The Cholinergic System in the Pathophysiology and Treatment of Alzheimer's Disease

Harald Hampel; M.-Marsel Mesulam; A. Claudio Cuello; Martin R. Farlow; Ezio Giacobini; George T. Grossberg; Ara S. Khachaturian; Andrea Vergallo; Enrica Cavedo; Peter J. Snyder; Zaven S. Khachaturian

Disclosures

Brain. 2018;141(7):1917-1933. 

In This Article

Abstract and Introduction

Abstract

Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.

Introduction

Late-onset Alzheimer's disease dementia, the most prevalent age-related neurodegenerative disease, is clinically characterized by a progressive loss of memory and other cognitive functions. In contrast to early-onset autosomal dominant forms of Alzheimer's disease, which are directly linked to abnormalities of amyloid-β, the cascade of pathophysiological events that leads to late-onset Alzheimer's disease is not yet fully understood. Contemporary evidence suggests that late-onset Alzheimer's disease is a complex polygenic disease that involves aberrant interaction among several molecular pathways. By definition, age is the strongest risk factor (Hebert et al., 1995) followed by the ε4 allele of apolipoprotein E (APOE ε4) (Liu et al., 2013; Shi et al., 2017), and probably also cardiovascular and lifestyle risk factors (de Bruijn and Ikram, 2014). The neuropathological features of Alzheimer's disease include the accumulation of several abnormal proteins such as amyloid-β in plaques and hyperphosphorylated-tau in neurofibrillary tangles, leading to massive loss of synapses, dendrites, and eventually neurons. Clinical expression of the disease reflects the dysfunction and eventual failure of both neurochemical and structural neural networks, including the 'cholinergic system'. Although the pivotal events in the pathogenesis of Alzheimer's disease are not fully understood, several competing theories on the underlying biology of the neurodegeneration have guided research into interventions to modify, arrest, or delay the progression of the disease and its clinical manifestations. In recent years, however, failure of clinical trials in Alzheimer's disease has been the rule rather than the exception, and no new drugs for Alzheimer's disease have been approved by the US Food and Drug Administration (FDA) since 2003. The multifaceted, heterogeneous, progressive, and interactive pathophysiology of Alzheimer's disease also suggests a likely need for individualized combination treatments that may need to be varied from one stage of the disease to another, and perhaps also from one patient to another.

The cholinergic hypothesis revolutionized the field of Alzheimer's disease research by transporting it from the realm of descriptive neuropathology to the modern concept of synaptic neurotransmission. It is based on three milestones: the discovery of depleted presynaptic cholinergic markers in the cerebral cortex (Bowen et al., 1976; Davies and Maloney, 1976); the discovery that the nucleus basalis of Meynert (NBM) in the basal forebrain is the source of cortical cholinergic innervation that undergoes severe neurodegeneration in Alzheimer's disease (Mesulam, 1976; Whitehouse et al., 1981); and the demonstration that cholinergic antagonists impair memory whereas agonists have the opposite effect (Drachman and Leavitt, 1974). The hypothesis received compelling validation when cholinesterase inhibitor therapies were shown to induce significant symptomatic improvement in patients with Alzheimer's disease (Summers et al., 1986). Although other relevant pathophysiological mechanisms have received more research attention in recent years, treatments that improve cholinergic function remain critical in the management of patients with Alzheimer's disease. The goal of this review is to characterize the nature of the cholinergic lesion in Alzheimer's disease, its potential interactions with other components of the pathology, and its relevance to treatment. We do not aim to provide a comprehensive review of Alzheimer's disease pathogenesis or to rank order the impact of the cholinergic lesion among all other components of this disease. Furthermore, our comments will be limited to late-onset Alzheimer's disease in patients who do not have disease-causing dominant mutations. We should also point out that the brain contains several cholinergic pathways, each with its unique receptor signature, postsynaptic targets and disease vulnerabilities. Unless noted otherwise, our comments in this review will address the forebrain pathway that originates in the basal forebrain and that innervates the neocortex and limbic system. This review also provides a comprehensive evaluation of the known benefits of cholinergic therapies throughout the various stages of Alzheimer's disease. We aim to demonstrate the enduring value of cholinergic drugs in the pharmacological therapy of Alzheimer's disease, especially in the context of future combination therapies that may affect both symptoms and disease progression.

Nature and Impact of the Cholinergic Lesion

Acetylcholine is a major neurotransmitter in the brain, with activity throughout the cortex, basal ganglia, and basal forebrain (Mesulam, 2013). Figure 1 illustrates the key steps in the synthesis, release, and reuptake of the neurotransmitter acetylcholine.

Figure 1.

Physiology of the cholinergic synapse. Choline is the critical substrate for the synthesis of acetylcholine. Acetyl coenzyme A (Ac CoA), which is produced by the breakdown of glucose (carbohydrate) through glycolysis (Krebs cycle), along with the enzyme choline acetyltransferase (ChAT) are critical for the synthesis of acetylcholine (Ach). Once the neurotransmitter acetylcholine is released into the synapse, it binds (activates) postsynaptic receptor (M1), thus transmitting a signal from one neuron to the other. The excess neurotransmitter in the synaptic cleft is broken down by the enzyme acetyl cholinesterase (AChE) into choline and acetate, which are returned by an uptake mechanism for recycling into acetyl coenzyme A.

Human studies assessing the neuropathological diagnosis of Alzheimer's disease have shown that the cholinergic lesion, emerging as early as asymptomatic or prodromal stages of the disease, is mainly presynaptic rather than postsynaptic. In other words, the cholinergic loss is based on the degeneration of NBM cholinergic neurons and of the axons they project to the cerebral cortex. As part of the cholinergic lesion, nicotinic (ionotropic) receptors and muscarinic (metabotropic) receptors of the cerebral cortex also undergo changes. Most studies show a loss of nicotinic receptors in the cerebral cortex. For example, there is a decrease of postsynaptic nicotinic receptors on cortical neurons (Nordberg and Winblad, 1986; Schroder et al., 1991). However, there may also be an equally important presynaptic component based on the loss of nicotinic receptors located on the degenerating cholinergic axons coming from the NBM. With respect to muscarinic receptors of the cerebral cortex, it is interesting that the muscarinic (M)1 receptors (mostly postsynaptic) are not decreased whereas the M2 receptors (mostly presynaptic) are decreased (Mash et al., 1985). However, there is evidence that the remaining postsynaptic M1 receptors of the cerebral cortex may be dysfunctional (Jiang et al., 2014). Thus, a progressive loss of basal cholinergic neurons represents a key neurochemical event with a subsequent anterograde cortical cholinergic deafferentation, of the cerebral cortex, hippocampus and amygdala (Sassin et al., 2000). The alternative possibility of an initial degeneration of cortical cholinergic endings that lead to a retrograde degeneration of NBM neurons cannot be ruled out but is unlikely.

As noted above, in contrast to M1 receptors, which are mostly preserved, there is a loss of cortical nicotinic receptors. Postsynaptic α7 nicotinic receptor enhances the neuronal firing rates contributing to the hippocampal long-term potentiation, a neuronal-level component of learning and memory (Francis et al., 2010). The application of cholinergic agonists and antagonists to rat hippocampal slices has clarified the role for acetylcholine in long-term potentiation (Blitzer et al., 1990; Auerbach and Segal, 1996). Therefore, altered patterns of nicotinic and muscarinic receptor distribution in Alzheimer's disease are likely to influence many functions of the cerebral cortex and limbic areas through perturbations of synaptic physiology. An upregulation of cortical choline acetyltransferase neuronal expression has been shown in prodromal Alzheimer's disease patients, suggesting that such neurochemical events may compensate for the depletion of basal cholinergic neurons (Ikonomovic et al., 2007). Moreover, it has been shown that Alzheimer's disease patients have higher levels of α7 nicotinic gene expression compared to healthy controls. The influence of these dynamic changes upon Alzheimer's disease pathogenesis remains to be elucidated.

There is also evidence implicating acetylcholine in a variety of essential functions that promote experience-induced neuroplasticity, the synchronization of neuronal activity, and network connectivity. For instance, variable stimulation of the rat NBM, an acetylcholine-rich area of the basal forebrain with wide projections to the cortex, has been shown to produce extensive cortical remodelling and to modulate cortical sensory maps (Kilgard and Merzenich, 1998). Through intrinsic (NBM) and extrinsic (perivascular postganglionic sympathetic nerve) innervation, the cholinergic system has also been shown to promote cerebral vasodilation and perfusion (Claassen and Jansen, 2006; Van Beek and Claassen, 2011). In mice, electrical and chemical stimulation of cholinergic neurons in the NBM results in a significant increase in cerebral blood flow in several cortical areas (Lacombe et al., 1989; Sato and Sato, 1990; Barbelivien et al., 1995; Lacombe et al., 1997; Vaucher et al., 1997). In addition to disrupting synaptic transmission in cortex and limbic areas, the cholinergic lesion of Alzheimer's disease may therefore also interfere with multiple aspects of neuroplasticity and with cerebral haemodynamic processes.

Anticholinergic Agents and Cholinergic Therapies

The negative pharmacological effects of anticholinergic drugs on human memory and learning have been reported since at least the 1970s (Drachman and Leavitt, 1974; Petersen, 1977; Mewaldt and Ghoneim, 1979; Izquierdo, 1989), and more recent data support these observations. The use of anticholinergic medications in non-demented older adults has been associated with significantly slower reaction times on a measure of rapid information processing and lower cognitive test scores (Stroop test) (Uusvaara et al., 2009; Sittironnarit et al., 2011). Moreover, the increased use of anticholinergic medications was correlated with reduced cognitive function in a systematic review of 33 studies performed in older adults (Fox et al., 2014). The cumulative effect of anticholinergic drugs has also been associated with poorer cognitive abilities, as well as poorer functional outcomes (i.e. activities of daily living) in cohort studies of older populations (Salahudeen et al., 2015). Furthermore, a recent meta-analysis demonstrated that the exposure of older adults with cardiovascular disease to anticholinergic drugs was associated with an increased risk of cognitive impairment (Ruxton et al., 2015). In that study, a greater burden of anticholinergic exposure was shown to more than double the odds of all-cause mortality.

Recent data also suggest that the negative cognitive effects of cumulative anticholinergic drugs in older adults may not be transient. Among cognitively healthy individuals in the ADNI (Alzheimer Disease Neuroimaging Initiative) and Indiana Memory and Aging Study, the 52 participants who had been regularly taking one or more medications with medium or high anticholinergic activity prior to study entry demonstrated worse immediate recall and executive function than the 350 participants who were not actively using anticholinergic medications at study entry (Risacher et al., 2016). Strikingly, cognitively normal adults taking anticholinergic medication were observed to have reduced total cortex volume, increased bilateral lateral ventricle volume, and increased inferior lateral ventricle volume. In addition, across both groups of participants, there was a significant longitudinal association between anticholinergic use and later progression to mild cognitive impairment (MCI) or Alzheimer's disease dementia (P = 0.01; hazard ratio, 2.47). Concordantly, in a prospective population-based cohort study of 3434 participants ≥65 years with no dementia at study entry, greater cumulative use of anticholinergic drugs over 10 years (based on computerized pharmacy dispensing data) was linked to a statistically increased risk for incident dementia and for Alzheimer's disease specifically. Thus, higher estimates of cumulative exposure to anticholinergic therapies were associated with a greater risk for incident dementia or Alzheimer's disease dementia than were lower levels of cumulative anticholinergic exposure (Gray et al., 2015). In addition to these findings, doses of anticholinergic medication appear to unmask signs of impending dementia in individuals with preclinical Alzheimer's disease. In a study of healthy older adults at risk for Alzheimer's disease, single-dose administration of the anticholinergic drug scopolamine unmasked cognitive deficits and poorer cognitive performance more often in patients with higher brain amyloid-β burden on PET images (Lim et al., 2015). More recently, impaired performance in response to a low-dose scopolamine challenge test among cognitively unimpaired adults at risk for Alzheimer's disease predicted both amyloid-β positivity on PET images and a decline in episodic memory at 27 months (Snyder et al., 2017).

Treatment that promotes cholinergic function in individuals with, or at risk for, Alzheimer's disease may also have more durable beneficial biological effects on the brain than a temporary augmentation of cognitive function. The French Hippocampus Study Group found, in a placebo-controlled trial in people with suspected prodromal Alzheimer's disease, that use of the cholinesterase inhibitor donepezil was associated with substantially less regional cortical thinning and basal forebrain atrophy over time (Cavedo et al., 2016, 2017). A placebo-controlled study on the same population found a 45% reduction in the rate of hippocampal atrophy after 1 year of treatment with donepezil (Dubois et al., 2015), a finding previously reported by another research group investigating patients with fully expressed dementia (Hashimoto et al., 2005). Although these results have not yet been linked to a specific biological mechanism, they raise the possibility of substantial brain structural protective effects of cholinergic treatment during various stages of Alzheimer's disease. Several studies have also explored the role of cholinesterase inhibitors on cerebrovascular perfusion in Alzheimer's disease and other dementias (Geaney et al., 1990; Ebmeier et al., 1992; Arahata et al., 2001; Venneri et al., 2002; Lojkowska et al., 2003; Ceravolo et al., 2006). Patients with Alzheimer's disease dementia receiving a single dose of cholinesterase inhibitor treatment showed an increase (Geaney et al., 1990; Ebmeier et al., 1992) or a stabilization of cerebral blood flow (Venneri et al., 2002; Van Beek and Claassen, 2011) in the posterior parieto-temporal and superior frontal regions. A recent study showed decreased regional cerebral blood flow in the parietal cortex, and an increase in the frontal and the limbic cortices after 18 months of treatment with donepezil or galantamine (Shirayama et al., 2017). Case reports and investigations with small sample sizes have reported increased cerebral blood flow after treatment with cholinesterase inhibitors in patients with vascular dementia, dementia with Lewy bodies, and dementia of Parkinson's disease (Arahata et al., 2001; Mori, 2002; Lojkowska et al., 2003; Ceravolo et al., 2006). The clinical impact of these haemodynamic events has not been clarified.

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