Reassessing the amyloid cascade hypothesis of Alzheimer's disease

Abstract

Since its inception, the amyloid cascade hypothesis has dominated the field of Alzheimer's disease (AD) research and has provided the intellectual framework for therapeutic intervention. Although the details of the hypothesis continue to evolve, its core principle has remained essentially unaltered. It posits that the amyloid-beta peptides, derived from amyloid precursor protein (APP), are the root cause of AD. Substantial genetic and biochemical data support this view, and yet a number of findings also run contrary to its tenets. The presence of familial AD mutations in APP and presenilins, demonstration of Abeta toxicity, and studies in mouse models of AD all support the hypothesis, whereas the presence of Abeta plaques in normal individuals, the uncertain nature of the pathogenic Abeta species, and repeated disappointments with Abeta-centered therapeutic trials are inconsistent with the hypothesis. The current state of knowledge does not prove nor disprove the amyloid hypothesis, but rather points to the need for its reassessment. A view that Abeta is one of the factors, as opposed to the factor, that causes AD is more consistent with the present knowledge, and is more likely to promote comprehensive and effective therapeutic strategies.

Figure 1. Many avatars of the amyloid hypothesis

The main tenet of the amyloid hypothesis is that Aβ is the primary cause of the disease. It was originally proposed that increased levels of Aβ resulted in plaque formation (1), which caused AD. Subsequent observations that fAD mutations increase Aβ42 generation, led to a proposal that it is the increased levels of Aβ42 peptide that is pathogenic and caused AD (2). Another variation on the theme is that the absolute levels of Aβ42 are less important than the ratio of Aβ42/40 in causing AD (3), and there seems inverse correlation between Aβ42/40 ratio and the age of disease onset. However, the currently most favored idea is that Aβ forms soluble oligomers (4), which are pathogenic in nature and cause AD. Despite intense investigations, there is no consensus regarding the chemical nature of such pathogenic oligomers.

Figure 2. Potential pathways of Aβ oligomerization in vivo

Almost nothing is known about how Aβ oligomerizes in vivo. One possibility (A) is that there is a single linear oligomerization pathway with Aβ monomers initially forming low molecular weight soluble aggregates (1). These oligomers further aggregate (step 2) into insoluble protofibrils, fibrils and plaques (2). In this view, both soluble oligomers and insoluble fibrils are considered to be pathogenic. An alternate possibility (B) is that there are two distinct pathways. A pathogenic pathway (1) that forms soluble oligomers (dimers/Aβ*56/ADDLs) which cause the disease, and a second non-pathogenic pathway (2) that leads to the formation of insoluble aggregates and plaques. The insoluble aggregates are thought to be benign, a view more consistent with the available data. It has also been suggested that the benign insoluble aggregates may slowly leach (3, dashed arrow) forming the pathogenic soluble oligomers (Meyer-Luehmann et al., 2008).

Figure 3. Reassessing the amyloid hypothesis

The classical view (A) of the amyloid hypothesis posits that Aβ is the primary cause of AD and occupies the top position in the cascade (green oval). Increased production or decreased degradation results in accumulation of Aβ, which in a yet uncertain pathogenic form (see Figure 1) triggers a number of downstream deleterious events (purple ovals). These events are caused by Aβ as a primary effect (green arrows) and/or as a secondary effect (double-headed purple arrows). A cumulative effect of these events over time results in synaptic dysfunction, and causes AD. A distinguishing feature of this view is that Aβ acts upstream of all other events, and blocking its effects will prevent all downstream events and prevent AD. A modified view (B), which is more consistent with the presently available data, suggests that the deleterious events leading to AD are caused by Aβ as well as non-Aβ factors (green boxes). One prediction of this model is that blocking the Aβ effects will be effective only in a limited number of cases, as has been observed in the recent drug trial.