Alzheimer Cholinergic

doi:10.
1093/brain/awy132 BRAIN 2018: 141; 1917–1933 | 1917
REVIEW ARTICLE
The cholinergic system in the pathophysiology
and treatment of Alzheimer’s disease
Harald Hampel,1,2,3,4 M.-Marsel Mesulam,5 A. Claudio Cuello,6,7,8 Martin R. Farlow,9
Ezio Giacobini,10 George T. Grossberg,11 Ara S. Khachaturian,12 Andrea Vergallo,1,2,3,4
Enrica Cavedo,1,2,3,4 Peter J. Snyder13,14 and Zaven S. Khachaturian12 for the Cholinergic
System Working Group
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-b 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 pharma-
cological approach in Alzheimer’s disease, particularly as we look ahead to future combination therapies that address symptoms as
well as disease progression.
1 AXA Research Fund and Sorbonne University Chair, Paris, France

2 Sorbonne University, GRC n 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l’hôpital,
F-75013, Paris, France
3 Brain and Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l’hôpital, F-75013, Paris, France
4 Institute of Memory and Alzheimer’s Disease (IM2A), Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Boulevard de
l’hôpital, F-75013, Paris, France
5 Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
6 Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada
7 Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
8 Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
9 Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA
10 Department of Internal Medicine, Rehabilitation and Geriatrics, University of Geneva Hospitals, Geneva, Switzerland
11 Department of Psychiatry and Behavioral Neuroscience, Saint Louis University School of Medicine, St Louis, MO, USA
12 The Campaign to Prevent Alzheimer’s Disease by 2020 (PAD2020), Potomac, MD, USA
13 Department of Neurology, Alpert Medical School of Brown University, Providence, RI USA
14 Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA
Received December 18, 2017. Revised March 12, 2018. Accepted March 29, 2018. Advance Access publication May 29, 2018
ß The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For permissions, please email: [email protected]
1918 | BRAIN 2018: 141; 1917–1933 H. Hampel et al.
Correspondence to: Professor Harald Hampel, MD, PhD, MA, MSc

AXA Research Fund and Sorbonne University Chair
Sorbonne University
Department of Neurology
Institute of Memory and Alzheimer’s Disease (IM2A)
Brain and Spine Institute (ICM)
François Lhermitte Building
Pitié-Salpêtrière Hospital
47 Boulevard de l’hôpital, 75651 Paris CEDEX 13
France
E-mail: [email protected]; [email protected]
Keywords: acetylcholine; Alzheimer’s disease; cholinergic system; cholinesterase inhibitors; cognition

Abbreviations: MCI = mild cognitive impairment; NBM = nucleus basalis of Meynert
The cholinergic hypothesis revolutionized the field of

Introduction Alzheimer’s disease research by transporting it from the
Late-onset Alzheimer’s disease dementia, the most prevalent realm of descriptive neuropathology to the modern concept
age-related neurodegenerative disease, is clinically charac- of synaptic neurotransmission. It is based on three mile-
terized by a progressive loss of memory and other cognitive stones: the discovery of depleted presynaptic cholinergic
functions. In contrast to early-onset autosomal dominant markers in the cerebral cortex (Bowen et al., 1976;
forms of Alzheimer’s disease, which are directly linked to Davies and Maloney, 1976); the discovery that the nucleus
abnormalities of amyloid-b, the cascade of pathophysio- basalis of Meynert (NBM) in the basal forebrain is the
logical events that leads to late-onset Alzheimer’s disease source of cortical cholinergic innervation that undergoes
is not yet fully understood. Contemporary evidence sug- severe neurodegeneration in Alzheimer’s disease
gests that late-onset Alzheimer’s disease is a complex poly- (Mesulam, 1976; Whitehouse et al., 1981); and the dem-
genic disease that involves aberrant interaction among onstration that cholinergic antagonists impair memory
several molecular pathways. By definition, age is the stron- whereas agonists have the opposite effect (Drachman and
gest risk factor (Hebert et al., 1995) followed by the "4 Leavitt, 1974). The hypothesis received compelling valid-
allele of apolipoprotein E (APOE "4) (Liu et al., 2013; ation when cholinesterase inhibitor therapies were shown
Shi et al., 2017), and probably also cardiovascular and to induce significant symptomatic improvement in patients
lifestyle risk factors (de Bruijn and Ikram, 2014). The with Alzheimer’s disease (Summers et al., 1986). Although
neuropathological features of Alzheimer’s disease include other relevant pathophysiological mechanisms have
the accumulation of several abnormal proteins such as received more research attention in recent years, treatments
amyloid-b in plaques and hyperphosphorylated-tau in that improve cholinergic function remain critical in the
neurofibrillary tangles, leading to massive loss of synapses, management of patients with Alzheimer’s disease. The
dendrites, and eventually neurons. Clinical expression of goal of this review is to characterize the nature of the cho-
the disease reflects the dysfunction and eventual failure of linergic lesion in Alzheimer’s disease, its potential inter-
both neurochemical and structural neural networks, includ- actions with other components of the pathology, and its
ing the ‘cholinergic system’. Although the pivotal events in relevance to treatment. We do not aim to provide a com-
the pathogenesis of Alzheimer’s disease are not fully under- prehensive review of Alzheimer’s disease pathogenesis or to
stood, several competing theories on the underlying biology rank order the impact of the cholinergic lesion among all
of the neurodegeneration have guided research into inter- other components of this disease. Furthermore, our com-
ventions to modify, arrest, or delay the progression of the ments will be limited to late-onset Alzheimer’s disease in
disease and its clinical manifestations. In recent years, how- patients who do not have disease-causing dominant muta-
ever, failure of clinical trials in Alzheimer’s disease has been tions. We should also point out that the brain contains
the rule rather than the exception, and no new drugs for several cholinergic pathways, each with its unique receptor
Alzheimer’s disease have been approved by the US Food signature, postsynaptic targets and disease vulnerabilities.
and Drug Administration (FDA) since 2003. The multifa- Unless noted otherwise, our comments in this review will
ceted, heterogeneous, progressive, and interactive patho- address the forebrain pathway that originates in the basal
physiology of Alzheimer’s disease also suggests a likely forebrain and that innervates the neocortex and limbic
need for individualized combination treatments that may system. This review also provides a comprehensive evalu-
need to be varied from one stage of the disease to another, ation of the known benefits of cholinergic therapies
and perhaps also from one patient to another. throughout the various stages of Alzheimer’s disease.
The cholinergic system in Alzheimer’s disease BRAIN 2018: 141; 1917–1933 | 1919
We aim to demonstrate the enduring value of cholinergic cholinergic lesion, nicotinic (ionotropic) receptors and mus-
drugs in the pharmacological therapy of Alzheimer’s dis- carinic (metabotropic) receptors of the cerebral cortex also
ease, especially in the context of future combination thera- undergo changes. Most studies show a loss of nicotinic
pies that may affect both symptoms and disease progression. receptors in the cerebral cortex. For example, there is a
decrease of postsynaptic nicotinic receptors on cortical neu-
rons (Nordberg and Winblad, 1986; Schroder et al., 1991).
Nature and impact of the cholinergic However, there may also be an equally important pre-
lesion synaptic component based on the loss of nicotinic receptors
located on the degenerating cholinergic axons coming from
Acetylcholine is a major neurotransmitter in the brain, with the NBM. With respect to muscarinic receptors of the cere-
activity throughout the cortex, basal ganglia, and basal bral cortex, it is interesting that the muscarinic (M)1 recep-
forebrain (Mesulam, 2013). Figure 1 illustrates the key tors (mostly postsynaptic) are not decreased whereas the
steps in the synthesis, release, and reuptake of the neuro- M2 receptors (mostly presynaptic) are decreased (Mash
transmitter acetylcholine. et al., 1985). However, there is evidence that the remaining
Human studies assessing the neuropathological diagnosis postsynaptic M1 receptors of the cerebral cortex may be
of Alzheimer’s disease have shown that the cholinergic dysfunctional (Jiang et al., 2014). Thus, a progressive loss
lesion, emerging as early as asymptomatic or prodromal of basal cholinergic neurons represents a key neurochemical
stages of the disease, is mainly presynaptic rather than event with a subsequent anterograde cortical cholinergic
postsynaptic. In other words, the cholinergic loss is based deafferentation, of the cerebral cortex, hippocampus and
on the degeneration of NBM cholinergic neurons and of amygdala (Sassin et al., 2000). The alternative possibility
the axons they project to the cerebral cortex. As part of the 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 recep-
tors. Postsynaptic 7 nicotinic receptor enhances the neur-
onal firing rates contributing to the hippocampal long-term
potentiation, a neuronal-level component of learning and
memory (Francis et al., 2010). The application of choliner-
gic 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 distri-
bution 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, sug-
gesting 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 7 nico-
tinic gene expression compared to healthy controls. The
influence of these dynamic changes upon Alzheimer’s dis-
Figure 1 Physiology of the cholinergic synapse. Choline is ease pathogenesis remains to be elucidated.
the critical substrate for the synthesis of acetylcholine. Acetyl co- There is also evidence implicating acetylcholine in a var-
enzyme A (Ac CoA), which is produced by the breakdown of glu- iety of essential functions that promote experience-induced
cose (carbohydrate) through glycolysis (Krebs cycle), along with the neuroplasticity, the synchronization of neuronal activity,
enzyme choline acetyltransferase (ChAT) are critical for the syn- and network connectivity. For instance, variable stimula-
thesis of acetylcholine (Ach). Once the neurotransmitter acetyl- tion of the rat NBM, an acetylcholine-rich area of the
choline is released into the synapse, it binds (activates) postsynaptic basal forebrain with wide projections to the cortex, has
receptor (M1), thus transmitting a signal from one neuron to the been shown to produce extensive cortical remodelling and
other. The excess neurotransmitter in the synaptic cleft is broken to modulate cortical sensory maps (Kilgard and Merzenich,
down by the enzyme acetyl cholinesterase (AChE) into choline and
1998). Through intrinsic (NBM) and extrinsic (perivascular
acetate, which are returned by an uptake mechanism for recycling
postganglionic sympathetic nerve) innervation, the cholin-
into acetyl coenzyme A.
ergic system has also been shown to promote cerebral
vasodilation and perfusion (Claassen and Jansen, 2006; cognitive impairment (MCI) or Alzheimer’s disease demen-
Van Beek and Claassen, 2011). In mice, electrical and tia (P = 0.01; hazard ratio, 2.47). Concordantly, in a pro-
chemical stimulation of cholinergic neurons in the NBM spective population-based cohort study of 3434
results in a significant increase in cerebral blood flow in participants 565 years with no dementia at study entry,
several cortical areas (Lacombe et al., 1989; Sato and greater cumulative use of anticholinergic drugs over 10
Sato, 1990; Barbelivien et al., 1995; Lacombe et al., years (based on computerized pharmacy dispensing data)
1997; Vaucher et al., 1997). In addition to disrupting syn- was linked to a statistically increased risk for incident de-
aptic transmission in cortex and limbic areas, the choliner- mentia and for Alzheimer’s disease specifically. Thus,
gic lesion of Alzheimer’s disease may therefore also higher estimates of cumulative exposure to anticholinergic
interfere with multiple aspects of neuroplasticity and with therapies were associated with a greater risk for incident
cerebral haemodynamic processes. 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 anticholiner-
Anticholinergic agents and cholinergic medication appear to unmask signs of impending de-
gic therapies mentia in individuals with preclinical Alzheimer’s disease.
In a study of healthy older adults at risk for Alzheimer’s
The negative pharmacological effects of anticholinergic disease, single-dose administration of the anticholinergic
drugs on human memory and learning have been reported drug scopolamine unmasked cognitive deficits and poorer
since at least the 1970s (Drachman and Leavitt, 1974; cognitive performance more often in patients with higher
Petersen, 1977; Mewaldt and Ghoneim, 1979; Izquierdo, brain amyloid-b burden on PET images (Lim et al., 2015).
1989), and more recent data support these observations. More recently, impaired performance in response to a low-
The use of anticholinergic medications in non-demented dose scopolamine challenge test among cognitively unim-
older adults has been associated with significantly slower paired adults at risk for Alzheimer’s disease predicted
reaction times on a measure of rapid information process- both amyloid-b positivity on PET images and a decline in
ing and lower cognitive test scores (Stroop test) (Uusvaara episodic memory at 27 months (Snyder et al., 2017).
et al., 2009; Sittironnarit et al., 2011). Moreover, the Treatment that promotes cholinergic function in individ-
increased use of anticholinergic medications was correlated uals with, or at risk for, Alzheimer’s disease may also have
with reduced cognitive function in a systematic review of more durable beneficial biological effects on the brain than
33 studies performed in older adults (Fox et al., 2014). The a temporary augmentation of cognitive function. The
cumulative effect of anticholinergic drugs has also been French Hippocampus Study Group found, in a placebo-
associated with poorer cognitive abilities, as well as controlled trial in people with suspected prodromal
poorer functional outcomes (i.e. activities of daily living) Alzheimer’s disease, that use of the cholinesterase inhibitor
in cohort studies of older populations (Salahudeen et al., donepezil was associated with substantially less regional
2015). Furthermore, a recent meta-analysis demonstrated cortical thinning and basal forebrain atrophy over time
that the exposure of older adults with cardiovascular dis- (Cavedo et al., 2016, 2017). A placebo-controlled study
ease to anticholinergic drugs was associated with an on the same population found a 45% reduction in the
increased risk of cognitive impairment (Ruxton et al., rate of hippocampal atrophy after 1 year of treatment
2015). In that study, a greater burden of anticholinergic with donepezil (Dubois et al., 2015), a finding previously
exposure was shown to more than double the odds of reported by another research group investigating patients
all-cause mortality. with fully expressed dementia (Hashimoto et al., 2005).
Recent data also suggest that the negative cognitive ef- Although these results have not yet been linked to a specific
fects of cumulative anticholinergic drugs in older adults biological mechanism, they raise the possibility of substan-
may not be transient. Among cognitively healthy individ- tial brain structural protective effects of cholinergic treat-
uals in the ADNI (Alzheimer Disease Neuroimaging ment during various stages of Alzheimer’s disease. Several
Initiative) and Indiana Memory and Aging Study, the 52 studies have also explored the role of cholinesterase inhibi-
participants who had been regularly taking one or more tors on cerebrovascular perfusion in Alzheimer’s disease
medications with medium or high anticholinergic activity and other dementias (Geaney et al., 1990; Ebmeier et al.,
prior to study entry demonstrated worse immediate recall 1992; Arahata et al., 2001; Venneri et al., 2002;
and executive function than the 350 participants who were Lojkowska et al., 2003; Ceravolo et al., 2006). Patients
not actively using anticholinergic medications at study with Alzheimer’s disease dementia receiving a single dose
entry (Risacher et al., 2016). Strikingly, cognitively of cholinesterase inhibitor treatment showed an increase
normal adults taking anticholinergic medication were (Geaney et al., 1990; Ebmeier et al., 1992) or a stabiliza-
observed to have reduced total cortex volume, increased tion of cerebral blood flow (Venneri et al., 2002; Van Beek
bilateral lateral ventricle volume, and increased inferior lat- and Claassen, 2011) in the posterior parieto-temporal and
eral ventricle volume. In addition, across both groups of superior frontal regions. A recent study showed decreased
participants, there was a significant longitudinal association regional cerebral blood flow in the parietal cortex, and an
between anticholinergic use and later progression to mild increase in the frontal and the limbic cortices after 18
months of treatment with donepezil or galantamine the cortex) is more robust, this correlation is not uniform
(Shirayama et al., 2017). Case reports and investigations throughout the brain—specifically in the cingulate cortex
with small sample sizes have reported increased cerebral (Geula et al., 1998; Potter et al., 2011).
blood flow after treatment with cholinesterase inhibitors Animal experiments have suggested that the cholinergic
in patients with vascular dementia, dementia with Lewy depletion promotes amyloid-b deposition and tau path-
bodies, and dementia of Parkinson’s disease (Arahata ology in ways that contribute to the cognitive impairment
et al., 2001; Mori, 2002; Lojkowska et al., 2003; (Ramos-Rodriguez et al., 2013). For example, selective le-
Ceravolo et al., 2006). The clinical impact of these haemo- sions of cholinergic neurons in the basal forebrains of
dynamic events has not been clarified. Alzheimer’s disease rodent models have been reported to
be associated with increased deposition of amyloid-b and
levels of hyperphosphorylated tau in the hippocampus and
Interactions between the cortex. These types of effects have been reported in the past
but have been difficult to replicate. Cholinergic deficits in
cholinergic system and the rat brains have also been shown to interact with acute
proinflammatory mechanisms to produce or exacerbate
other pathophysiological cognitive impairment (Field et al., 2012).
hallmarks of Alzheimer’s Stimulation of 7 nicotinic receptors may have a neuro-
protective effect against amyloid-b-induced toxicity trough
disease activation of the PI3K-Ak axis, the anti-apoptotic factor
bcl2 and downregulation of glycogen synthase kinase-3
The main pathological hallmarks of Alzheimer’s disease in-
clude not only amyloid-b plaques and neurofibrillary tan- (GSK3) (Beaulieu, 2012). GSK3 over activation is corre-
gles but also neuroinflammation, altered insulin resistance, lated with high levels of toxic amyloid-b oligomers, hyper-
oxidative stress and cerebrovascular abnormalities. These phosphorylated tau strains and neurofibrillary tangles
pathological hallmarks have complex reciprocal inter- (Jaworski et al., 2011; Chu et al., 2017), activation of
actions with the cholinergic lesion. Previous post-mortem the 7 nicotinic receptor is associated with anti-inflamma-
studies have shown that the loss of cortical cholinergic in- tory pathways also through downregulation of NFB via
nervation is associated with and probably caused by the Jak2 (Kalkman and Feuerbach, 2016).
neurofibrillary tangles in the NBM (Geula and Mesulam, Nitsch et al. (1992) and Mori et al. (1995) demonstrated
1994; Braak and Del Tredici, 2013; Mesulam, 2013). The that the stimulation of cholinergic receptors either by mus-
basal forebrain cholinergic neurons are among the cell carinic agonists or by cholinesterase inhibitor treatment
bodies most susceptible to neurofibrillary degeneration shifted the processing of amyloid precursor protein (APP)
and neurofibrillary tangle formation (Mesulam, 2013). towards non-amiloidogenic pathways.
There exists a long-established relationship between cholin- Additional evidence has shown that muscarinic agonists,
ergic abnormalities and amyloid-b pathology. Perry et al. mainly M1 and less so M3, can downregulate amyloido-
(1978) correlated diminishing activity of the acetylcholine- genic and tau-generating pathways. The mechanisms are
synthesizing enzyme choline acetyltransferase with increas- not fully understood yet. However, it has been shown
ing numbers of neuritic plaques in the post-mortem brains that M1 agonist may act as functional activators of protein
of patients with Alzheimer’s disease (Perry et al., 1978). kinase C (PKC) signalling which, in turn, promotes a meta-
This correlation was also shown in cognitively unimpaired bolic shift towards -secretase activity via upregulating
persons whose brains at autopsy revealed amyloid-b pla- ADAM17 [also known as tumour necrosis factor--con-
ques. More recently, an inverse correlation was found be- verting enzyme (TACE)]. In support of this hypothesis,
tween choline acetyltransferase activity and amyloid-b animal studies have demonstrated that orthosteric M1-se-
deposition in the inferior temporal gyrus of persons, at lective agonists are associated with increased levels of APPs
autopsy, who had had normal cognitive function (Beach cleaved by alpha secretase (Cisse et al., 2011; Welt et al.,
et al., 2000). Moreover, presynaptic and postsynaptic mar- 2015). Conceivably, 7 nicotinic and coupling of M1 to
kers of cholinergic activity were significantly reduced in PKC may lead to a downregulation of detrimental cell pro-
non-demented individuals whose brains demonstrated neur- cesses occurring in Alzheimer’s disease such as GSK3-
itic plaques at autopsy—an effect that was even more pro- mediated tau hyperphosphorylation (Espada et al., 2009).
nounced in demented individuals with pathologically The loss of acetylcholine-mediated vasomotor control of
confirmed Alzheimer’s disease (Potter et al., 2011). the blood–brain barrier could also potentially lead to an
Studies investigating regional correlations between the aberrant diffusion and transportation of metabolites be-
loss of cholinergic axons and the density of amyloid-b tween the interstitial fluid and the CSF. One possible con-
deposits in Alzheimer’s disease-affected human brains sequence for this is the impairment of the clearance of
have also shown conflicting results. Although the correl- amyloid-b from brain (Hunter et al., 2012). As shown by
ation between cholinergic loss and neurofibrillary tangle Weller and colleagues, cholinergic deafferentation may alter
(both presynaptically in the NBM and postsynaptically in the blood–brain barrier and the dynamics of arterial and
perivascular lymphatic drainage of amyloid-b (Engelhardt Waring et al., 2015). These studies suffer from methodo-
et al., 2016). logical limitations that might have remarkably biased their
These observations illustrate the highly complex inter- results. In particular, several potentially confounding fac-
actions that are likely to exist between cholinergic denerv- tors have not been taken into account i.e. stage of patho-
ation and other pathological features of Alzheimer’s disease physiological processes, pharmacogenomic background,
(Ramos-Rodriguez et al., 2013; Szutowicz et al., 2013; and comorbidities. Interestingly, it has been recently
Hartig et al., 2014; Kolisnyk et al., 2017). In addition, shown that APOE genotype may influence cholinergic com-
important neurophysiological relationships with other pensatory mechanisms. In particular, the APOE "4 allele is
major neurotransmitter (serotonergic, dopaminergic, associated with deficits in the cholinergic hippocampal
GABAergic) and neurohormonal (renin-angiotensin) sys- compensatory sprouting and remodelling in response to
tems that are also likely to take place remain to be eluci- cholinergic deafferentation (Bott et al., 2016). Based on
dated (Bodiga and Bodiga, 2013). these considerations, further work needs to be performed
Complex interactions among different neurotransmitter to investigate whether the APOE "4 status influences the
systems are essential for adaptive responses and compensa- response to cholinomimetic therapy.
tory mechanisms both in physiological and pathophysio-
logical conditions. For example, the activity of
presynaptic 7 nicotinic receptor may facilitate glutamate
Anatomy, selectivity and specificity of
release, while activation of muscarinic receptors may de- the cholinergic deficit in Alzheimer’s
crease both the release and the concentration of glutamate disease
in the synaptic cleft (Higley et al., 2009). Although changes
The cholinergic loss is one of the most prominent compo-
of neurotransmitters other than acetylcholine have been
nents of the neuropathology of Alzheimer’s disease. In the
demonstrated in Alzheimer’s disease (Limon et al., 2012;
mid-1970s in the UK, investigators autopsied the brains of
Chalermpalanupap et al., 2013; McNamara et al., 2014) it
people with Alzheimer’s disease and reported a selective
should be underlined than no drugs selectively acting on
and statistically significant reduction in the activity of cho-
noradrenergic, serotoninergic or GABAergic systems have
line acetyltransferase in the limbic system and cerebral
been approved. Supplementary Table 1 provides an over-
cortex (Bowen et al., 1976; Davies and Maloney, 1976;
view of the available evidence regarding the involvement of
Perry et al., 1977a, b). At the time, the origin of this cho-
different neurotransmitter in Alzheimer’s disease, as well as
linergic innervation was unknown. In 1976, axonal trans-
the main molecular mechanisms associated with each recep-
port studies, combined with cholinergic histochemistry,
tor activity and their interplay with acetylcholine.
revealed the NBM as the source of cholinergic innervation
in the cerebral cortex of the primate brain (Mesulam,
The cholinergic system and APOE 1976). These studies led to the investigation of the NBM
in Alzheimer’s disease and to the post-mortem data from
genetic risk factor Whitehouse et al. (1981, 1982), which demonstrated a pro-
The APOE "4 allele is the strongest genetic risk factor for found loss of cholinergic neurons in the basal forebrain,
sporadic/late onset Alzheimer’s disease. The presence of specifically the NBM, of patients with Alzheimer’s disease.
two APOE "4 alleles has been linked to disruptions of The NBM can be considered a rostral extension of the
amyloid-b and tau proteostasis (Liu et al., 2013; Shi brainstem reticular formation. It innervates the entire cere-
et al., 2017), impaired clearance, aberrant post-transla- bral cortex and limbic system, including the hippocampus,
tional modifications (i.e. hyperphosphorylation), mitochon- and the entorhinal cortex. It has been well established that
drial dysfunction, and neuroinflammatory processes in cholinergic deficits play a key role in the neuropathology of
ageing and Alzheimer’s disease. The APOE "4 allele is Alzheimer’s disease, not only in late disease, but in preclin-
strongly correlated with faster cognitive and functional de- ical and early stages as well. Accumulated abnormal phos-
cline (Whitehair et al., 2010). It is still unclear whether the phorylated tau, in the form of neurofibrillary tangles and
presence of APOE "4 allele affects the NBM neuronal func- pretangles, has been found specifically in the cholinergic
tioning, and if it does whether this happens indirectly neurons of the basal forebrain in cognitively normal elderly
through amyloid-b and tau accumulation in the basal fore- subjects and patients with MCI and to correlate signifi-
brain. To date, only two human retrospective post-mortem cantly with performance in memory tasks (Mesulam
studies have shown that both healthy older individuals and et al., 2004). A progression of abnormalities has been
mild Alzheimer’s disease patients, carrying the "4 allele, observed in the cholinergic neurons of the basal forebrain
had reduced neuronal metabolic activity in the NBM as of non-demented younger adults, non-demented elderly
measured by the size of the Golgi apparatus (Salehi et al., people, and people with mild or severe Alzheimer’s disease
1998; Dubelaar et al., 2004). Previous studies showed that (Geula et al., 2008). Thickened cholinergic nerve fibres and
APOE genotype does not significantly influence the magni- ballooned terminals, demonstrated in middle-aged adults,
tude of the cholinesterase inhibitor response in mild-to- have been shown to increase with age, suggesting that cho-
moderate Alzheimer’s disease (Miranda et al., 2015; linergic loss in established Alzheimer’s disease is preceded
by this cholinergic pathology (Geula et al., 2008). Bateman, 2017). However, intracerebrally- and exogenously-
Cholinergic function outside of the NBM—namely, in the applied NGF has so far shown to be unsuccessful. It is
caudate, putamen, and thalamus—appears relatively spared important to keep in mind that exogenous NGF may
in this process. There is, therefore, no generalized ‘cholin- reach undesirable ectopic targets producing undesirable ef-
ergic vulnerability’ in Alzheimer’s disease but, instead, a fects (pain, anorexia, other). On the other hand, the
preferential vulnerability of the NBM. The underlying pharmacological normalization of the NGF metabolic path-
mechanism may be the location of the NBM within the way, if attainable at early Alzheimer’s disease pathology
corticoid-limbic belt of the forebrain, which includes stages, could potentially halt the NBM degeneration by se-
other limbic structures such as the hippocampus, amygdala, lectively boosting the trophic influence of NGF with greater
and entorhinal cortex, areas that are collectively the most physiological selectivity.
vulnerable to neurofibrillary degeneration and neurofibril- Pathology of the NBM is not unique to Alzheimer’s dis-
lary tangle formation in the ageing–MCI–Alzheimer’s disease. Synucleinopathies such as Parkinson’s disease and es-
ease continuum (Mesulam, 2013). With the use of pecially Lewy body dementia are also associated with NBM
longitudinal MRIs and amyloid-b biomarkers, it has been degeneration and the resultant cortical cholinergic denerv-
shown that volume loss in the NBM precedes and predicts ation. In Lewy body dementia this effect may be even more
memory impairment and degeneration of the entorhinal severe than in Alzheimer’s disease. In contrast to
cortex (Schmitz et al., 2016). This observed relationship Alzheimer’s disease where the NBM degeneration is based
strengthens the conclusion that the loss of NBM neurons on neurofibrillary tangle formation, in Lewy body dementia
is an early and perhaps also clinically relevant event in the degeneration is associated with intracellular Lewy
Alzheimer’s disease. bodies. It is interesting that cholinesterase inhibitors can
Unlike the cholinergic neurons and synaptic terminations improve cognition also in Parkinson’s disease and Lewy
of the caudate, putamen, and thalamus, the NBM and body dementia (Graff-Radford et al., 2012).
medial septum cholinergic neurons are fully dependent on
the retrograde transport of nerve growth factor (NGF) for
the maintenance of their anatomic and biochemical charac- The role of cholinergic therapy for
teristics and their terminal synapses in the cerebral cortex Alzheimer’s disease
and hippocampus (Cuello et al., 2007, 2010; Cuello, 2013).
It is well accepted that the interactions of NGF with the The prevailing therapeutic strategy in the management of
forebrain cholinergic system is of significance in Alzheimer’s disease is based on the restoration of choliner-
Alzheimer’s disease (Mufson et al., 2008; Schliebs and gic function through the use of compounds that block the
Arendt, 2011; Cattaneo and Calissano, 2012; Triaca and enzymes that break down acetylcholine (Lovestone and
Calissano, 2016; Turnbull et al., 2018). There is evidence Howard, 1995; Massoud and Gauthier, 2010).
that cholinergic neurons in the NBM may well be deprived Cholinesterase inhibitors are designed to inhibit the break-
of trophic support even before clinical manifestations of down of acetylcholine and sustain its activity at cholinergic
Alzheimer’s disease. While the biosynthesis of NGF in the synapses. Currently available FDA-approved cholinesterase
cerebral cortex is not affected in Alzheimer’s disease, inhibitors for the treatment of Alzheimer’s disease are done-
experimental animal data and human post-mortem brain pezil, rivastigmine, and galantamine (Table 1). These drugs
material would indicate that trophic support of the NGF- have been shown to statistically significantly improve cog-
dependent cholinergic neurons in the NBM may be com- nition, daily and global function, and some behavioural
promised by defective retrograde transport of NGF or the manifestations of Alzheimer’s disease, compared with pla-
diminished conversion of pre-NGF to mature NGF (neuro- cebo treatment (Massoud and Gauthier, 2010). As such,
guidin) (Cuello et al., 2007, 2010; Iulita and Cuello, 2014; cholinesterase inhibitors are generally considered symptom-
Iulita et al., 2017). In individuals with Down syndrome, atic treatments for Alzheimer’s disease. For the purpose of
who are at high risk for early-onset Alzheimer’s disease the discussion on therapy, we will use the term ‘Alzheimer’s
by amyloid-b-mediated mechanisms, rising plasma levels disease’ to mean ‘Alzheimer disease dementia’ rather than
of amyloid-b and inflammatory markers have been asso- ‘Alzheimer disease pathology.’ This distinction is important
ciated with biomarker evidence of NGF dysregulation because Alzheimer’s pathology emerges many years before
(Iulita et al., 2016a, b). These data suggest that NGF dys- symptom onset and there are currently no approved guide-
regulation may be precipitated by the accumulation of lines concerning cholinergic therapy during preclinical
amyloid-b and amyloid-b-driven inflammation, the end stages of the disease.
result of which is cholinergic loss in the NBM. The poten- A meta-analysis of 26 studies of donepezil, rivastigmine,
tial downstream effects of amyloid-b on cholinergic neu- and galantamine showed a modest but clinically meaningful
rons in the NBM, by way of dysregulated NGF, deserve overall benefit of these drugs for stabilizing cognition, func-
further exploration. Therefore, the NGF metabolic pathway tion, behaviour, and global clinical change (Hansen et al.,
remains a potential pharmacological target in the effort to 2008). Results from the few existing head-to-head compari-
slow the loss of critical cholinergic function in Alzheimer’s sons of cholinesterase inhibitors have been mixed; however,
disease, especially at preclinical stages (McDade and an adjusted analysis of placebo-controlled data suggested
Table 1 FDA-approved cholinesterase inhibitors for Alzheimer’s diseasea
Cholinesterase inhibitors First FDA Indication(s) Dosages

Approval
Donepezil tablets (or oral solution) 1996 Mild–moderate Alzheimer’s disease 5 or 10 mg daily
(Aricept, 2016) Moderate–severe Alzheimer’s disease 10 or 23 mg daily
Rivastigmine transdermal system 2000 Mild–moderate Alzheimer’s disease 4.6, 9.5 or 13.3 mg/24 h
(Exelon Patch, 2016) Severe Alzheimer’s disease 13.3 mg/24 h
Rivastigmine capsules (Elexon, 2016)b 2000 Mild–moderate Alzheimer’s disease 3, 4.5, or 6 mg twice daily
Galantamine extended-release capsules, 2001 Mild–moderate Alzheimer’s disease 8 or 12 mg twice daily (tablets, oral solution)
tablets, or oral solution (Razadyne 16 or 24 mg once daily (extended-release)
ER/Razadyne, 2013)
a
Minimum effective dosages are provided.
b
Rivastigmine is also available as an oral solution, at a concentration of 2 mg/ml.
FDA = US Food and Drug Administration.
that donepezil might have a slight advantage over rivastig- studies in individuals with Alzheimer’s disease treated with
mine and galantamine in efficacy and tolerability (Hansen cholinesterase inhibitors, only patients treated with galan-
et al., 2008). These results did not include the rivastigmine tamine showed a decreased odds-ratio of mortality when
transdermal delivery system, which has fewer side effects compared with placebo (Tricco et al., 2018). It has been
than the oral formulation of rivastigmine. In a systematic reported that cholinesterase inhibitors delay the need for
review of seven studies that examined the economics of nursing home placement and institutionalization (Jelic and
cholinesterase inhibitors, treatment of Alzheimer’s disease Winblad, 2016). This interesting finding has been linked
with cholinesterase inhibitors appeared to be a cost-effect- also to a potential effect of such drugs on behavioural
ive, if not a cost-saving, strategy—although a considerable and psychological symptoms of dementia (BPSD) (Cumbo
number of variables, such as the length of treatment and and Ligori, 2014). It is demonstrated that BPSD are posi-
medication discounts, contributed to general uncertainty as tively associated with a faster decline in global functioning
to their benefits (Pouryamout et al., 2012). A large and higher caregiver burden (Lyketsos et al., 2011; Collins
Medicare beneficiary study concluded that each additional et al., 2016). Loss of cerebral dopaminergic tone has been
month of cholinesterase inhibitors treatment is associated likened to apathetic syndrome, which is one of the most
with a 1% reduction in total all-cause healthcare costs frequent and persistent BPSD in Alzheimer’s disease. The
(Mucha et al., 2008). impaired dopamine release in the brain reward system has
Long-term data indicate that the use of a cholinesterase been hypothesized as a potential trigger of apathy in
inhibitor in Alzheimer’s disease reduces the risk for nursing Alzheimer’s disease. Despite this interesting rationale,
home placement by 30% for each year of treatment RCTs investigating the potential cholinomimetic influence
(Feldman et al., 2009). In addition, patients with on dopamine release effects have not been performed so far
Alzheimer’s disease who are treated with a higher mean (Lanctot et al., 2017). It is generally believed that cholin-
dose of cholinesterase inhibitors compared with patients esterase inhibitors are a part of the standard of care for
receiving a lower mean dose have been shown to experi- management of Alzheimer’s disease, and the foundation of
ence delayed nursing home placement (Wattmo et al., Alzheimer’s disease pharmacotherapy (Hort et al., 2010;
2011). These data are supported by a post hoc analysis O’Brien et al., 2011; Segal-Gidan et al., 2011; Moore
of the DOMINO-AD trial, in which the nursing home et al., 2014). In mild–moderate Alzheimer’s disease, the
placement of community-dwelling patients with moderate- expected treatment benefit of cholinesterase inhibitors is a
severe Alzheimer’s disease was assessed (Howard et al., mean of 3 to 4 points on the cognitive subscale of the
2015). Patients who were randomized to discontinue done- ADAS-Cog (Alzheimer’s Disease Assessment Scale), when
pezil therapy (10 mg/day) were twice as likely to enter a placebo treatment is the reference standard. This score dif-
nursing home after 1 year as were individuals who contin- ference corresponds roughly to the expected cognitive de-
ued treatment with cholinesterase inhibitors; however, this cline in people with mild–moderate Alzheimer’s disease
effect lost statistical significance after 3 years. Finally, cho- over 6 months if the disease is left untreated at these
linesterase inhibitors have also been shown to reduce the stages (Hort et al., 2010).
burden experienced by caregivers of patients with Additional data from both laboratory-based investiga-
Alzheimer’s disease, by reducing caregiver time devoted to tions and clinical trials have suggested that cholinesterase
the patient, caregiver stress, and some of the behavioural inhibitors may have a broader mechanism of action than
symptoms (Feldman et al., 2003; Hashimoto et al., 2009; enhancing cholinergic activity and that these drugs are
Schoenmakers et al., 2009; Adler et al., 2014). associated with a stabilizing effect on the course of
A recent meta-analysis carried out on 142 randomized Alzheimer’s disease dementia that may be greater than ex-
controlled trials (RCTs), quasi-RCTs, and non-randomized pected by cholinesterase inhibition alone (Giacobini, 1997,
2002). Prospective long-term observational studies suggest drawing on data from 2006 to 2010 (Brewer et al., 2013).
that cholinesterase inhibitors offer a benefit over the long- Among elderly patients with Alzheimer’s disease who
term course of Alzheimer’s disease (Atri et al., 2008). received cognition-enhancing drugs, rates of non-persist-
Cognitive decline has been observed to occur significantly ence (a prescription gap exceeding 63 days) were 30% at
more slowly with cholinesterase inhibitors compared with 6 months and 44% at 12 months; although rates of imper-
no treatment, suggesting a delay relative to typical clinical sistence were lower in the more recent cohort and in pa-
course (Giacobini, 2001). These observations are supported tients taking multiple anti-dementia medications. European
by other long-term data showing declines in cognitive and and Australian studies suggest that the reasons for not pre-
global functioning were slower with the persistent use of scribing cholinesterase inhibitors and the impersistence of
donepezil over a mean follow-up period of 3 years (Wallin Alzheimer’s disease therapy are complex and highly vari-
et al., 2007). At least two other prospective observational able across clinical settings (Pariente et al., 2008; Robinson
Alzheimer’s disease studies offer similar results, demonstrat- et al., 2009; Hollingworth and Byrne, 2011; van den
ing slower cognitive and functional deterioration with the Bussche et al., 2011; Tifratene et al., 2012; Ray and
persistent and continued use of cholinesterase inhibitors Prettyman, 2013; Zilkens et al., 2014).
(Rountree et al., 2009; Gillette-Guyonnet et al., 2011). Despite physician ambivalence about the efficacy of cho-
linesterase inhibitors in Alzheimer’s disease and their incon-
sistent and limited use, data support the prescription of
Suboptimal use of cholinesterase cholinesterase inhibitors throughout all stages of the dis-
inhibitors is common ease. In an analysis of four placebo-controlled studies of
people with severe Alzheimer’s disease, statistically signifi-
Despite clinical data and guideline recommendations sup-
cant cognitive improvement, and in some cases improve-
porting the use of cholinesterase inhibitors throughout all
ment in global functioning, was observed at 24 or 26
stages of Alzheimer’s disease, these drugs are often inappro-
weeks with donepezil treatment at a dosage of 10 mg
priately regarded as ineffective in Alzheimer’s disease and
daily (Deardorff and Grossberg, 2016). In a pooled analysis
therefore are underused. According to a US survey of
of these trials, relative improvement was observed across all
25 561 outpatient visits for Alzheimer’s disease specifically
levels of cognitive score, including patients with the most
or dementia more generally, fewer than half (46%) of pa-
severe cognitive impairment (Cummings et al., 2010). In an
tients were prescribed cholinesterase inhibitors, with done-
expansive compendium of cholinesterase inhibitor trials in
pezil being the most frequently prescribed (68%) (Maneno
patients with more advanced Alzheimer’s disease, including
et al., 2006). Of note, psychiatrists and neurologists were
patients in a nursing home setting, less decline in daily and
significantly more likely to prescribe cholinesterase inhibi-
global function was consistently documented with donepe-
tors than were other physicians (odds ratios 5.5 and 2.6,
zil or rivastigmine treatment, although clinical evidence
respectively). In a Canadian survey of 803 physicians, doc-
supporting rivastigmine use was less extensive (Kerwin
tors reported that they would be more likely to prescribe a
and Claus, 2011). Although choline acetyltransferase activ-
cholinesterase inhibitor if it enabled a person with mild
ity in the neocortex, as a marker of cholinergic function,
Alzheimer’s disease to remain clinically stable for 15
keeps declining, some residual choline acetyltransferase ac-
months and a person with moderate Alzheimer’s disease
tivity can be detected in advanced dementia (Bierer et al.,
to remain clinically stable for 11 months (Oremus et al.,
1995; Davis et al., 1999). This suggests that residual cho-
2007). Survey responses also suggested that a cholinesterase
linergic input may be present in severe Alzheimer’s disease
inhibitor prescription was more likely if a physician had
and thus provides a biological target for cholinesterase in-
less stringent requirements for clinical efficacy. In another
hibitor therapy in this late stage. Other studies, however,
survey, 40 US primary care physicians held mostly ambiva-
have shown near total destruction of cholinergic axons in
lent (51%) or negative (31%) views about cholinesterase
the cerebral cortex of patients with advanced Alzheimer’s
inhibitor treatment for dementia (Franz et al., 2007).
disease, suggesting that the effect of cholinesterase inhibi-
Potential barriers to the use of cholinesterase inhibitors
tors at these stages may be mediated through spared cho-
were physicians’ lack of knowledge and experience with
linergic pathways of the thalamus and basal ganglia rather
cholinesterase inhibitor treatment, although these primary
than cerebral cortex and limbic regions (Mesulam, 2013).
care clinicians often yielded to pressure from family mem-
bers to prescribe it.
Overall treatment persistence with cholinesterase inhibi- Dosing cholinesterase inhibitors to
tors is suboptimal. In a large Medicare beneficiary study of
more than 3000 patients with Alzheimer’s disease treated
achieve maximum benefits
between 2001 and 2003, treatment persistence at 1 year Incremental increases in cholinesterase inhibitor dosages
among patients with Alzheimer’s disease who initially have shown further benefit in Alzheimer’s disease, specific-
received cholinesterase inhibitors ranged from 64% to ally in more advanced disease. In a phase 3 24-week study
68% (Mucha et al., 2008). Persistence of cholinesterase of patients with moderate–severe Alzheimer’s disease who
inhibitors therapy was even lower in a large Irish study, were taking a stable dose of 10 mg donepezil per day, a
dosage increase to 23 mg per day was associated with stat- 26 weeks, rivastigmine provided statistically significant
istically significant increases in cognitive scores (Farlow symptomatic benefits to patients with mild–moderate
et al., 2010). A post hoc analysis of individuals with Alzheimer’s disease or more severe disease compared with
more severe cognitive dysfunction in this study revealed patients on placebo. However, when patients initially trea-
significantly improved cognitive and global function ted with placebo received rivastigmine for the second 26
scores for individuals who received the higher dosage weeks, they failed to ‘catch up’ to individuals who received
(Sabbagh and Cummings, 2011). In both assessments, the the drug for the full year. In a similar trial of galantamine
magnitude of score change was considered clinically mean- in people with mild–moderate Alzheimer’s disease, patients
ingful. Although treatment-emergent adverse events— originally assigned to placebo for the first phase of the trial
nausea (6.1% versus 1.9%), vomiting (5.0% versus did not attain a similar level of cognitive benefit at the end
0.8%), and diarrhoea (3.2% versus 1.5%)—were higher of the open-label phase of the study as did patients origin-
with the increased cholinesterase inhibitors dosage, these ally taking galantamine (Raskind et al., 2000).
adverse events were reportedly infrequent after 1 month Clinical data to support the use of cholinesterase inhibi-
of therapy. Similar clinical data support the use of high- tors earlier in the trajectory, specifically in patients with
dose rivastigmine in severe Alzheimer’s disease for improve- MCI who are at risk for Alzheimer’s disease, are mixed
ments in cognitive function and activities of daily living at (Russ and Morling, 2012; Petersen et al., 2018; Richter
16 and 24 weeks (Farlow et al., 2013). When considering et al., 2018). Donepezil, at a dosage of 10 mg daily,
the value of pharmacological management of Alzheimer’s showed either marginal or no cognitive benefits, relative
disease, it is essential to consider the natural progression of to placebo, in two well-controlled studies (Salloway et al.,
untreated disease (Geldmacher et al., 2006). The initial sta- 2004; Doody et al., 2009). Similar disappointing results
bilization of—or even improvement in—cognition and daily were reported with rivastigmine and galantamine
functioning with the use of currently approved anti-demen- (Feldman et al., 2007; Winblad et al., 2008). Investigators
tia drugs cannot be sustained indefinitely. Yet, with consist- cautioned, however, that cognitive changes during this pro-
ent treatment, a less precipitous decline can be expected dromal phase of Alzheimer’s disease are subtler and there-
over the long term, relative to the known, progressive fore harder to measure (Doody et al., 2009). In a 3-year
manifestations of untreated disease. study, donepezil appeared to reduce the risk for conversion
It is also interesting to highlight that acetylcholine is one of MCI to Alzheimer’s disease, but only during the first
of the core neuromodulators involved in the regulation of year of treatment (Petersen et al., 2005). Nevertheless, in-
the sleep-wake cycle, the preservation of which has been dividuals at higher genetic risk for Alzheimer’s disease
reported to be essential for many cognitive functions (with 51 APOE e4 alleles) experienced greater benefit
related to memory processes (Aston-Jones et al., 2001; with donepezil treatment for the entire duration of the
Power, 2004). There is a circadian rhythm in central cho- study. A recent practice guideline update could find no
linergic transmission with a shift to low levels of acetylcho- Level A evidence that cholinesterase inhibitors offer symp-
line release during slow-wave sleep compared with tomatic improvement at the MCI stage (Petersen et al.,
wakefulness. In addition, circadian fluctuations have been 2018). Some of these negative results may be attributed
reported for cholinergic enzyme activity and cholinergic re- to the heterogeneity of MCI. In the future, when MCI
ceptor regulation, raising the possibility that therapeutic trials are based exclusively on patients with biomarker evi-
strategies may need to consider the diurnal timing of ad- dence of Alzheimer’s disease pathology, results may become
ministration and the half-life of the agent. Age-related al- more encouraging.
terations of this circadian rhythm occur in Alzheimer’s Cholinesterase inhibitors may also provide pathological
disease in tandem with the progression of clinical features and anatomical benefits, particularly before the emergence
(Mitsushima et al., 1996). Whether cholinesterase inhibi- of clinical symptoms of Alzheimer’s disease. As noted ear-
tors influence these altered circadian rhythms in lier, the effects of donepezil (10 mg/day) on brain structure
Alzheimer’s disease remains to be determined. were recently demonstrated in a placebo-controlled longi-
tudinal study of community-based adults with prodromal
How early to treat with cholinester- Alzheimer’s disease (Dubois et al., 2015; Cavedo et al.,
2016, 2017). Over the course of 4 years, patients who
ase inhibitors? received donepezil demonstrated a statistically significant
In patients with early-stage Alzheimer’s disease specifically, lessening in the annual rate of hippocampal atrophy on
an initial lapse in cholinesterase inhibitors therapy may lead MRI. During the first year of treatment specifically, the
to the irretrievable loss of potential treatment benefits. For rate of hippocampal atrophy was reduced by 45% in done-
example, in placebo-controlled studies of rivastigmine, an pezil-treated subjects in comparison with untreated patients
initial 26-week phase was followed by a 26-week open- with Alzheimer’s disease (Dubois et al., 2015).
label extension in which all patients received rivastigmine In the future, indications for cholinomimetic therapies,
(Farlow et al., 2000; Doraiswamy et al., 2002). For the first including cholinesterase inhibitors, may become limited to
patients with biomarker confirmation. This more rational The ultimate goal of precision medicine is to be able to
approach may show that cholinergic therapies are even administer a personalized therapy that specifically targets
more effective than heretofore suspected when applied to an individual’s known disease risks and disease process at
a more homogeneous patient population with cholinergic the molecular level (Reitz, 2016). Given the complexity and
dysfunction as a known component of dementia pathology. heterogeneity of Alzheimer’s disease pathophysiology, pre-
Novel technologies such as quantitative magneto- and elec- cision medicine may involve the determination of genetic
tro-encephalogram may also allow the detection of subtle risk profiles, the use of brain imaging, and the detection of
neurophysiological alterations induced by cholinesterase in- biomarkers in plasma or CSF to fashion a specific prevent-
hibitors and other cholinergic drugs that may not be de- ive or therapeutic regimen for a particular individual at risk
tected at the clinical level. Thus, besides ‘classical’ clinical for or with Alzheimer’s disease. To this end, ongoing trials,
outcomes, even electrophysiological outcome measures such as DIAN (Dominantly Inherited Alzheimer Network
could be introduced into clinical trials, hopefully helping trial), the Alzheimer’s Prevention Initiative, and the A4
to identify more effective novel therapies. (Anti-Amyloid Treatment in Asymptomatic Alzheimer
Disease) trial, are studying people at high risk for
Alzheimer’s disease and tracking biomarkers to identify in-
Integrating complex disease-related dividuals who might be most responsive to specific, tar-
processes: future paradigms and geted, disease-modifying interventions (Reiman et al.,
implications 2011; Mills et al., 2013; Sperling et al., 2014). In the mean-
time, extensive clinical investigations into cholinesterase in-
The neuropathological and clinical data summarized above hibitors have already been conducted in broad and largely
make it very likely that cholinesterase inhibitors or other heterogeneous populations, with success seen across mul-
cholinomimetic interventions will remain essential compo- tiple patient ‘types’ defined by severity and other important
nents of therapy for Alzheimer’s disease. The demonstra- characteristics. These developments consolidate the role of
tion of early involvement (Schmitz et al., 2016; Richter cholinomimetic agents as essential elements of the com-
et al., 2018) of the cholinergic system starting at preclinical bined pharmacologic treatments for Alzheimer’s disease
stages of the disease, suggests that cholinomimetics, along that will be developed in the future.
with anti-amyloid and anti-tau interventions, may each
have a distinct role in disease prevention. Future research
and clinical paradigms related to Alzheimer’s disease may
rely more heavily upon the ‘systems biology’ approach to
Summary
the disease, stressing the interaction of factors such as gen- The cholinergic system is important for neuronal function
etic predisposition, oxidative stress, mitochondrial dysfunc- in memory, learning, and other essential aspects of cogni-
tion, inflammatory mechanisms, vascular insufficiency, the tion and plays a wider role in the promotion of neuronal
accumulation of amyloid-b, neurofibrillary degeneration, plasticity. Multidisciplinary investigations are revealing
cholinergic deficits, and other neurotransmitter abnormal- how dysfunction in cholinergic networks arising from the
ities. A systems biology approach explicitly recognizes the basal forebrain, interact with other important pathophysio-
multifactorial, dynamic nature of diseases like Alzheimer’s logic aspects of Alzheimer’s disease—including amyloid-b
disease and helps clinicians customize therapeutic regimens plaques, neurofibrillary tangles, inflammation, oxidative
that are targeted at multiple levels of pathology over the stress, and vascular insufficiency to undermine cognition.
course of the disease. A wealth of clinical literature supports the benefit of pro-
At its most basic level, the pharmacological management moting cholinergic activity in Alzheimer’s disease through
of Alzheimer’s disease will likely incorporate tailored com- the use of cholinesterase inhibitors. Moreover, new data
bination therapies—by using, for example, currently avail- based on MRI are showing evidence of hippocampal pro-
able and novel cognition-enhancing treatments [e.g. tection and, perhaps, disease course alterations in individ-
cholinesterase inhibitors, NMDA (N-methyl-D-aspartate) re- uals who receive cholinesterase inhibitors for long periods
ceptor antagonists, and other therapies in development] of time. Interest remains high in understanding the tem-
with medications that are potentially disease-modifying poral sequence and cascade of these complex interactions
(e.g. anti-amyloid-b or anti-tau therapies). As our under- and their synergistic feedback mechanisms over the course
standing of Alzheimer’s disease pathophysiology expands of Alzheimer’s disease. It is anticipated that optimal
and we identify additional clinically useful risk factors Alzheimer’s disease management will integrate a systems
and biomarkers, the therapeutic approach to Alzheimer’s biology approach based on precision medicine to help
disease will likely parallel the way in which physicians cur- tailor combinatorial therapeutic regimens for different
rently manage other complex, variable, and highly idiosyn- stages of Alzheimer’s disease on the basis of genetic risks,
cratic diseases. brain imaging, and biomarkers. As we anticipate major
An extension of tailored therapy for complex diseases lies developments in the treatment strategies of Alzheimer’s dis-
at the core of precision medicine, which should guide future ease, cholinergic interventions are likely to maintain their
strategies for preventing or treating Alzheimer’s disease. critical roles in the therapeutic armamentarium.
Zinfandel, Oryzon Genomics and Roche Diagnostics.

Funding H.H. is co-inventor in the following patents as a scientific
H.H. is supported by the AXA Research Fund, the expert and has received no royalties:
‘Fondation partenariale Sorbonne Université’ and the In Vitro Multiparameter Determination Method for The
‘Fondation pour la Recherche sur Alzheimer’, Paris, Diagnosis and Early Diagnosis of Neurodegenerative
France. Ce travail a bénéficié d’une aide de l’Etat Disorders Patent Number: 8916388. In Vitro Procedure
‘Investissements d’avenir’ ANR-10-IAIHU-06. The research for Diagnosis and Early Diagnosis of Neurodegenerative
leading to these results has received funding from the pro- Diseases Patent Number: 8298784. Neurodegenerative
gram ‘Investissements d’avenir’ ANR-10-IAIHU-06 (Agence Markers for Psychiatric Conditions Publication Number:
Nationale de la Recherche-10-IA Agence Institut Hospitalo- 20120196300. In Vitro Multiparameter Determination
Universitaire-6). A.C.C. is supported by the CIHR Method for The Diagnosis and Early Diagnosis of
(Canadian Institutes of Health Research), the NSERC Neurodegenerative Disorders Publication Number:
(National Research Council) and the Alzheimer Society of 20100062463. In Vitro Method for The Diagnosis and
Canada. A.C.C. is a Member of the Canadian Consortium Early Diagnosis of Neurodegenerative Disorders
of Neurodegeneration in Aging and has received unre- Publication Number: 20100035286. In Vitro Procedure
stricted support from Merck Canada, Dr. Alan Frosst and for Diagnosis and Early Diagnosis of Neurodegenerative
the Frosst Family. A.V. is supported by Rotary Club Diseases Publication Number: 20090263822. In Vitro
Livorno ‘Mascagni’/The Rotary Foundation (Global Grant Method for The Diagnosis of Neurodegenerative Diseases
No GG1758249). M.M.M. has received research support Patent Number: 7547553. CSF Diagnostic in Vitro Method
from the ADC grant (AG013854). for Diagnosis of Dementias and Neuroinflammatory
Diseases Publication Number: 20080206797. In Vitro
Method for The Diagnosis of Neurodegenerative Diseases
Conflicts of interest Publication Number: 20080199966. Neurodegenerative
Markers for Psychiatric Conditions Publication Number:
Axovant supported the travel and lodging expenses of the 20080131921. G.T.G. is a consultant for Acadia,
authors for two meetings of the CWG in New York City. Allergan, Avanir, Axovant, GE, Lundbeck, Novartis,
The authors were also paid as consultants at customary Otsuka, Roche, Takeda. Research Support for Janssen,
rates for the time spent at the two meetings of the CWG; NIA. M.F. has received research support from Accera,
there were no other honoraria provided to the authors. A Biogen, Eisai, Eli Lilly, Genentech, Roche, Lundbeck,
science writer, paid by Axovant help to compile the contri- Chase Pharmaceuticals, Boehringer Ingelheim, Novartis,
butions of the authors into a coherent document. However, and Suven Life Sciences, Ltd.; and has been a consultant
the various sections of the paper were prepared exclusively and/or advisory or DSMB board member for Accera,
by the authors who were not paid in any way or the time AstraZeneca, Avanir, Axovant, AZTherapies, Eli Lilly &
spent in writing-editing the manuscript. All proceedings of Company, FORUM Pharmaceuticals, INC Research,
the CWG were independent from Axovant. The support for KCRN Research, Longeveron, Medavante, Merck and
the meetings was accepted by the CWG with the stipulation Co., Inc., Medtronic, Proclara (formerly Neurophage
that Axovant would have no input to the deliberations of Pharmaceuticals), Neurotrope Biosciences, Novartis,
the Workgroup and/or influence in anyway the final con- Sanofi-Aventis, Stemedica Cell Technologies, Inc., Takeda,
clusions/recommendations of the WG. Thus, no member of United Neuroscience Inc., and vTv Therapeutics. He also
the company participated in development, discussion or holds a patent for a transgenic mouse model that is licensed
drafting of this manuscript. Axovant has had under devel- to Elan. A.C.C., E.G., P.J.S., E.C. and A.V. have nothing of
opment a compound RVT-101 (aka Intepirdine) an antag- relevance to declare.
onist of the serotonin receptor 6 (5-HT6) (which was found
to lack efficacy for the treatment of Alzheimer’s disease), as
well as RVT-104 (combination of glycopyrrolate and high-
dose rivastigmine) a compound that targets the cholinergic
Supplementary material
mechanism Supplementary material is available at Brain online.
H.H. serves as Senior Associate Editor for Alzheimer’s &
Dementia; he received lecture fees from Biogen and Roche,
research grants from Pfizer, Avid, and MSD Avenir (paid to
the institution), travel funding from Axovant, Eli Lilly and
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Alzheimer Cholinergic

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doi:10.

1093/brain/awy132 BRAIN 2018: 141; 1917–1933 | 1917

1 AXA Research Fund and Sorbonne University Chair, Paris, France

Correspondence to: Professor Harald Hampel, MD, PhD, MA, MSc

Keywords: acetylcholine; Alzheimer’s disease; cholinergic system; cholinesterase inhibitors; cognition

The cholinergic hypothesis revolutionized the ﬁeld of

Table 1 FDA-approved cholinesterase inhibitors for Alzheimer’s diseasea

Cholinesterase inhibitors First FDA Indication(s) Dosages

Zinfandel, Oryzon Genomics and Roche Diagnostics.

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