In recent years, our knowledge base has broadened considerably, affording us the luxury of being able to revisit our hypotheses about causes of AD. Based on its prevalence, it now makes sense to begin this exercise with the more common sporadic form of the disease rather than with the rare familial forms. The precise etiology of sporadic AD is not known in detail. We do know, however, that the most critical risk factor by far is age. This makes intuitive, if not mechanistic sense. In all species, age brings a progressive slowing of brain function in virtually every domain. Our cognition slows; our ability to form new memories is reduced; our motor functions deteriorate; even our brain’s homeostatic functions become less and less robust. This functional decline is correlated with the loss of structural complexity of our brain cells. Neuronal dendrites become less complex, spine and synapse density decrease, the cell bodies of the larger neurons accumulate lipofuscin, astrocytic function declines (e.g., glutamate uptake and recycling), our immune systems become less responsive, etc. And as this list of insufficiencies grows, the brain’s defenses against many diseases, Alzheimer’s included, is weakened. The question is: how do the signature symptoms of AD emerge from this state. The new model envisions 3 key events that occur sequentially when an individual develops Alzheimer’s disease (). The first is a precipitating injury that is begins the pathogenic process. This injury in turn triggers the second key event: a chronic inflammatory process that adds additional relentless stress to brain cells already weakened by age. The third event is a major shift in the cellular physiology of the brain cells. Described in more detail below, it represents a tipping point that marks the beginning of a cell’s degenerative process and leads to major synaptic dysfunction and neuronal death – the final and most direct cause of Alzheimer’s dementia.
The age-dependent hypothesis of Alzheimer’s disease
In the beginning – a divergence from normal aging
Although aging gradually takes its toll on our brains, the hypothesis stipulates that some event – a physical head trauma, a major illness or infection, a vascular event (possibly so small as to be clinically undetectable), the metabolic stress associated with adult-onset diabetes or even the stress associated with a major life event such as a death in the family – is required to initiate the disease process. A genetic mutation can be such an injury, but only if it must interact with the aging process to be expressed. The injury triggers a protective response among the cells of the brain, but the age-related failure of the normal homeostatic mechanisms means that the response continues, even if after injury itself abates. The key concept is that it is the nature of the response, not the nature of the injury, that determines the outcome of Alzheimer’s disease.
A useful analogy to consider is hip fracture. For a wide variety of reasons, the risk of breaking our hipbone increases dramatically with age. Bone density decreases; osteoporosis becomes more likely; balance is less sure; reaction times slow; muscles weaken; visual acuity fades; etc. Each of these is a risk factor, but the factors themselves do not cause the hipbone to break; there has to be a precipitating injury (usually a fall). Applied to AD, the analogy is meant to suggest that while any of the changes in the brain that come with advancing age may increase our risk of Alzheimer’s, without an injury none can cause dementia.
The idea that AD begins with an initiating injury has both theoretical and practical relevance. Theoretically, it means that Alzheimer’s is not a part of normal aging any more than breaking your hip is a part of normal aging. They are both pathological events with an underlying biology. The practical relevance is that, if research can identify the most common sources of injury, we may be able to intervene proactively and delay disease onset. Currently, it is not possible to identify a single candidate for this precipitating injury. But the frequent co-occurrence of vascular pathology with AD, and the protective effects of genetic and environmental factors that improve cardiovascular health suggest that a common if not exclusive initiating injury would be a vascular event such as a head trauma or microstroke.
The role of inflammation
A cardinal feature of the neuropathology of most AD brains is the evidence for a chronic neuroinflammatory process. Many recent reviews have summarized this topic in some detail (McGeer et al., 1996
; Akiyama et al., 2000
; Bamberger and Landreth, 2002
; Wyss-Coray and Mucke, 2002
; Wyss-Coray, 2006
; Glass et al., 2010
). While it is true that an inflammatory response accompanies tissue damage in many brain diseases including Parkinson’s (McGeer et al., 2001
; Nagatsu and Sawada, 2005
), ALS (Henkel et al., 2009
; Ilieva et al., 2009
), and others, AD is unique in the intimate association found between chronic inflammation and disease. There is also solid epidemiological evidence that inflammation serves as a cause of AD. Long-term use of high doses of certain non-steroidal anti-inflammatory drugs (NSAIDs) lowers the lifetime risk of AD from 30–60% (McGeer et al., 1996
; Stewart et al., 1997
; Vlad et al., 2008
), and there is biochemical evidence for elevated levels of cytokines such as Il-1, Il-6, TNFα and S100β in human AD brain (Griffin et al., 1998
; Akiyama et al., 2000
). Microgliosis as well as astrocytosis are prevalent, and most plaques are surrounded by activated astrocytes and invaded by activated microglia (McGeer et al., 1987
; Heneka and O'Banion, 2007
; El Khoury and Luster, 2008
; Rodriguez et al., 2009
Discussions of brain inflammation tend to focus on the microglial cell; however, a variety of cell types participate in the AD inflammatory response. These cell:cell interactions have been reviewed for other diseases (Ilieva et al., 2009
) and evidence for their importance appears in the AD literature as well (Griffin et al., 1998
; Mucke et al., 2000
; Wegiel et al., 2001
; Giri et al., 2002
; Griffin, 2006
). Through a variety of feed-forward loops, the microglial cells are assisted by the responses of astrocytes and brain vascular endothelial cells (Giri et al., 2002
) in maintaining a chronic shift in the inflammation status of the brain. The result of this network-like response is a chronic stress on neurons and their function. Cell cycle proteins are activated (Wu, Q. et al., 2000
), reactive oxygen species are produced (Keller et al., 1999
; Fuller et al., 2010
), mitochondrial function is reduced (Chen and Chan, 2009
), dendritic/axonal transport is impaired (Wu, H. Y. et al., 2010
), etc. A second tenet of the new model, therefore, is that a chronic immune response, persisting over months and years, creates the unique chemistry and cellular physiology that results in the core symptoms we recognize as dementia of the Alzheimer’s type.
Two biologies – early and late stages of Alzheimer’s disease
Thus far, the re-envisioning of AD has included two important tenets. The first is that Alzheimer’s must be triggered by an injury. The second is that the establishment of unique type of chronic inflammation is required to set the brain’s chemistry on the path to AD. To fully capture the neurobiology of the disease, however, a third tenet must be introduced: the progression to full Alzheimer’s disease requires a functional discontinuity between the physiology of the brain cells in early and late stages of the disease. This dramatic change-of-state results in a ‘new normal’ biology, primed towards neurodegeneration and dementia. The exact meaning of this transition in biological terms is only beginning to be understood but some of its consequences are already becoming apparent. It is envisioned as a one-way cellular door; once a cell crosses the threshold, it can never return to its earlier state.
The best example of this change-of-state concept can be found in the paradoxical association of neuronal cell cycle events with the process of neurodegeneration. Neurons are generally considered to be permanently post-mitotic cells. But when they are stressed, fully differentiated neurons can and do re-initiate the enzymatic cascades of a normal cell cycle. Curiously, the cycle stalls after DNA replication such that the neurons can neither proceed into late G2/M-phase and complete division, nor can they reverse and turn off the cell cycle proteins. This new neuronal ‘state’ is of more than academic interest as it is dramatically elevated in populations of neurons that are at risk for death in several neurodegenerative diseases, the best studied of which is AD. The at-risk neurons re-express cell cycle proteins (Arendt et al., 1996
; Vincent, I et al., 1996
; McShea et al., 1997
; Vincent, I. et al., 1997
; Busser et al., 1998
; Nagy et al., 1998
), accompanied by true DNA replication (Yang et al., 2001
; Kingsbury et al., 2005
; Yang et al., 2006
; Mosch et al., 2007
). These unscheduled neuronal cell cycles appear during early disease stages (Yang et al., 2003
; Arendt et al., 2010
), which argues that they are an integral part of the disease process. The full mechanistic implications of the appearance of cell cycle events (CCEs) in a ‘post-mitotic’ adult neuron are not yet understood, but certainly the doubling of the DNA content of any cell would seem to qualify as a profound and irreversible change-of-state.
Findings in the mouse models of AD enhance this view. In one carefully studied AD model, both the anatomical and temporal appearance of the CCEs follow the course of the neuropathology seen in human AD (Yang et al., 2006
; Varvel et al., 2008
). Further, the CCEs in this model do not appear in a slow progressive manner. Rather, in any one population of neurons, the percentage of ‘cycling’ neurons rises rapidly from near zero to final values and then remains stable – a rapid change-of-state. A similar progression is likely to occur in the human AD brain (Arendt et al., 2010
). The results of anti-inflammatory treatments of AD mouse models are also consistent with a change-of-state model. While 3 months of NSAIDs treatment can block new CCEs from appearing, even 6 months of NSAIDs treatment do not reverse the cell cycle protein expression pattern once it has begun (Varvel et al., 2009
Neurons are not the only cells of the brain whose cell biology is changed during the progression of AD. Astrocytes become activated in regions of AD neuropathology, as do the microglial cells. Equally intriguing from the change-of-state perspective, the microglia can apparently adopt a phenotype found in macrophages known an “alternate activation state” (Colton et al., 2006
; Cameron and Landreth, 2010
). This state is accompanied by a shift from an acute pro-inflammatory reaction to a chronic state of activation more suited towards vascular growth and tissue repair (Allavena et al., 2008
). Though not yet fully documented for microglia in AD, evidence from spinal cord injury studies suggest that this alternate activation can be achieved in CNS (Kigerl et al., 2009
Hypothesizing that AD involves a cellular change-of-state from early to late disease has theoretical as well as practical importance. At the theoretical level, it encourages us to revisit the cellular events that occur after the change. The prediction is that the biology of early AD differs in qualitative ways from the biology that ultimately produces the dementia. As an analogy, if someone were to stop smoking after they developed lung cancer, they would not be likely to alter the progression of the cancer. The biology of the cells involved has changed and the process is now independent of the initiating injury and transformation. It also offers a theoretical explanation for the failure of the prospective human trials of NSAIDs: the trials were all begun after AD symptoms were manifest. With the disease already in progress, it is likely that many of the neurons in the subjects’ brains had gone through their change of state. Their biology no longer required chronic inflammation to sustain their abnormal state. Coupled with the evidence cited above that the change of state may be quite abrupt in entire cohorts of neurons (Varvel et al., 2009
; Arendt et al., 2010
), the human NSAIDs trail data are consistent with the new model. At the practical level the model predicts that there is a post-amyloid, post-inflammatory biology that offers important new areas for neuroprotective drug discovery.