to have progressive cognitive decline comes close to disproving the amyloid hypothesis of Alzheimer's disease, but leaves open the possibility that soluble or oligomeric amyloid ? has a role consistent with the amyloid-? hypothesis.

The amyloid-?/amyloid hypothesis has been the prevalent hypothesis of the pathogenesis of Alzheimer's disease for two decades; it deserves to be thoroughly tested.

Patrick McGeer discusses the possibility that the antibodies generated in response to amyloid-? immunisation might stimulate complement activation with neurotoxic consequences. Although the mechanism he proposes is credible, we have insufficient evidence to support or refute it at present. However, it is worth noting that the tangles remaining after the plaques have been removed are not “ghost” tangles (ie, tangles remaining after the neurons in which they have formed have died), but are intraneuronal tangles in viable neurons, as typically seen in unimmunised Alzheimer's disease. In other words there is no evidence for “bystander lysis” of neurons. The plaque-associated tau-containing dystrophic neurites are indeed no longer present when the plaques have been removed, but at present we do not know whether this is because they have been removed by microglial phagocytosis or have resolved by a repair process.2, 3

The resulting level of cognitive function might be the consequence of the balance between beneficial and harmful effects of immunisation on the brain.4 However, it is worth noting that, although our study found no evidence that the immunised patients fared better in terms of cognitive function, there was no statistical evidence that they did any worse, therefore justifying further studies.

We agree that, although amyloid precursor protein transgenic mice are very good models of both amyloid-? accumulation and the effects of immunisation on accumulated amyloid ?,4 there are also crucial differences between human Alzheimer's disease and the mouse models and that, as a result, the models might not predict what occurs in human beings. The unexpected occurrence of encephalitis in some of the patients immunised with amyloid ? is a good example of this.5

We declare that we have no conflict of interest.

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Contributors

Author: James Nicoll

Author: Delphine Boche

Author: Clive Holmes

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