Review
Revisiting the cholinergic hypothesis in the development of Alzheimer's disease

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Abstract

Alzheimer's disease (AD) is the most common form of dementia affecting the elderly population today; however, there is currently no accurate description of the etiology of this devastating disorder. No single factor has been demonstrated as being causative; however, an alternative co-factors theory suggests that the interaction of multiple risk factors is responsible for AD. We have used this model, in combination with the original cholinergic hypothesis of AD to propose a “new” cholinergic hypothesis that we present in this review. This new version takes into account recent findings from the literature and our reports of removal of medial septum cholinergic projections to the hippocampus reduces both behavioural and anatomical plasticity, resulting in greater cognitive impairment in response to secondary insults (stress, injury, disease, etc.). We will first summarize the experimental results and discuss some potential mechanisms that could explain our results. We will then present our ‘new’ version of the cholinergic hypothesis and how it relates to the field of AD research today. Finally we will discuss some of the implications for treatment that arise from this model and present directions for future study.

Highlights

Acetylcholine status is linked to Alzheimer's disease but its role is poorly understood. ► An alternative theory of the etiology of Alzheimer's disease is presented. ► The theory posits that multiple combinations of co-factors produce variants of this disorder. ► Cholinergic depletions are viewed as one of these etiological factors. ► Cholinergic depletions combined with other factors can impair residual hippocampal plasticity.

Section snippets

The cholinergic hypothesis of Alzheimer's disease

The cholinergic hypothesis was the first theory proposed to explain AD and has since led to the development of the only drugs currently approved to treat mild to moderate AD (Bartus, 2000, Bartus et al., 1982). This theory was based on the finding that a loss of cholinergic activity is commonly observed in the brains of AD patients (Davies and Maloney, 1976, Perry et al., 1981) and experimental studies in humans and non-human primates have suggested a role for ACh in learning and memory. These

The debate surrounding role of the cholinergic neurotransmitter system in the etiology of AD: clinical studies

Many scientists do not believe that alterations in the cholinergic system make a significant contribution to the etiological onset of AD. This conclusion seems to be based, in part, on evidence from early clinical reports of cortical cholinergic cell loss in patients with advanced AD. Since then, other important reports have supported the view that cholinergic depletions of the medial temporal lobe are present in patients with early stage AD (Perry et al., 1981, Bowen et al., 1982), but there

Single-factor theories of the etiology of Alzheimer's disease

A number of single factor theories have been proposed to explain the etiology of AD. The rare early onset cases have been linked to genetic factors which affect the processing, trafficking and recycling of the amyloid peptide (Finch and Tanzi, 1997, Pericak-Vance and Haines, 1995). Abnormalities at various stages of the processing and distribution of this peptide can result in amyloid plaques that might lead to brain damage. The more common sporadic form of AD has been linked to multiple risk

Multiple combinations of co-factors theory of Alzheimer's disease

Single factor theories (such as the cholinergic hypothesis) of AD proposed to date do not adequately account for the clinical and neuropathological symptoms of the sporadic form of AD. McDonald (2002) has put forward a co-factors model of aging as an alternative theory to explain the etiology of AD. This model predicts that different combinations of risk factors for AD interact to produce variants of this disorder. A selected list of risk factors linked to AD are shown in Table 1. One of the

Evaluation of the multiple combinations of co-factors theory: proof of principle experiments

We have completed a large set of experiments showing that different combinations of co-factors linked to AD produce hippocampal dysfunction and learning and memory impairments. These factors included: aging, cholinergic depletions, seizure activity, mini-strokes, stress, and circadian dysfunction. These experiments were designed to provide proof of the principle that multiple combinations of co-factors linked to dementia would produce neuronal death in hippocampus and associated cognitive

Multiple combinations of co-factors model of AD

Taken together these results have provided support for the co-factor theory of AD (summarized in Table 2). Five out of the six combinations of co-factors examined on measures of learning and memory and hippocampal damage, resulted in hippocampal dependent memory impairment. Interestingly only two combinations [aging and stroke (Driscoll et al., 2008) and stress and stroke (McDonald et al., 2008)] reported an increase in hippocampal damage following the second factor that was likely responsible

Revisiting the cholinergic hypothesis of Alzheimer's disease

It is now 29 years after the cholinergic hypothesis of geriatric memory dysfunction was first proposed by Bartus et al. (1982). After an initially promising start, recent studies have called many of the previous findings supporting this theory into question and it is no longer widely believed that the cholinergic depletion alone is responsible for causing AD. This has been clearly demonstrated by the lack of efficacy of AChEIs in clinical trials (Mohs et al., 2001, Winblad et al., 2001) and the

A neuroprotective or compensatory role for acetylcholine in response to injury

The cholinergic system has been implicated in mediating plasticity in the brain in response to experience or injury. There are four lines of evidence that support this hypothesis. First, there are numerous reports of the beneficial effects of cholinergic agonists on enhancing recovery and minimizing neuronal damage in various injury models. Secondly, cholinergic depletion has been found to impair experience-dependent plasticity in the cortex and hippocampus and similar mechanisms are involved

A look at our results using the ‘new’ cholinergic hypothesis

Using the hippocampus as the initial site of AD memory loss and pathology, we propose that the normal role of ACh is to mediate a number of compensatory mechanism (neurogenesis, neurotrophic factors, changes in dendritic branching) that participate in learning and memory and functional recovery from injury. An explanation of our results using the ‘new’ cholinergic hypothesis is depicted in Fig. 1. In a normal, healthy individual a sub-threshold injury often goes unnoticed as ACh-mediated

Treatment implications

One of the strengths of McDonald's (2002) co-factor theory is its ability to explain the inherent variability of AD by dividing patients into subgroups based on the presence or absence of various risk factors. The subgroup described in this review can be defined by its early cholinergic depletion and associated decrease in compensatory mechanisms as the driving force behind the progression of this disorder. We do not see this decline in ACh levels as a causal factor, but instead, as an

Future studies

We have evaluated a co-factor theory of AD and described an important role for cholinergic depletion and/or dysfunction in the development of hippocampal-dependent memory impairments that are reminiscent of those seen in early AD. Though we were able to replicate the hippocampal specific cognitive impairment, as well as the cholinergic depletion, we did not look for, or manipulate, the other two classic hallmarks of AD: amyloid plaques and neurofibrillary tangles. For the sake of simplicity,

Conclusions

Our primary conclusion is that the cholinergic depletion impairs the rats’ ability to compensate for secondary insults that target the hippocampus. We present a ‘new’ version of the cholinergic hypothesis to explain our results and have discussed the importance of prevention and early intervention when treating AD. We remain unaware of the specific underlying mechanism of this effect, but we suggest decreases in BDNF may be important. It is clear from a behavioural perspective that the removal

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    We would like to thank several reviewers of this manuscript who provided excellent comments that significantly improved this paper.

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