Received: 2 October 2018Revised: 21 November 2018Accepted: 3 December 2018

DOI: 10.1111/bph.14581

Themed Section: Therapeutics for Dementia and Alzheimer's Disease: BJP

New Directions for Precision Medicine

REV I EW A R T I C L E

A short perspective on the long road to effective treatments

for Alzheimer's disease

David S. Reynolds

Research & Policy, Alzheimer's Research UK,

Cambridge, UK
Correspondence
David S. Reynolds, Research & Policy,
Alzheimer's Research UK, Riverside 3, Granta Park,
Great Abington, Cambridge CB21 6AD, UK.
Email: david.reynolds@alzheimersresearchuk. org
Globally, there are approximately 47 million people living with dementia, and about two thirds of
those have Alzheimer's disease (AD). Age is the single biggest risk factor for the vast majority
of sporadic AD cases, and because the world's population is aging, the number of people living
with AD is set to rise dramatically over the coming decades. There are currently no disease‐
modifying treatments for AD, and the few symptomatic agents available have limited impact on
the disease. Perhaps surprisingly, there is relatively little activity in the AD research and
development field compared with other diseases with a high mortality burden, such as cancer.
There is enormous economic incentive to discover and develop the first disease‐modifying
treatment, but previous failure has significantly reduced further industrial investment in this
field. The short review looks at the historical path trodden to develop treatments and reflects
on the journey down the road to truly effective treatments for people living with AD.
LINKED ARTICLES: This article is part of a themed section on Therapeutics for
Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other
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1 | INTRODUCTION globally living with dementia (World Alzheimer Report, 2015). Given that age
is the single biggest risk factor for developing most forms of dementia, including
Alzheimer's disease (AD) is the most common form of dementia accounting
AD, and the world's population is aging, that num- ber is set to rise to
for approximately two thirds of all cases, with vascular dementia, fronto‐
approximately 131 million by 2050 (World Alzheimer Report, 2015). AD, like
temporal dementia, dementia with Lewy bodies, and a host of rarer dementias
most forms of dementia, is progres- sive, slowly robbing the patient of their
making up the rest. Different countries have different ways of recording disease
cognitive abilities, which then impacts on daily activities and their ability to
and its impact on mortality and morbidity, and AD is not always broken out
live independently. Not surprisingly, this places a huge burden on health and
separately. The World Health Organization lists dementia as the fifth largest
social care, with the estimated global cost hitting $1 trillion in 2018 and set to
cause of death across the globe (World Health Organization, 2018). Dementia
rise to
has recently become the single biggest cause of death in the United
$2 trillion by 2030 (World Alzheimer Report, 2015). Unlike many major diseases,
Kingdom responsible for approximately 13% of all deaths (UK Office of
the direct health care cost makes up a relatively small propor- tion of these costs,
National Statistics, 2018). There are approximately 47 million people
social care and unpaid care (e.g., a family member giving up work to look after
someone) being a much larger component
(Prince, Comas‐Herrera, Knapp, Guerchet, & Karagiannidou, 2016). AD
Abbreviations: AD, Alzheimer's disease; ApoE, apolipoprotein E; APP, amyloid precursor protein; Aβ,
and dementia are frequently referred to as the most pressing health care
amyloid peptide; Aβx, amyloid peptide of a specific length (i.e., x amino acids); BACE 1/2, β‐secretase
1/2; FAD, familial Alzheimer's disease challenge of our time, and the numbers above demonstrate why.
3636© 2019 The British Pharmacological Society Br J Pharmacol. 2019;176:3636–3648.
 REYNOLDS
FIGURE 1 Comparison of the number of publications in different disease
areas. The graph shows the total number of publications in PubMed in 3‐year
time bins using the search terms “cancer,” “heart disease,” “HIV,” “dementia,”
and “Alzheimer.” All diseases show that the number of publications has
consistently increased over the last 30 years, with cancer showing the steepest
rise. It is also clear that the volume of research activity is far higher in other
diseases that have effective drug therapies than it is for Alzheimer's disease
(AD) or dementia. Whilst the number of publications is not a measure of the
amount of drug discovery or development activity for a given disease, it does
act as a surrogate for how much is understood about a given disease, which is
very important for successful drug discovery
The large, and growing, patient population coupled with high impact on quality of
life for patients and their families clearly makes the treat- ment of dementia an
attractive opportunity for pharmaceutical compa- nies. Not surprisingly, most drug
discovery efforts have been focussed on AD because the size of patient
population and this article will dis- cuss these primarily. Therefore, it is
perhaps surprising that there is such a dearth of approved medications and
comparatively little R&D activity in this area compared with cancer or heart
disease. Figure 1 indicates that scientific productivity, as measured by number of
publi- cations, is 28‐fold and eightfold lower for AD, compared with cancer or
heart disease. Whilst publications alone do not lead to new therapies, they do
act as a good surrogate of the level of investment and research activity for a
given disease. The dearth of AD literature compared with cancer or heart
disease is likely why these latter diseases have many effective treatments and
AD does not. A look back at the efforts, activ- ities, and subsequent failures in
AD research is informative for where the field stands today and how to
achieve success in the future.
2 | EXISTING TREATMENTS FOR AD
In common medical practice, clinical AD diagnosis has typically been made
based on symptoms, rather than via pathophysiological mea- surements such as
MRI, PET, or biomarker analyses of blood or CSF samples. It should be noted
that the situation is rapidly changing with increased use of biomarker assessment.
Availability of new treatments will likely accelerate that change further.
Biomarker studies and amy- loid PET scans have shown that disease
pathology is evident many
3
years before the onset of overt cognitive decline (Jack et al., 2010), such that
AD is now usually described as having preclinical (i.e., pre- symptomatic),
prodromal, mild, moderate, and severe stages. Defini- tions vary in the literature,
but preclinical AD is typically defined as someone with positive AD
biomarkers but not yet showing cognitive impairment. This progresses to the
prodromal stage once mild cognitive impairment is observed, and this may
progress on to mild AD and sub- sequently to moderate and severe AD
followed by death (Amieva et al., 2008; Ballard et al., 2011; Weintraub et al.,
2018). The annual conver- sion rate from mild cognitive impairment to mild AD
varies considerably across studies because of differences in definitions of clinical
symptoms and use of biomarker data, but meta‐analyses suggest that it is approx-
imately 10% (Ward, Tardiff, Dye, & Arrighi, 2013).
The pathological hallmarks of AD were first described by Alois
Alzheimer in 1906 consisting of extracellular plaques, intracellular tan- gles, and
widespread neurodegeneration (Figure 2), although it was not until many decades
later that amyloid and tau were identified as the main constituents of these
aggregates (Brion, Passareiro, Nunez, & Flament‐Durand, 1985; Glenner,
Wong, Quaranta, & Eanes, 1984). In the 1970s, the relative vulnerability of the
septal cholinergic system was first identified (Davies & Maloney, 1976;
Whitehouse et al., 1982), and this led to the first effective drugs for treating the
cognitive symptoms of AD that were launched around the turn of the last
century (Francis, Palmer, Snape, & Wilcock, 1999). Donepezil,
rivastigmine, and galantamine are all AChE inhibitors approved for the
symptomatic treatment of mild‐to‐moderate AD patients (Birks, 2006). AChE
inhibitors prevent the breakdown of synaptically released ACh and thereby
prolong postsynaptic activation of nicotinic and mus- carinic receptors. It is
thought that the therapeutic benefit largely derives from potentiation of
septo‐hippocampal cholinergic activity improving attention and thus enabling
better cognitive performance (Muir, Everitt, & Robbins, 1994; Sahakian &
Coull, 1993). However, the cholinergic system is also involved in many other,
notably auto- nomic, functions, which is the reason these drugs have a range
of adverse effects (e.g., nausea, diarrhoea, and vomiting). The clinical dose of these
drugs has been empirically selected to balance their tolerabil- ity against
therapeutic benefit (Gauthier, 2001; Thompson, Lanctôt, & Herrmann, 2004),
although it is likely that greater efficacy could be achieved if tolerability could be
improved (Felder et al., 2018). The only other approved symptomatic treatment
for AD is memantine, which is a non‐competitive NMDA glutamate
receptor blocker, although its mechanism of action was only discovered
during its clinical develop- ment, which was driven by empirical observation of
symptomatic ben- efit (Lipton, 2006; McShane, Areosa Sastre, & Minakaran,
2006). None of these drugs have any significant impact on the progression of
AD, instead just offering modest amelioration of some symptoms.
3 | THE AMYLOID CASCADE HYPOTHESIS
The search for disease‐modifying treatments for AD is the primary goal of most
therapeutic research efforts, and it was a field that grew rapidly in the 1990s but
then began to wane over the next 10 years (Figure 2).
 36
B

FIGURE 2 The long road to anti‐amyloid therapies. Starting with the first description of Alzheimer's disease (AD) in 1906 through to ongoing clinical trials with
amyloid‐lowering therapies, this timeline indicates some of the key discoveries and clinical trial outcomes. Relatively little progress was made through the 20th
century until genetic studies clearly linked amyloid processing to disease causation. Since the 1990s, therapeutic research and development has explored several
different approaches to lowering amyloid in the brain with the aim of providing therapeutic benefit in the form of slowing, or stopping, disease progression. Most of
these approaches have been stopped due to either safety issues or lack of robust efficacy. Several anti‐amyloid antibodies are in late stage clinical trials and will
hopefully prove to be effective in patients. FAD: familial Alzheimer's disease; MCI: mild cognitive impairment; APP: amyloid precursor protein

Two key factors drove the large‐scale pharmaceutical investment; the first was
functional changes, and empirical observations. At that time, it appeared that
economic and the second scientific advances. The 1990s saw enormous
genetics had paved a clear path to effective medicines.
economic success of neuroscience drugs such as the atypical antipsychotics for
In 1991, the first Alzheimer's autosomal dominant mutation (V717I) was
schizophrenia (e.g., olanzapine and risperidone), selective 5‐HT (serotonin)
discovered in a family in London in the gene that codes for the amyloid
reuptake inhibitors for depression (e.g., flu- oxetine and paroxetine), α2δ
precursor protein (APP; Goate et al., 1991). It was quickly followed by a
ligands for neuropathic pain (gabapentin and pregabalin), and a range of whole series of other disease‐causative mutations in this gene (Tcw & Goate,
new mechanisms to treat epilepsy (e.g., lamotrigine and topiramate). These 2017). Biochemical studies determined that APP was preferentially cleaved by
successes instilled the (not unreasonable) belief in senior pharmaceutical
enzymes α‐secretase and β‐secretase (more typically referred to as
executives that psychiat- ric and neurological conditions were lucrative
BACE) as well as the γ‐secretase com- plex, to produce peptide fragments of
opportunities for R&D investment given the large patient populations and
varying sequences (De Strooper, Vassar, & Golde, 2010), the most important of
significant unmet patient need, along with advancing scientific understanding of
which was β‐amyloid (Aβ), which was already known to be the primary
the molecular underpinnings of these diseases. AD was top of the neurosci- ence
constituent of amy- loid plaques (Glenner et al., 1984). The cleavage of APP
priority list for many companies. The key scientific advance that increased
into various fragments with a range of biological functions is complex and has been
confidence that effective disease‐modifying drugs could be developed was the
reviewed in detail elsewhere (Gralle & Ferreira, 2007; Ludewig & Korte,
identification of causative genes for human disease. Discovery of the genes
2017). Sequential BACE and γ‐secretase cleavage are required to produce Aβ
responsible for autosomal dominant diseases for the first time directly linked
peptides (De Strooper et al., 2010), whereas α‐secretase cleaves in the middle of
potential drug targets with human disease bypassing the need for less direct linkage
the Aβ sequence and yields nonamyloidogenic fragments (Jorissen et al., 2010;
provided by animal models,
Kuhn et al., 2010). Intriguingly, nearly
 REYNOLDS
all of the disease‐causing mutations on APP cluster around the BACE and γ‐
secretase cleavage sites, implicating inappropriate processing as the
pathophysiological mechanism in AD. Two further genes linked to familial AD
(FAD), presenilin 1 and 2 (Bertram, Lill, & Tanzi, 2010; Lendon, Ashall,
& Goate, 1997; Sherrington et al., 1995), were a few years later shown to be
the critical aspartyl protease components in the γ‐secretase complex (De
Strooper et al., 2010; Sisodia & St George‐Hyslop, 2002). FAD cases make
up <1% of all AD cases, but the clinical symptoms, disease progression, and
biochemical and neu- ropathological changes are all remarkably similar to typical
late‐onset sporadic AD, except that symptom onset is usually in the third to fifth
decades of life rather than in old age (Ryman et al., 2014).
The amyloid cascade hypothesis of AD was proposed by Hardy in the early
1990s, in which build‐up of longer forms of Aβ, particularly the aggregation‐
prone Aβ42, led sequentially to the formation of neu- rotoxic oligomers,
insoluble amyloid fibrils, and ultimately amyloid plaques (Hardy & Allsop,
1991; Hardy & Selkoe, 2002). Most FAD mutations shift the ratio of Aβ
peptides towards the longer, more aggregation‐prone forms. In sporadic
forms, it was not clear if there was over production of Aβ generally, an
increase in the ratio Aβ42/ Aβ40, or alternatively, insufficient clearance from
the brain of Aβ42, any of which could lead to accumulation and in turn
aggregation. The critical involvement of BACE and γ‐secretase in disease
pathology presented two obvious drug targets, especially as enzyme inhibitors
are a well‐precedented class of drugs (Vassar et al., 2014).
γ‐Secretase was the target most heavily pursued initially, largely because
assays of γ‐secretase activity existed before the complete make‐up of the
enzymatic complex was elucidated and presenilins identified as the catalytic
subunit (Sisodia & St George‐Hyslop, 2002). γ‐Secretase inhibitors, such as
semagacestat from Eli Lilly, were relatively quickly identified and advanced
into large clinical trials on AD patients. Unfortunately, γ‐secretase has around 40
cellular substrates, which resulted in significant on‐target toxicity. Notch, a key
compo- nent of the Wnt signalling pathway, is a substrate of γ‐secretase
(Geling, Steiner, Willem, Bally‐Cuif, & Haass, 2002; Micchelli et al., 2003),
and blocking Notch cleavage is likely the reason increases in skin cancers and
infections were observed in these clinical trials (Chávez‐Gutiérrez et al.,
2012; Doody et al., 2013). These adverse effects, plus the fact that the
semagacestat‐treated patients actually had worse cognitive decline than those in
the placebo group, resulted in its discontinuation in 2011 (Doody et al., 2013).
Several companies pursued other γ‐secretase inhibitors into the clinic and
experienced similar challenges, eventually resulting in them all being stopped. Two
alternative approaches to γ‐secretase have been proposed and to some extent
persued: (a) γ‐secretase modulators (Bursavich, Harrison, & Blain, 2016; Hall &
Patel, 2014) that reduce APP cleavage but have reduced effect on the cleavage
of other substrates and (b) γ‐secretase stabilizers that shift cleavage to shorter,
less toxic Aβ peptides such as Aβ38 (Szaruga et al., 2017). γ‐Secretase
modulators have reached clin- ical trials, but clinical benefit has not yet been
demonstrated, whereas γ‐secretase stabilizers are still at the preclinical
discovery stage.
BACE inhibitor development has also been an area of intense focus once
BACE was cloned by five independent groups in 1999 (Hussain
3
et al., 1999; Lin et al., 2000; Sinha et al., 1999; Vassar et al., 1999; Yan et al.,
1999). There are two BACE isoforms (BACE1 and BACE2), which initially
appeared to have fewer alternative substrates than γ‐secretase. It was therefore
reasoned that BACE inhibitors may be safer than γ‐ secretase inhibitors; however,
subsequent investigation demonstrated a range of important substrates for both
BACE1 and BACE2 (Dislich & Lichtenthaler, 2012). The active site of BACE
is very open compared with other aspartyl proteases (Hong et al., 2000), which
made it very dif- ficult to find potent and selective inhibitors that also possessed
drug‐ like properties (Ghosh, Brindisi, & Tang, 2012; Vassar et al., 2014). Many of
the early inhibitors were peptide mimetic molecules with poor absorption,
stability, and brain or cell penetration making them unsuit- able even for rodent in
vivo studies let alone for clinical development (Ghosh et al., 2012). Concerted
medicinal chemistry efforts eventually yielded appropriate molecules, and Merck
Inc. led the way into large‐ scale clinical trials with verubecestat (MK‐8931)
in 2012 (Scott et al., 2016). BACE inhibitors have demonstrated an acceptable
safety profile for large‐scale clinical trials in AD patients at doses that robustly
reduce Aβ levels in plasma and CSF (Kennedy et al., 2016). Verubecestat has
been tested in prodromal, mild, and moderate AD patient populations, but despite
lowering CSF Aβ levels (Kennedy et al., 2016), no cognitive or functional
benefit was observed in patients (Alzforum, 2018c; Egan et al., 2018). Since the
negative Phase III results of verubecestat, other BACE inhibitor studies have also
been terminated (Alzforum, 2018b,d). The third major approach to therapeutically
target Aβ directly is active or passive immunization. Encouraging efficacy was
first shown by Schenk et al. (1999) at Elan Corporation using the PDAPP
Alzheimer's mouse model. PDAPP mice overexpress a mutant form of human
APP (APP V717F) and show age‐dependent deposition of amyloid plaques
(Masliah et al., 1996). Active immunization of these mice with Aβ42 peptide and
QS‐21 adjuvant blocked the development of amyloid plaque pathology when
given to young mice (6 weeks of age) and markedly reduced established
pathology in 11‐month‐old mice (Schenk et al., 1999). Elan then progressed this
agent, known as AN‐1792, into a clinical trial in mild‐to‐moderate AD patients.
Unfortu- nately, a small number of patients developed serious brain inflamma- tion
that was later shown to be aseptic meningoencephalitis (Nicoll et al., 2003).
Given the serious nature of this adverse event and no means of
predicting/excluding patients at greatest risk, development of AN‐1792 was
terminated in 2002 (Check, 2002). Only a subset of patients in the trial mounted
a significant antibody response to the treatment, mostly directed to the N‐
terminus portion of Aβ, and this was not correlated with those experiencing aseptic
meningoencephali- tis (Lee et al., 2005). Importantly, post‐mortem analysis of the
patients who mounted a response showed that some clearance of amyloid
plaques from their brains had occurred (Nicoll et al., 2003). However, there
were conflicting results as to whether the patients experienced
clinical benefit or not (Holmes et al., 2008; Vellas et al., 2009).
The mechanistic success of AN‐1792 (i.e., clearance of amyloid plaques in
humans) encouraged the field to find similar approaches with an improved safety
profile. Several companies developed passive immunotherapies where humanized
antibodies targeting Aβ peptides were administered to patients. The major safety
advantage to this
REYNOLDS 36

approach is that the host immune system is not directly stimulated, thereby
4 | Aβ‐ LOWERING THERAPIES: HAVE WE
avoiding the inflammatory response seen with AN‐1792. Additionally, the
REACHED A DEAD END?
epitope of the therapeutic antibody is defined so that therapies aimed at soluble
monomers, oligomers, or fibrillar Aβ could be designed. The disadvantage of
The lack of reproducible success of amyloid‐targeting therapeutics to date is
the passive immunotherapy response is that the antibodies administered will
clearly disappointing for researchers, pharmaceutical compa- nies, and most of
be cleared from the body necessitating regular dosing (usually every 4 weeks).
all to patients who are still without an effective treatment to slow down or
Antibodies are also very poorly brain penetrant with only approximately 0.1%
stop the course of their disease. However, does this mean that the amyloid
of the dose getting into the brain (Banks et al., 2002; Levites et al., 2006),
hypothesis of AD is incorrect? Cer- tainly, there are voices saying that it is, but
resulting in a high peripheral load of antibody and consequently a higher dose
is this really true? A careful look at the research data and clinical trial findings
needing to be given, which greatly increases the cost of manufacturing the
is required to deter- mine how thoroughly the hypothesis has actually been
therapy. In the decade following AN‐1792 termina- tion, a number of Aβ‐
tested. Three key questions need to be answered to understand how well we
targeting antibodies, including solanezumab (Eli Lilly), crenezumab
have tested the amyloid hypothesis. These are (a) have we been treating the
(Roche), gantenerumab (Roche), and bapineuzumab (Johnson &
right patients, (b) when do we need to treat with Aβ‐lowering therapies to
Johnson/Pfizer), entered clinical trials and demonstrated an improved safety
be effective, and (c) how long do we need to treat for? Over the last 20 years
profile. Some instances of amyloid‐related imaging abnormalities associated with
of clinical studies in AD, we have learnt a huge amount about the disease
either microhaemorrhage or vasogenic oedema were observed in subsets of
course of AD, improved the tools available for studying the disease in
patients, but these have proved manageable for the running of large clinical trials
patients (Blennow & Zetterberg, 2018; Pietrzak, Czarnecka, Mikiciuk‐Olasik,
aimed at establishing efficacy in AD patients (Ostrowitzki et al., 2012; Salloway
& Szymanski, 2018; Rice & Bisdas, 2017), and increased our understanding of
et al., 2014; Sperling et al., 2012). Sadly, the therapeutic benefit in terms of rate
which endpoints are the most informative (Aisen et al., 2017; Reiman et al.,
of cognitive or functional decline has been minimal in prodromal, mild, and
2016). It is therefore much more accurate to say that these large clinical devel-
moderate patient AD populations for many of these antibodies (Cummings,
opment programmes have been negative (i.e., failed to meet their pri- mary
Cohen, et al., 2018; Doody, Farlow, et al., 2014; Doody, Thomas, et al., 2014;
endpoint), rather than failed (i.e., the trial design or execution was flawed such
Ostrowitzki et al., 2017; Siemers et al., 2016). Subgroup analyses, usually
that the results are uninterpretable).
performed post hoc, have indicated some cognitive benefits, but these have failed
The question of whether we have been treating the right patients
to be robustly reproduced.
may seem a simple one to answer, but for dementias, it is actually far from
On a more positive note, two other amyloid antibodies, aducanumab
trivial. In fact, in the earlier antibody trials where an amyloid PET scan was not
and more recently BAN2401, have reported positive effects (Alzforum,
available and therefore was not an entry criterion, it is estimated that up to a
2018a; Sevigny et al., 2016). Aducanumab demon- strated dose‐dependent
third of patients enrolled did not have elevated amyloid levels (Siemers et al.,
clearance of amyloid plaques, as determined by amyloid PET, in a 12‐month
2016; Vellas et al., 2013). It is critical to get the inclusion criteria for enrolment
Phase Ib safety study with approxi- mately 25–30 prodromal and mild AD
into a clinical trial correct such that only patients with a high amyloid load
patients. Impressively, it also showed largely dose‐dependent reductions in the
resulting in AD are studied in the trial. From a scientific point of view, these
Clinical Dementia Rating Scale sum of boxes after 12 months of dosing
criteria need to be as stringent as possible to avoid recruiting inappropriate
(Sevigny et al., 2016). Presentation of data from subsequent open‐label
patients, as those not possessing an amyloid pathology will only add to the
extension phases from this study shows that those benefits are sustained over 4
noise and potentially obscure a genuine positive effect. However, that strin-
years of dosing. This is a small study, and therefore, replication of these
gency needs to be balanced against the practical reality that enough patients
findings in large Phase III trials is required to establish robust safety and
need to be identified to make the running of the trial feasible from both a time
efficacy data. Two Phase III studies completed enrolment in mid‐2018, and the
and cost perspective. The gold‐standard method of diagnosis is
outcomes are awaited. BAN2401 reported the results of an 856 patient dose‐
neuropathological confirmation of plaques and tangles post‐mortem, which is
ranging study in prodromal and mild AD (Alzforum, 2018a). Again, there was
obviously not applicable. Cognitive assessment alone determines that the patient
a dose‐dependent reduction in amyloid PET signal, but only the highest dose (10
has cognitive deficits consistent with AD, but given the wide variation in
mg·kg−1 biweekly) showed a statistically significant improvement in cogntive
symptoms for AD and other dementias such as vascular dementia and fronto‐
decline. Interpretation of the results is complicated by the adaptive randomi-
temporal dementia (Pasquier, 1999), those findings alone are insufficient (Fox
zation design of the study and a change in regulatory safety guidance part way
& Rossor, 1999). Assessment of plasma Aβ concentrations, whether Aβ42 or
through the study resulting in an inbalance in the percentage of apolipoprotein
the ratio of Aβ42/Aβ40, generally has a poor correlation to brain Aβ load
E (ApoE) ε4 carriers in the different arms (Alzforum, 2018a). These results
(Beach, Monsell, Phillips, & Kukull, 2012), although recent meth- odological
are encouraging because of the size of the study but will likely require
advances may be starting to overcome that issue (Nakamura et al., 2018;
replication in pivotal Phase III studies before approval. The reasons why
Ovod et al., 2017). CSF Aβ concentrations are much more predictive of the
aducanumab may be effective when several other antibodies have failed have
brain amyloid load (Clark et al., 2003; Galasko et al., 1998), but there are
not been determined.
concerns over patient
 36
B
willingness to undergo a lumbar puncture, which has limited its usage. A key
role of amyloid in AD is yet to be fully determined, but accumulating evidence
advance in biomarker tools for accurate diagnosis of AD patients was the
suggests that it may be more likely to act as a trigger for other pathologies
development of amyloid PET ligands over the last 10 years (Chételat et al.,
and may be less important, or even irrelevant, later in the disease course
2013; Morris et al., 2016). Several agents such as florbetapir and
(Karran, Mercken, & De Strooper, 2011).
flutemetamol are available for use in clinical trials and approved for
Our understanding of this sequence of progressive brain pathol- ogy in
diagnostic use in medical practice. These ligands bind to aggregated Aβ
advance of overt clinical symptoms points to the most likely reason that
(Klunk et al., 2001) and allow the clear determination of elevated amyloid
amyloid‐lowering therapies have not been beneficial in most trials run to date:
load. Their use in screening patients for AD trials is now very wide spread
They were administered too late (van Dyck, 2018). Amyloid load plateaus
and ensures that patients are appropriate for amyloid‐lowering therapy trials.
many years before a patient would be given a diagnosis of prodromal or mild
Trials run before these ligands were widely available recruited a high propor- tion
AD, by which time amyloid may not be the primary driver of disease
of amyloid negative subjects (Siemers et al., 2016; Vellas et al., 2013), which
progression (Jack et al., 2010; Weiner et al., 2010). The ability of amyloid
was initially thought to be a contributory reason for the lack of robust
therapies to lower brain amyloid load, even to the point of being classified as
clinical efficacy. However, a more recent solanezumab trial that included a
amyloid negative by PET scanning and yet have little to no benefit on
positive amyloid PET scan as an inclusion criterion also did not show
cogni- tive decline, would certainly be consistent with this hypothesis (Egan et
robust efficacy (Honig et al., 2018).
al., 2018; Panza et al., 2014). Clinical intervention earlier in the dis- ease
The second question of when patients need to be treated with amyloid‐
course is the obvious next step for these therapies, and several studies in
lowering therapies to have a beneficial effect on disease is still somewhat of an
prodromal or preclinical disease are being conducted (Reiman et al., 2016;
open question because there are no approved therapies. Genetic findings from
Sperling, Mormino, & Johnson, 2014). Recom- mended inclusion criteria for
FAD mutations indicate that increased production of Aβ42 is sufficient to
such studies include a positive amyloid PET scan, lack of significant cognitive
cause AD (Tcw & Goate, 2017). Additionally, a protective mutation, A673T
impairment, and one or more risk factors such as family history or being a
which is close to the BACE cleavage site, has also been discovered that
carrier of the ApoEε4 allele (Dubois et al., 2016). The primary outcome of
reduces Aβ production by approximately 40% in cell culture models (Jonsson
these studies is a slowing of the rate of cognitive decline as measured by a
et al., 2012; Maloney et al., 2014) and protects human carriers from developing
composite cognitive score. The challenge with such studies is the length of time
AD or cognitive decline (Jonsson et al., 2012). The protec- tive genetic
that they take to conduct and the number of patients required given the
mutation is carried from birth, suggesting that in the worst‐case scenario,
variability in rates of disease progression. Both of these factors make such trials
life‐long reduction in Aβ production is required for protection. On the flip‐
prohibitively expensive, but thankfully, industrial and philanthropic funding is
side even in FAD patients, the disease is rarely diagnosed before the age of
allowing a small number of such studies to be carried out. An alternative
30 (Ryman et al., 2014) and more usually in their 40s or 50s, suggesting that
approach to test the early interven- tion hypothesis is selection of a much more
the brain is resilient for several decades before the onset of cognitive decline.
defined patient popula- tion, that is, those with FAD mutations. These
The use of amyloid PET ligands allowed the longitudinal mapping of amyloid
patients will definitely progress to AD, and we know that their APP/PS
deposition and, in combination with other scanning techniques (Wei- ner et al.,
mutation is the driving cause of their disease. Additionally, they are often
2010), built a relatively clear picture of the sequence of events leading to
much more motivated to participate in clinical trials than healthy older indi-
cognitive decline and a clinical diagnosis of AD (Jack, Holtzman, &
viduals in the general population who are currently symptom free. Research
Holtzman, 2013; Jack et al., 2010). Amyloid levels start to rise at least 20
networks of FAD carriers have been established, and amyloid‐lowering
years prior and actually plateau about 10–15 years before the onset of overt
therapy preventive trials, such as DIAN‐TU, have been ongoing for the last few
clinical symptoms resulting in a diagnosis of AD (Schott & Petersen, 2015).
years (Mills et al., 2013; Sperling, Rentz, et al., 2014).
Additional scanning techniques such as fluorodeoxyglucose uptake to look at
The third question of how long we need to treat for is also
metabolic activity (O'Brien et al., 2014), volumetric MRI to assess atrophy
something of an unknown and likely to depend on the exact mech- anism of
(Jack et al., 2010), microglial activation (Edison, Donat, & Sastre, 2018;
the therapy. PET studies in mild‐to‐moderate AD patients using antiamyloid
Varley, Brooks, & Edison, 2015), and tau (Okamura et al., 2018) PET ligands
antibodies have shown that amyloid load can be reduced over a period of 6–18
have built up a picture of the sequence of events in the brain leading up to
months in a dose‐dependent manner (Ostrowitzki et al., 2017; Sevigny et al.,
cognitive decline. These can be plotted as a series of sequential but
2016). The relatively slow clearance of already deposited amyloid is probably
overlapping curves first clearly summarized by Jack et al. (2010) and Jack et
a combination of preventing further deposition plus removal of plaques via
al. (2013): Amyloid build up occurs first, followed by metabolic decline,
activa- tion of microglial clearance mechanisms (Ostrowitzki et al., 2012;
then tau accumulation leading to reductions in brain volume. Only at this
Sevigny et al., 2016). Verubecestat has likewise shown a gradual clearance
relatively late stage in terms of brain pathology are obvious symptoms of
of plaques over several months even though a reduction of CSF or plasma Aβ
cognitive decline observed and a clinical diagnosis of AD typically given. The
occurs much more quickly. Understanding the kinetics of amyloid plaque
precise
clearance is interesting from a scientific
 3 B
point of view, but evidence to date shows that it offers limited patient
benefit. Instead, prevention of deposition in the first place may be a more
relevant goal, which hopefully, the ongoing second- ary prevention trials will
tell us. The duration of treatment for sustained beneficial effect is likely to be
life long as the longitudinal data suggest that amyloid deposition is probably
the triggering event for AD rather than necessary throughout the disease
(Karran et al., 2011). As such amyloid levels will need to be kept low for
long periods to avoid the disease processes reinitiating. This in turn requires
that therapies have a very good safety profile such that the benefit–risk is still
favourable even in people who have no overt disease. Any ongoing safety
monitoring requirements, such as regu- lar MRI scans for signs of amyloid‐
related imaging abnormalities, could be detrimental to the real‐world uptake
of these therapies for long‐term secondary prevention.
5 | ALTERNATIVE ROADS TO SUCCESS?
The disproportionate amount of academic research effort and indus- trial
investment into the amyloid cascade hypothesis has probably slowed the field
down in investigating alternative mechanisms and developing drugs for other
targets (Figure 3). The most obvious alter- native target is tau: Tau tangles are
a diagnostic criterion for AD
diagnosis, and their accumulation correlates much better with cogni- tive
decline (Arriagada, Growdon, Hedley‐Whyte, & Hyman, 1992; Nelson et al.,
2012; Tomlinson, Blessed, & Roth, 1970). Interestingly, disease‐causing
mutations in tau are not linked to AD, rather to various other forms of
neurodegenerative diseases such as fronto‐ temporal dementia, progressive
supranuclear palsy, Pick's disease, and corticobasal degeneration (Ghetti et
al., 2015; Hutton et al., 1998; Spillantini et al., 1998). Whilst this may appear
to weaken tau as a therapeutic target for AD, it does strengthen the case that
aberrant tau and its aggregation into intracellular tangles are sufficient to
drive neurodegeneration, albeit with varied clinical pre- sentation. Additionally,
tau is necessary for Aβ‐induced neurotoxicity (Rapoport, Dawson, Binder, Vitek,
& Ferreira, 2002). The challenge with tau as a drug target has been how to
modulate it. The normal function of tau is as an intracellular scaffolding
protein forming microtubules (Weingarten, Lockwood, Hwo, & Kirschner,
1975). Hyperphosphorylation of tau leads to aggregation first in the form of
paired helical filaments and then into tangles (Grundke‐Iqbal et al., 1986; Iqbal
et al., 1986). As a scaffolding protein, it is much less obvi- ous if there is an
amenable binding site for small molecule drugs to interfere with its
pathophysiological function compared with the active site of an enzyme or
ligand binding site on a GPCR. Additionally, being an intracellular protein, it
was not thought to be amenable to antibody therapies that do not readily
penetrate into cells. It is only

FIGURE 3 Alternative routes to effective treatments for Alzheimer's disease (AD). The schematic illustrates nonamyloid mechanisms that have or are being
investigated for therapeutic potential in AD over the last 30 years. The neurochemical analyses of 1970s and 1980s led to the development and launch of
symptomatic treatments for AD around the turn of the century. AChE inhibitors and the glutamate antagonist memantine are the only approved drugs to treat the
cognitive symptoms of AD. Most of the research activity is now focused on disease‐modifying treatments rather than more symptomatic drugs. Tau and apolipoprotein E
were recognized in the 1990s as key players in AD pathophysiology but have yet to be successfully targeted for disease‐modifying therapies. Advances in genetic
technologies led to genome‐wide association studies (GWAS) uncovering small‐effect size risk alleles, which have fuelled most of the avenues of active research
today. These include lipid processing, mitochondrial dysfunction, protein folding, and clearance mechanisms as well as the role of the innate immune system in
neurodegeneration
 REYNOLDS
in recent years, when it was discovered that tau accumulation follows a specific
pattern of spreading through the brain, which is hypothe- sized to occur via
trans‐synaptic transmission of tau “seeds” (Clavaguera et al., 2009, 2013;
Frost & Diamond, 2010), that there has been renewed interest in tau as a target.
Several anti‐tau antibod- ies have been developed (Golde, Lewis, & McFarland,
2013) and are moving into Phase II clinical trials (Cummings, Lee, Ritter, &
Zhong, 2018). The knowledge gained from negative amyloid trials in terms of
patient selection, appropriate endpoints, and effective use of bio- markers
including tau PET ligands will all hopefully enable much faster testing of the tau
hypothesis in AD patient trials. The evidence with tau suggests that it remains an
important driver of disease progression later into the disease course than amyloid,
and hence, trials in prodro- mal or mild‐to‐moderate stage AD patients perhaps
have a greater chance of success.
ApoE function is a second area of great interest, as ApoE is the big- gest
genetic risk factor in the general population (Corder et al., 1993; Holtzman,
Herz, & Bu, 2012; Strittmatter et al., 1993). Unlike APP and PS mutations that
are causal for FAD, ApoE just increases the risk of developing late onset AD.
There are three common allelic forms ε2, ε3, and ε4 with a frequency of 8%,
78%, and 14%, respectively (Farrer et al., 1997). Compared with someone with
the ε3/ε3 genotype, the odds ratio of developing AD is 3 and 15 times higher
for the ε3/ε4 and ε4/ε4 genotypes, respectively (Farrer et al., 1997). The
precise role ApoEε4 plays in AD pathophysiology has been difficult to deter-
mine, but it has been shown to increase amyloid deposition (Bales et al.,
1997), impair degradation (Jiang et al., 2008), and exacerbate tau‐mediated
neurodegeneration (Shi et al., 2017). Finding ways to modulate ApoE
function safely as a drug target for AD has so far proved extremely
difficult.
The third major step towards alternative drug targets for AD has again
come from the field of genetics. The advance in sequencing technologies over
the last 30 years has enabled genome‐wide associ- ation studies so that genes
with small effect sizes could be identified, rather than just the large effect size
of familial genes first discovered in the 1990s. Several genome wide association
studies involving hun- dreds of thousands of subjects have now identified
approximately
30 risk alleles (Guerreiro & Hardy, 2014; Zhu, Tan, Tan, & Yu, 2017) and
two protective variants (ApoEε2 and PLCγ2; Corder et al., 1994; Sims et
al., 2017). Other than ApoEε4, which has been known as a significant risk
factor for many years (Corder et al., 1993; Farrer et al., 1995), few of the
newer risk alleles are directly involved in amyloid or tau processing. Instead,
pathway and network analyses have shown them to be primarily related to
the innate immune system, energy metabolism, and proteostasis/autophagy
(De Strooper & Karran, 2016; Zhu et al., 2017). These discoveries have
also revealed a convergence of the mechanisms involved
neurodegeneration, so that despite different clinical presentations and
neuropathological signatures in other dementia‐causing diseases, the underlying
biology shares many commonalities (Brettschneider, Del Tredici, Lee, &
Trojanowski, 2015; Salter & Stevens, 2017). The above factors have
reinvigorated the dementia research field and industrial drug discovery
investment. Although many of the risk
3
alleles are not themselves particularly obvious drug targets, they sit on
pathways with tractable targets that are now at the preclinical stages of drug
discovery. In the next few years, many of these will move into clinical
testing and hopefully yield positive results on dis- ease progression in
patients.
Whilst the main drug development focus is on finding a drug that is
efficacious, it is most likely that polypharmacy will be required for effective
clinical management of AD. The genetic studies indicate that more than one
pathophysiological mechanism can cause AD and it is likely that multiple
mechanisms will be active in any given patient. Recent post‐mortem studies are
increasingly demonstrating that many patients have overlapping neuropathological
features of AD, vascular dementia, dementia with Lewy bodies, and so forth
(Attems & Jellinger, 2014; Irwin et al., 2017; Spires‐Jones, Attems, &
Thal, 2017). These data indicate that mixed pathologies may be relatively
common, and therefore, treating the patients' disease with drugs of multiple
mechanisms will likely be necessary. The use of biomarkers, MRI/PET scans,
and other means of appropriately stratifying patients will need to develop
significantly from where they are today to be able to correctly identify which
mechanisms are relevant to a specific patient and therefore start treatment
with the appropriate drugs. Such precision medicine approaches for cancer
therapy are now common place and hopefully will become so for AD and
other dementias in the future.
Improvements in the research landscape and drug target pipeline over the
last decade have also been matched by changes in the political and funding
landscape. Several governments have woken up to the impact of dementia on
health and social care systems and developed routes and action plans to address
the issue. A prom- inent example was the G8 summit in 2013 focused on
dementia (Fox & Petersen, 2013) that led to the setting of a key therapeutic
goal: to identify a cure or disease‐modifying therapy for dementia by 2025
(Vradenburg, 2015). Many organizations around the world have aligned
themselves with this goal, which could be achieved by several agents in late
stage clinical trials (Cummings, Lee, et al., 2018), although this is by no means
a certainty! The setting of polit- ical goals has also brought increased
government funding into the dementia research field with big increases in the
U.S.'s National Institute of Health dementia budget in recent years (Alzforum,
2018e) and the establishment of the Dementia Research Institute in the United
Kingdom (https://ukdri.ac.uk/). Increased venture cap- ital funding has also
been created through targeted investment mechanisms such the Dementia
Discovery Fund, which now has
$350 million to invest in dementia drug discovery and development
(https://theddfund.com/). Finally, philanthropists with global profile such as Bill
Gates (Marais, 2018) and the Chan‐Zuckerberg Initiative
in
(https://www.chanzuckerberg.com/) are increasingly turning their attention to
dementia research funding, which attracts further public and political interest
in the area.
In summary, we are still travelling down the long road to effective disease‐
modifying treatments for dementia, but several alternative routes are hopefully
increasing our chance of successfully reaching our destination. Experience in
how to run clinical trials should help
 3 B
avoid some of the inefficiencies of previous trials. Rapidly improving
understanding of the mechanisms involved in neurodegenerative dis- eases is
opening up new areas of biology and offering a wealth of potential drug
targets. Increased political and public awareness and interest in dementia is
leading to more funding and increased research as well as drug discovery and
development capacity. Hopefully, they will all help us find the urgently
needed treatments and better out- comes for people living with dementia.
5.1 | Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to
corresponding entries in http://www.guidetopharmacology.org, the common portal
for data from the IUPHAR/BPS Guide to PHARMA- COLOGY (Harding et
al., 2018), and are permanently archived in the Concise Guide to
PHARMACOLOGY 2017/18 (Alexander, Christopoulos et al., 2017;
Alexander, Fabbro et al., 2017; Alexander, Kelly et al., 2017; Alexander, Peters
et al., 2017).
CONFLICT OF INTEREST
D.R. holds shares in Pfizer Ltd and was a past employee of Pfizer Inc. and
Merck Inc.
ORCID
David S. Reynolds https://orcid.org/0000-0002-5461-3166
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