Despite
enormous efforts to develop disease-modifying drugs for Alzheimer's
disease (AD), effective therapies have yet to be found. We have endured
failure for a number of reasons, such as low specificity in drug
candidates, inaccurate diagnosis and incorrect timing in the
intervention. To help overcome these problems, modern research findings
have been incorporated into new criteria and guidelines for the clinical
diagnosis of AD. In addition, attempts to intervene during the earliest
stages of the disease are planned, as this is probably when AD is most
receptive to disease-modifying therapies. We discuss these issues and
provide perspective into the future of drug development.
Introduction
Alzheimer's
disease (AD) is the most prevalent neurodegenerative disease among the
elderly population. The latest figures estimate that up to 2 million AD
dementia patients reside in Japan, with 30 million patients living
worldwide. With the graying of society in both developed and developing
countries, the number of AD dementia patients in the entire world is
estimated to reach over 100 million by 2050, the impact of which will be
economically and socially disastrous.[1]
The disease is characterized by the slow progressive loss of memory and
a decline in executive functions, leading to impairment in the quality
of life of patients. There are three burdens that AD dementia brings to
society: (i) the first is a loss in the working population, as a
significant number of patients lose their jobs as a result of the
disease; (ii) the second is the cost for caregiving, losing the working
population from otherwise different industries; and (iii) the third, and
sometimes overlooked burden, is the care for the caregivers themselves,
as they are frequently depressed as a result of their heavy caregiving
and worried about their future. There are some symptomatic treatments
available for AD dementia, such as choline esterase inhibitors or
N-methyl-D-aspartate (NMDA) antagonist, but they do not affect the
underlying disease etiology or halt the progression of symptoms. Thus,
even if patients receive the ideal therapy available today, the effect
would not be long lasting and the patient's condition would eventually
return to basal levels after a certain period of time.[2, 3]
Therefore, there is a huge demand for the development of
disease-modifying drugs for AD, which if possible, will change the
course of the disease and reduce its associated burdens.
Disease-modifying therapy has a direct impact on the biology of the
disease, thus changing the clinical course and delaying symptomatic
progression[4] (Fig. 1).
Various estimates show that if we could delay the onset of AD dementia
by only a few years, we could reduce the economic burden by tens of
billions of dollars. However, although enormous effort has been expended
to develop disease-modifying drugs for AD, no tested candidates have
survived the evaluation of phase 3 trials. Potential reasons for these
piled-up failures[5]
are the focus of the present review. Furthermore, we address possible
solutions and future perspectives for the field of AD disease-modifying
drug development.
Figure 1. Theoretical
effect of disease-modifying therapy in Alzheimer's disease (AD). The
number of neurons decreases while the disease progresses.
Disease-modifying therapy shown by dotted lines would affect the total
disease progression curve, thus delaying symptomatic progression.
Amyloid β as a key molecule in AD pathogenesis
Since
the incorporation of molecular biological methodologies into the field
of AD research, huge advances have been made regarding its
pathophysiology. We now understand that the sequential cleavage of
amyloid precursor protein (APP) by two different enzymes, beta- and
gamma-secretases, produces toxic amyloid β (Aβ) peptides, especially Aβ1-42, that tend to aggregate and stick together, resulting in its abnormal accumulation in the brain.[6] Toxic Aβ oligomers impair synaptic function,[7]
while long exposure to them promotes neuronal tau phosphorylation and
accumulation, causing neuronal dysfunction and ultimately neuronal cell
death. Most cases of AD are sporadic, whereas autosomal dominant
familial AD, caused by mutations in PSEN1, PSEN2 or APP
genes, comprises a tiny fraction of all cases. These “familial” cases
have almost indistinguishable symptoms and pathological findings to
those of sporadic cases, except that the disease onset is earlier and
the distribution of senile plaques is slightly different.[8]
Interestingly, mutations found in these genes are usually associated
with increased toxic Aβ production, which highlights the considerable
role Aβ plays in sporadic cases as well.[9-11]
Failure of anti-Aβ therapy: How and why?
In 1999, Schenk et al.
reported that Aβ vaccination successfully removed amyloid plaques and
resulted in functional improvement in a mouse model of AD.[12, 13]
This result had a huge impact on the research community, and a clinical
trial was subsequently initiated; however, frequent adverse effects,
such as encephalitis,[14] forced the study to a halt, and disappointingly, the immunization had no effect on cognitive function decline.[15]
Indeed, so many AD dementia clinical trials have failed without
extracting any beneficial effects. Researchers are disappointed by the
results, while pharmaceutical companies are becoming increasingly
discouraged by the notion of further drug trials given the huge cost
involved.
Thus, it is important to
investigate the reasons for these failures and to find sufficient
solutions. One possible reason for failure is that targeting Aβ might be
the entirely wrong approach. Indeed, Aβ accumulation might have nothing
to do with sporadic AD pathogenesis, or at best, merely the result of
an unknown upstream event. Nonetheless, the results from human genetic
studies discussed earlier in the present review suggest that Aβ has at
least some role in the disease pathogenesis. Furthermore, a recent study
has even suggested a protective effect of low Aβ production against AD.[16]
From these reasons, we believe that targeting Aβ has at least some
rationale. A second possibility is that a significant number of
non-Alzheimer's disease dementia cases might have been misdiagnosed as
AD dementia, and thus have contaminated the past trials. A third
possibility is that we are targeting the disease at the incorrect
time-point. The latter two possibilities are discussed in further
detail.
Does misdiagnosis matter?
Unlike
symptomatic drugs, disease-modifying drugs for AD are designed to
target specific molecular pathways that underlie the entire disease
process, which are thus destined to be ineffective for non-AD dementia
patients. Thus, accurate diagnosis before enrolment in clinical trials
is required in order to extract the maximum efficacy of
disease-modifying drugs. As the final diagnosis of AD is based on
neuropathological examination, there is always a possibility of clinical
misdiagnosis. In most past clinical trials, National Institute of
Neurological and Communicative Disorders and Stroke and the Alzheimer's
Disease and Related Disorders Association (NINCDS-ADRDA) criteria[17]
have been used to clinically define AD dementia. We have been using
these criteria for almost 30 years, yet our knowledge has been quite
dramatically refined in that time; thus, the criteria are obsolete. When
the criteria were first developed, AD dementia was considered as
dementia with AD pathology, whereas normal was considered cognitively
normal without any AD pathology. We now know that there are other causes
of dementia, such as frontotemporal lobar degeneration (FTLD) and Lewy
body dementia, which are given little consideration in the criteria. We
also know that AD pathology can exist in cognitively normal brains.
NINCDS-ADRDA criteria have a policy of excluding other causes of
dementia by negative findings, such as normal computed tomography scans
or normal cerebrospinal fluid (CSF). Furthermore, positron emission
tomography (PET) scans and magnetic resonance imaging (MRI) findings are
not even mentioned. We now know that AD is associated with significant
morphological changes, especially in the medial temporal region, and
with Aβ1-42 and phosphorylated tau abnormalities in CSF, as
well as reduced glucose metabolism in various areas of the brain. Thus,
for an active diagnose of AD dementia, there has long been a demand to
incorporate such vital research findings. The new criteria were
developed with this in mind, and will hopefully lead to more accurate
diagnoses of AD dementia[18, 19] (Fig. 2).
Figure 2. Comparison of old and new criteria for Alzheimer's disease diagnosis. MCI, mild cognitive impairment.
Right target but wrong timing?
As
discussed earlier, we have at least some pieces of evidence that
targeting Aβ could be beneficial in AD. Then why did clinical trials
targeting Aβ fail? Unlike dementia as a result of stroke or head injury,
it is impossible to identify the exact date of AD dementia onset. This
is because the onset of AD dementia is insidious and the disease
progresses very slowly. This is one of the characteristics of
neurodegenerative diseases. For example, in Parkinson's disease, it is
known that the appearance of Lewy bodies precedes symptomatic onset, and
that the patient will be asymptomatic until there is more than 50% cell
loss in the substantia nigra.[20]
These phenomena are possibly a result of neuronal plasticity that
enables compensatory mechanisms to mask circuit dysfunctions and cell
losses in neurodegeneration.
Incidentally,
amyloid plaques are usually found at autopsy in individuals aged over
40 years, with their appearance increasing with age. This is
approximately 10–20 years before the symptomatic onset of dementia.[21-23]
From this result, it can easily be speculated that there are a
significant number of people with amyloid plaques without any cognitive
decline. This is confirmed by the discovery of Pittsburgh
compound B-positive individuals among the cognitive normal population;
that is, they have detectable amounts of fibrillar amyloid, but no
cognitive decline.[24]
The
major symptom of AD is cognitive impairment. When patients are
diagnosed with dementia, the deterioration is so advanced that they can
no longer live independently; this is in fact the definition of
dementia. Neuropathological changes are also quite prominent at this
stage. Accumulation of amyloid plaques and neurofibrillary tangles are
almost maximally developed when a diagnosis of dementia is made (Fig. 3). So, what if we could intervene in the disease process at an earlier stage? If so, when is it?
Figure 3. Hypothetical disease timeline of Alzheimer's disease. MCI, mild cognitive impairment. Adapted from Jack et al. with permission.41
Mild
cognitive impairment (MCI), especially of the amnestic type, is
diagnosed when there is evidence of memory impairment, preserved general
cognitive and functional abilities, and an absence of dementia.[25] When an individual is diagnosed with MCI, they have ~50% chance of progressing (conversion) to dementia within 3 years[26]; however, there are a certain number of patients whose symptoms are quite stable who will not show progression to dementia.[27]
This is because MCI is a syndrome that consists of various pathological
backgrounds including AD, and MCI as a result of non-neurodegenerative
disorder will not progress to dementia, and MCI as a result of non-AD
neurodegeneration will have a different clinical course. Thus, if we
could extract MCI caused by AD, it might be worthwhile planning an
intervention therapy at this stage. To achieve this, we need to know
which MCI patients are more likely to progress to dementia. Various
studies, including cognitive tests,[28] CSF,[29] structural MRI,[30] amyloid PET,[31] 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET)[32] or a combination of those[33]
have been carried out to showed their usefulness as predictors of
conversion to AD dementia. By using these pieces of information, we
might be able to treat AD at the MCI stage.
Another
issue is related to clinical trial design for disease-modifying
therapy. A recent trial on spinal and bulbar muscular atrophy[34]
showed that it is extremely difficult to prove efficacy of the therapy,
even if it acts right on the target and efficacy has been well
demonstrated in mouse models. These experiences highlight the issues of
disease-modifying therapies in humans, and the details are discussed by
the authors.[35]
Importance of prospective cohorts and biomarker studies
Although
our knowledge regarding AD is accumulating, it has mostly been obtained
from cross-sectional studies. We have still not identified the
triggering step in the disease course. Furthermore, longitudinal studies
of patients are required with careful observations recorded in order to
assess their disease progression in its entirety.
Biomarkers
are measurements of biological states, such as blood pressure, blood
glucose levels and QT intervals on electrocardiograms. Those
measurements are highly reproducible and help evaluate or predict one's
disease. What are the biomarkers for AD and how useful are they? At
present, there are four major biomarkers that represent AD pathology.
They are as follows:
- Aβ pathology, as detected in the CSF or by amyloid imaging PET.
- Neurodegeneration and dysfunction, as detected by CSF tau, phosphorylated tau, and FDG-PET imaging.
- Neuronal loss, as measured by MRI.
- Memory loss and cognitive decline, as measured by cognitive assessment batteries.
Recent
studies have shown that the first three markers are useful for
diagnosing AD, as they are abnormal even before the diagnosis of
dementia.[36, 37]
However, there are no confirmed biomarkers that represent the actual
disease progression other than cognitive assessment. In other words,
even if there were effective disease-modifying drugs, the outcome must
be measured by cognitive assessment. In present clinical trials for AD
dementia, the primary end-point is change in Alzheimer's disease
assessment scale-cognitive subscale (ADAS-cog), which is a cognitive
battery designed for mild-to-moderate dementia. As cognitive measurement
is affected by the patient's physical condition, and the
reproducibility of results is relatively low compared with biomarkers
from imaging and CSF measurements, the numbers of participants required
in phase 3 clinical trials would be high enough to achieve statistical
significance, usually more than 500 participants per arm, thus
increasing the cost of the study. So, what if there was a biomarker that
had a high correlation with cognitive function, was highly reproducible
and could represent the severity of AD? To achieve this, there are
several issues that must be solved first. They are as follows:
- We need to standardize various cognitive batteries, MRI and PET data acquisition protocols, and CSF biomarker measurement protocols in order to eliminate laboratory-to-laboratory, site-to-site variations.
- We need to establish the time-course change of those biomarkers.
- We need to establish a method to identify individuals with AD pathology before they reach the symptomatic stage, preferably at the earliest stage possible.
By clearing these
issues, we might be able to develop biomarkers that represent the
disease progression, in other words, a surrogate marker for AD.
There
are currently prospective multicenter cohorts in operation. One of them
is the Alzheimer's disease neuroimaging initiative (ADNI; http://adni.loni.ucla.edu).
The first phase of ADNI in North America dealt with biomarkers related
to MCI to AD dementia conversion, and they are now at their second phase
of study (ADNI2) to detect biomarkers related to the early phase of
MCI. Similar studies have been carried out in the European Union
(EU-ADNI; http://www.centroalzheimer.org/), Australia (AIBL; http://www.aibl.csiro.au/) and Japan (J-ADNI; http://www.j-adni.org/),
and those protocols are designed to be partially compatible so that
they can provide a worldwide platform for the next generation of
clinical trials. The result from the ADNI study showed accelerated
hippocampal atrophy rates in AD compared with MCI subjects.[38]
We believe that the most important part of these prospective cohorts is
data sharing and project-to-project collaboration, as AD treatment is a
worldwide issue, requiring the whole intelligence we humans have.
Is there any option to go earlier?
As
discussed above, considering the natural course of AD, setting the
disease onset at the time of dementia is too late. Then when should the
onset of the disease be considered? Is MCI the beginning of AD? Or is
there an earlier time-point for the disease onset? To settle this issue,
two criteria for the early diagnosis of AD have been proposed[23, 39] (Fig. 4).
According to these criteria, the appearance of amyloid plaques defines
the disease onset. This can be detected by either amyloid PET or a low
CSF Aβ1-42 profile. The patient undergoes an asymptomatic
preclinical phase, possibly for more than 10 years, and neurofibrillary
tangle accumulation marks the beginning of the second stage of
preclinical AD. When there is a very subtle change in cognitive
function, the patient enters the third stage of preclinical AD.
Cognitive decline progresses until they are below 1–1.5 SD for their age
and educational standards, after which they could possibly be diagnosed
with MCI.[40]
According to previous understandings, MCI was thought to be a risk
factor for AD dementia. However, the new criteria define MCI due to AD
as a relatively late stage in AD, whereas dementia is defined as the
end-stage of the entire disease process. This is quite a drastic way of
redefining the disease course, but it is required for cutting-edge
research purposes.
Figure 4. Comparison of two criteria for early diagnosis of Alzheimer's disease (AD). Alz Assn, Alzheimer's association.
It
is quite important to note that both criteria do not recommend or
indeed oppose the incorporation of these preclinical stages into regular
clinical practice, as there is a huge problem regarding ethical issues.
We still do not have effective intervention against AD. Under these
circumstances, a diagnosis of AD has a very serious impact on one's
life. Thus, we need to be extremely careful about the concept
surrounding this issue, and a meaningful public debate is required in
order to obtain general consensus.
Attempts
to carry out intervention at preclinical stages have been planned in
the USA. The Alzheimer's Prevention Initiative (API) is designed for a
large PSEN1 kindred in Columbia; the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) is for PSEN1, 2 and APP
familial cases in USA, Europe and Australia; and the Anti-amyloid in
asymptomatic AD (A4) trial is for sporadic cases of amyloid-positive
cognitively normal cases in the USA. In Japan, the J-ADNI2 study is
planned as an observational study to include amyloid-positive and
cognitive normal individuals.
Limitations in AD drug development
Aβ
is like a small piece of garbage that neurons produce along with their
activity. Accumulation of Aβ requires a certain amount of time, thus the
lifespan of an individual is important for their accumulation. Animals,
such as rodents, have a short lifespan that is not long enough for Aβ
accumulation, thus there are no rodents that develop AD in natural
conditions. Canines might develop dementia in their second decade of
life, but they do not develop neurofibrillary tangles in their brains,
probably because neuronal exposure to toxic Aβ is not long enough.
Animal models of AD that we are currently using for drug development are
mostly transgenic mice that produce very high amounts of Aβ and tau.
Preclinical development using these animals has its own problems, such
as: (i) the animals are generated under the hypothesis that Aβ and tau
play the central role in the disease pathogenesis, which is likely but
not yet proven; and (ii) the effect of drugs are measured by cognitive
batteries developed for rodents, such as successfully navigating through
mazes and finding safe spots, which could be different from human
cognitive function. Thus, we need to be very cautious when we interpret
the results from preclinical experiments.
Future perspectives
We would like to propose some future perspectives for AD drug development in this last section.
- Dementia is the end-stage phenotype of AD, which begins with the accumulation of Aβ in the 40s or 50s; therefore, intervention targeted towards Aβ should be initiated as early as possible, even in patients without symptoms. We still need to determine at which stage of the disease intervention is most efficacious. If drugs, such as statins, that which have very few side-effects, could be developed, we might recommend taking those drugs after some screening tests for Aβ accumulation in cognitively normal individuals.
- Surrogate biomarker development is required. Objective biomarkers, such as MRI shrinkage rate or CSF biomarkers, would be useful to determine if the intervention is effective or not. The cost of clinical studies using cognitive batteries is enormous, but if we could incorporate those biomarkers as an end-point for clinical studies, it would help reduce the cost of running clinical studies. As a result, we could test more drugs.
- Tau might be the next target for drug development, as it can be effective even after the development of dementia; also, there are other neurodegenerative diseases that possess tau pathology, but do not show Aβ accumulation.
Conclusion
We
reviewed and discussed the current achievements and problems in the
field of AD disease-modifying drugs. We hope these issues can soon be
solved and that the successful development of drugs for this
debilitating disease will soon be achieved.
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