COVER STORY • Super Aging Society Where Elderly People Foster Vitality • 3Interview with Takeshi Iwatsubo, Professor of the Department of Neuropathology, Graduate
School of Medicine, The University of TokyoV

ery Early Treatment of
Alzheimer’s Disease & Impactof Public-Private Partnership

By Japan SPOTLIGHT
Aging in Japan is proceeding more rapidly than in any other country. It is thus very urgent for theJapanese medical profession to develop a cure for Alzheimer’s disease, which becomes more widespread as
the population ages. Dr. Takeshi Iwatsubo, one of the most distinguished experts in this domain in Japan,
talked to Japan SPOTLIGHT about the latest developments in Japanese medical science for the treatment of
Alzheimer’s disease and how the nation and society can promote them.
(Interviewed on Jan. 31, 2017)
JS: Could you tell us briefly what

you have been researching as a
medical doctor?

Therapy for Alzheimer’s inan Aging Society

JS: It is often said by journalists
Iwatsubo: I was originally a medical doctorthat we are now within reach ofof neurology and working on patients. My
realizing a society where people
expertise is in the diseases caused by thecan continue to work in good
aging of the nervous system, and I am now
health until the age of 90, thanks
working on neuropathology and doing
to the remarkable progress ofsome experimental studies on the
medical science. Of course, wemechanism of Alzheimer’s disease and its
would need to reform our social
remedies.
systems, in particular our work
Alzheimer’s disease is a dementia caused
systems, and change ourby atrophy of the cerebral cortex. In themindset to achieve it. But if webrain, with such contraction, a number of
can manage to do it, we could
neurons are lost and two kinds of abnormal
reduce our medical costs andproteins get deposited. These abnormal
also mitigate the labor force
proteins have been a big mystery for a longshortage. Do you think such an
time and at the same time a big clue toidealistic society could becuring the disease. We have been studying
realized soon?
what kind of abnormal proteins are kept
Takeshi Iwatsubo, Professor of the Department of
there and how they are accumulated and
Iwatsubo: I can show you interesting data
Neuropathology, Graduate School of Medicine, The
how they turn into this disease. To make ain the Table describing the social andUniversity of Tokyo
long story short, we have found that one of
economic cost of Alzheimer’s disease in thethose proteins forms amyloid deposits called senile plaques and that
United States, United Kingdom and Japan. In Japan, we can calculate
this may be deeply related to the cause of Alzheimer’s disease. Today,
the number of patients with dementia at around 4.6 million, of whom
medical researchers and pharmaceutical companies are working on
60% are suffering from Alzheimer’s disease.
how to prevent this amyloid. We also discovered that this senile plaqueThe economic loss possibly caused by Alzheimer’s disease in Japanconsists of around 40 amino acids and is created by a short scrap ofmade public in 2015 amounted to 14.5 trillion yen for the year 2014. It
protein of which the longer original protein has been cut twice by two
consisted of 1.9 trillion yen in medical expenditure narrowly defined,
enzymes named secretases that gather in the brain. Therefore, we are
6.4 trillion yen in expenditure on public caregiving, and 6.2 trillion yen
now working on research to analyze the function of secretases andin informal care cost which is the sum of the costs of a patient’s family
invent a medicine to prevent it or discover a therapy to eliminate thelabor provided free of charge and loss of working opportunity for asenile plaque by using antibodies to amyloid.
patient. This figure will constantly increase from now on in light of the
spread of Alzheimer’s disease. Thus, we definitely need to make ourJapan SPOTLIGHT • May / June 201711

COVER STORY 3

best efforts to reduce the number of new dementia
patients or retard the progress of the disease at thevery early stage.
Meanwhile, we see so many aged people today ingood health, and this is certainly a reality. The Japan
Gerontological Society recently announced their
proposal that we should redefine “aged people” fromthose over 65 to those over 70 or 75. As this episodetells us, we see our enthusiasm rising today to let aged
people in good health and still full of vitality continue towork and be active and even take care of other aged
people not in good health, and above all to make ouraging society more resilient by institutional reforms,
whether or not an idealistic society can be fully realized.

TABLE

Number of patients with dementia & the
economic loss caused by the disease
US

UK

World

Japan

Population(number ofpatients)

316 million(AD 5.2 million)

64 million(Dementia:
815,000)

7 billion(Dementia >35 million)

127 million(Dementia:
4.6 million)

Total cost$214 billion$17.3 billion(26.3 billion pounds)$604 billion$120 billion(14.5 trillion yen)Contents

Direct $150 billion(Medicare$113 billion,
Medicaid$37 billion)

Medical expenditure
4.3 billion pounds

Direct $352 billion(including medical$96.4 billion)

Medical expenditure$16 billion(1.9 trillion yen)

Indirect $252 billion

Public caregiving
expenditure$55 billion(6.4 trillion yen)

Indirect $64 billion

JS: I think the percentage of patients

suffering from dementia in Japan seems
to be higher than in the US or UK, is thatright?

Sources

Iwatsubo: We cannot say so immediately, sinceresearch methodologies differ among the nations.
However, as the percentage of aged people to the total
population in Japan is higher than any other country, we would have aslightly larger number of patients suffering from dementia than othercountries. But my guess is China should have the largest number ofpatients suffering from dementia. Though it is not clear in their official
statistics, I guess so given its huge population and its population
structure by age.
JS: So dementia is truly a worldwide phenomenon to

be tackled internationally, I suppose.

Iwatsubo: Yes, exactly. It is a big issue not only among developed
nations but also among emerging nations with big populations such as
China and India. Any country in the world probably faces this issue.
JS: Thinking about how long one can be in good

health, would it be possible for a human being to live
biologically until 120 years old? If not, could medical
experts predict our life expectancy in the future? This
question is important in drawing up a blueprint for an
aging society, in particular devising an institutionalframework to enable all people living in an aging
society to be happy.

Iwatsubo: I am not quite sure how long we can live exactly. But it iscertainly true that we see an increasing number of people living ingood health over the age of 90 or 100. But the primary factor
provoking Alzheimer’s disease is aging, and so as the number of aged
people increases we would have a high risk of an increase in thenumber of patients suffering from Alzheimer’s disease.
We recently discovered an inspection method named PET (positronemission tomography) scan to detect brain amyloid (we call it amyloidbeta) that accumulates in the brain, a cause of Alzheimer’s. There is a
12 Japan SPOTLIGHT • May / June 2017

Facts and Figures2014; Alzheimer’s
Association US

Public caregiving
expenditure
10.3 billion pounds
Householdcaregiving
expenditure
11.6 billion pounds
Dementia UK:
Second edition(2014); Alzheimer’ssociety UK

Informal care cost
$53 billion(6.2 trillion yen)
World Alzheimer
Report 2010: The
Global Economic
Impact of Dementia;(Alzheimer’s Disease
International)

Ministry of Health,Labour and Welfare(Released on May,2015)

$1 = 0.68 pounds = 116.38 yencertain period during which we would not be able to find this symptomof dementia before the accumulation persists for 10 or more years,
and then memory symptoms will emerge. Generally speaking, we seesuch an accumulation of this amyloid among 10% of people in their60s, 30% in their 70s, and 50% in those over 80.
JS: So we may as well think about preventing thisdisease in our daily life without going to a doctor. For
example, would doing physical exercise or being
more careful in our eating habits be effective in
disease prevention?

Iwatsubo: According to an epidemiologic study, lifestyle-relateddiseases, or in broader sense metabolic syndrome or diabetes, thecore disease of metabolic syndrome, would increase the risk ofdementia. This is drawing much attention today, so it is good to bringlifestyle diseases under control by diet and aerobic exercises, which
can be expected to prevent dementia to a certain extent. To prevent all
diseases, we often say that we should not eat too much and takeappropriate physical exercise. This is effective for dementia as well. As
for meals, Mediterranean cuisine with fewer lipids would be better for
preventing dementia than other Western-style cuisines with more
lipids from cooking meat. However, Alzheimer disease emerges with
rapid speed of expansion and intensity and it would be difficult tocontrol it only by such prevention efforts in daily life.
JS: Would using our brains more lead to prevention ofdementia? As we get older and have less to do after
retirement, we might become depressed and use ourbrains much less than before. Would this lead tofurther deterioration of our brain functions?

Most Advanced Therapies for Alzheimer’s
JS: Could you tell us about the most advanced
therapies for Alzheimer’s disease? And how do you
assess the capacity of Japanese medical science inthis domain in comparison to global standards?
Iwatsubo: Basic research on Alzheimer’s disease in Japan was started
as early as in many countries, and our study on how amyloid isgathering in the brain has been done in parallel with other developed
nations’ research on it. However, on clinical research including
research on remedies, the US has a longer history than Japan.
At this moment, there are four medicines for Alzheimer’s disease
officially authorized to be used and all of them are medicines for
symptomatic treatment. The most well-known one is “Aricept”
produced at the end of the 1990s by Eisai, a Japanese pharmaceuticalcompany. In Alzheimer’s disease, a neuron releasing acetylcholine, oneof the substances working on neurotransmission in the brain, is
reduced and does not work well. Acetylcholine is expected to activate
neurons in the cerebral cortices which would be lost with Alzheimer’s
disease. A symptomatic treatment, in this light, is to supplement
acetylcholine and try to keep this neuron receiving it as vital as ever.
Aricept prevents acetylcholine from breaking down by blocking a
breakdown enzyme in acetylcholine.
There is another similar medicine called “Galantamine” (brand
name: Reminyl) produced by Johnson & Johnson. The Chart showsthe effect of Galantamine. The time lapse is on the horizontal axis andcognitive function on the vertical axis, showing that cognitive function
worsens as the data move downward. With Galantamine
supplementing acetylcholine, cognitive functions would improve a little
and the level of improvement would be maintained for about a year,
but after functions slowly worsen again.
What I would like you to learn from this Chart is that there is nodifference between the group with Galantamine and the group without
it regarding the speed of the worsening of cognitive functions,represented by the slope. This means that we supplement thenecessary substance running short but we cannot change the speed ofa neuron being lost.
Hereafter, I believe that we should be able to make this Chart slope
more gentle and retard the progress of the disease, even though wecannot stop it completely, if we manage to find a theory for Alzheimer’s
disease and discover a remedy to prevent the production of amyloid
beta or eliminate it by using antibodies. This is what is called
fundamental therapy or disease-modifying therapy. As of now, we havenot been able to find any medicine with a definite effect on the disease,but our R&D efforts are proceeding on this point.
JS: Younger people could also suffer from Alzheimer’s

disease. Would there be different therapies for aged
people and for younger people?

Iwatsubo: There would not be any difference. Whether a patient is oldor young, the factor of aging matters for both. The basic story is thesame: amyloid beta gathers in the brain and causes Alzheimer’s
disease, and then tau proteins gather inside a neuron and kill it andcause dementia symptoms. These two processes go together andmake Alzheimer’s disease progress. The medicines for its treatment
may be basically similar, though in the case of young patients the
progress of the disease is more rapid and its symptoms are muchworse.
JS: A possible vaccine against Alzheimer’s disease is
drawing a lot of attention today. How would it work as
a therapy?
Iwatsubo: Immune therapy for Alzheimer’s disease is to provide apatient with a specific antibody to amyloid beta. An antibody therapy toprevent amyloid beta from gathering or eliminate it in the brain has
been developed and large-scale clinical trials have been done bypharmaceutical companies to put this into practice.
At the beginning of the 21st century, a clinical trial for a remedy
using a vaccine against amyloid beta was carried out. But after having
found that human antibodies would work safely and better, we areshifting our research from vaccine therapy to antibody therapy. In

CHART

Medical effects of Galantamine
-6
-4
-2
0
2
4
6
8
10
12
14
16
18
20
22
24

Mean±SE Change from Baseline
in ADAS-cog/11 Score

Iwatsubo: We do not know yet if we can prevent the process of
Alzheimer’s disease by using the brain. On the other hand, as thehuman brain has an extremely large capacity, even if some neurons
were lost with the progress of aging or through Alzheimer’s disease,
the remaining neurons or neural circuit could work as a substitute. In
this light, I believe that how we can activate the remaining neurons inour daily life or intellectual activity would be a key to controlling
symptoms. Yes, it would certainly be crucial to the health of aged
people to maintain a high level of brain activity by socializing withothers or doing sports or being engaged in an intellectual activity.
However, even with such activities to avoid solitude among the elderly,
Alzheimer’s disease could occasionally invade a brain and stop thesepeople from enjoying those activities. We will certainly need to pursue
a more in-depth approach to this disease.

Baseline 3

Pla

ceb

Gala

og

ntam

rou

p

ine-

trea

ted

grou

p

6-month Placebo group12-month Placebo group
Estimation of decline
Galantamine-treated group.
24-32/24 mg
6

9

12

18

Time, months

24

30

36

Source: Adopted and modified from Raskind et al. The Cognitive Benefits of Galantamine Are
Sustained for at Least 36 Months: A Long-term Extension Trial, Arch Neurol. 61:252256, 2004

Japan SPOTLIGHT • May / June 201713

COVER STORY 3

December 2016, in San Diego, Eli Lilly and Co. announced theoutcome of a clinical trial at an international conference on Clinical
Trials on Alzheimer’s Disease. This trial was a large-scale one covering
2,000 people in the mild stage of Alzheimer’s dementia. The therapy
was successful in having a certain effect upon the disease, but
unfortunately the size of effect was not large enough, and then Eli Lilly
announced it would give up the clinical trials thereafter.
Alzheimer’s disease has a very long time span for progress. Theirclinical trial targeted patients at an early stage of the symptomatic
disease. Even before that stage, there is a stage of mild cognitive
impairment where forgetfulness has clearly reached a pathologic levelbut is not yet judged as dementia because no other impairment in daily
life is observed. Even at this early stage, there is an abnormal change
under progress in the brain. Thanks to PET scan, we can recognize
amyloid beta gathering even at the stage called preclinical Alzheimer’s
disease prior to mild cognitive impairment where any memory
problem has not yet emerged. Our most recent research is to try toprove that antibody therapy for those people at such a very early stageof the disease could lower the speed of the disease’s progresssignificantly.
In the US, they started a clinical trial for an antibody called
solanezumab to be used for patients at the preclinical stage, twostages earlier than that of the failed clinical trial. This is called AntiAmyloid treatment in Asymptomatic Alzheimer’s Disease (A4). This
very large-scale clinical trial was initiated by Harvard University a few
years ago and joined by pharmaceutical companies like Eli Lilly
organized as a PPP (Public–Private Partnership). The University ofTokyo Hospital also joined this experiment in September 2016. We callthis pre-emptive therapy or very early treatment, since it is a treatment
to deal with the disease at a very early stage where no clinicalsymptoms are manifested.
JS: If it is crucial for a therapy’s success to discover

the disease at an early stage, regular medical checks
for the whole nation would be necessary. That would
be very expensive.

Iwatsubo: Yes. Amyloid PET scan is the inspection method used incurrent research or clinical trials, but it is not officially approved by theauthorities yet. There are two obstacles to this inspection method
being used broadly. The first is its high price. It costs several hundred
thousand yen for each scan. The second is that we do not have any
effective medicines yet to cure Alzheimer’s disease even though we
can detect the risk of it through the scan. This raises an ethicalquestion if you cannot cure a disease even though you find the risk of
it in a medical check. So we need to develop a simpler method forinspection while pursuing studies on therapies.

Iwatsubo: I would like to mention one example in the US. There are
now two PET drugs for the diagnosis of Alzheimer’s approved by theauthorities and on a waiting list of insurance companies’ approval for
reimbursement. One is developed by a venture company, Avid
Radiopharmaceuticals acquired by Eli Lilly, and the other developed byGeneral Electric. In both cases, the key to their success was open
innovation. Large pharmaceutical companies in general would hesitate
to publish the data of clinical trials, since they would not want to see
undesirable data made public. By contrast, venture businesses would
be very active in publishing their data on clinical studies, since theywant the US ADNI (Alzheimer’s Disease Neuroimaging Initiative), a
group of medical researchers working on Alzheimer’s disease, to use
their developed medicines in clinical studies as much as possible. As
one of them was used in a number of academic studies and then by
mega-pharmaceutical companies as well, the medicine became a defacto standard and the venture that developed it was finally acquired
by Eli Lilly, a mega-pharmaceutical company. This is certainly one way
for a venture to achieve business success.
In Japan, we at J-ADNI also founded a consortium in collaboration
with the New Energy and Industrial Technology Development
Organization (NEDO), a Japanese public organization. It was joined bymost Japanese pharmaceutical companies and imaging diagnosis
companies, together with academia in Alzheimer’s clinical medicine.
Among those companies, MICRON Inc. (Molecular Imaging CRO
Network), the first Japanese contract research organization to support
clinical trials with its expertise in imaging diagnosis, has been working
on standardizing amyloid PET scan and promoting it. This company
achieved a big business success by participating in this project. It was
successful in raising its market share and is now playing a key role in aclinical experiment on a fundamental therapy.
JS: PPP or open innovation seem to be the key tosuccess in containing the enormous costs of dealing
with Alzheimer’s disease, don’t they?
Iwatsubo: Yes. That is exactly what the US is doing now and they
initiated this process as a pioneer. In Japan as well we have started
talking about creating a new platform on dementia based on PPP. As
I told you, the battle against dementia must be considered from thelong-term perspective, and so the Ministry of Health, Labour andWelfare founded a research team headed by a well-known
nephrologist, Dr. Kiyoshi Kurokawa, emeritus professor of the
University of Tokyo’s Graduate School of Medicine, and we havestarted talking about how PPP should work in our project. Given thatprevention of Alzheimer’s disease will be vital to the success of ourbusiness community as well, we would encourage our businessleaders to be actively engaged in our project as a part of our PPP.

Role of Ventures in Containing Alzheimer’s
JS: PPPs could be very important in that case to deal

with costs. Ventures could also be expected to play arole in such partnerships. What do you think about
the role of ventures in this area in Japan?

14 Japan SPOTLIGHT • May / June 2017

Written with the cooperation of Naoko Sakai who is a freelance writer.