Reimagining Alzheimer's disease--an age-based hypothesis

Abstract

The historical roots of Alzheimer's disease provide a sound conceptual basis for linking the behavioral and neurological symptoms of the disease with the frequently associated pathology of amyloid plaques and neurofibrillary tangles. Out of these roots has grown the "amyloid cascade hypothesis"--a vision of the etiology of Alzheimer's that has spurred the discovery of many important insights into the neurobiology of the disease. Despite these successes, the wealth of new data now available to biomedical researchers urges a full review of the origins of Alzheimer's, and such a reconsideration is offered here. It begins with the most widely accepted risk factor for developing Alzheimer's disease: age. Then, for an individual to progress from normal age-appropriate cognitive function to a condition where the full palette of clinical symptoms is expressed, three key steps are envisioned: (1) an initiating injury, (2) a chronic neuroinflammatory response, and (3) a discontinuous cellular change of state involving most, if not all, of the cell types of the brain. The amyloid cascade is integrated into this sequence, but reconfigured as an amyloid deposition cycle. In this way, the pathology of amyloid plaques is envisioned as highly correlated with, but mechanistically distinct from, the three obligatory steps leading to Alzheimer's disease. The implications of this new model are discussed with respect to our current diagnostic criteria, and suggestions are put forward for expanding our future research efforts.

Figure 1.

The amyloid cascade hypothesis of Alzheimer's disease. This hypothesis represents the classic theory of the origins of Alzheimer's disease. Both familial forms of Alzheimer's (fAD) and later-onset forms with no known etiology (sporadic AD) lead to the production of excess Aβ_1-42. Once this toxic peptide begins to aggregate, a cascade of events is triggered that produces the biological and neurological symptoms of Alzheimer's disease. The diagram is modified from that found on the AlzForum web site (http://www.alzforum.org/images/res/adh/cur/sequence2005.gif).

Figure 2.

The age-dependent hypothesis of Alzheimer's disease. The new model begins with the cell biology of the brain, weakened by the normal course of aging. Under ideal circumstances, this leads only to a modest natural slowing of function. The new hypothesis postulates three events that divert the brain into the pathophysiology of Alzheimer's disease. These are numbered and highlighted in red text. The first is an initiating injury; the second is a chronic neuroinflammation; the third is a discrete change in the cell biological state of the cells of the brain that alters their normal functions and predisposes them to undergo a degenerative process.

Figure 3.

The amyloid deposition cycle. In this diagram, the amyloid cascade of Figure 1 is reenvisioned as a feedforward cycle of amyloid deposition and inflammatory responses. The inflammation step of the cycle connects it directly to the age-dependent hypothesis (grayed text on the right side of the diagram), integrating the two models. As the processes are mechanistically distinct, however, the presence of amyloid is not required for the inflammation, and the chronic inflammation is not required for the deposition of amyloid.

Figure 4.

The expanded age-dependent hypothesis of Alzheimer's disease. The three tenets of the new hypothesis are displayed in bold type on blue ovals and numbered for clarity. The interconnected amyloid deposition cycle is displayed in a similar fashion. Added to the diagram are a few of the cell biological and biochemical processes that play significant roles in Alzheimer's disease. Blue arrows (single- and double-headed) provide a small bit of the interactive nature of the various events. For clarity, some events are illustrated twice (e.g., “autophagy defects”). The light blue text and arrows at the top of the diagram are meant to symbolize the possibility discussed in the text that other late-onset neurodegenerative diseases may begin from the same origin as Alzheimer's disease, but differ based on their initiating injury and downstream response.