Update on Alzheimer’s Research
and Clinical Trials
Dr Cathy Short
Neurologist
Memory Disorders Unit
Department of Neurology
The Queen Elizabeth Hospital
September 2015
INTRODUCTION
• There are more than 342,800 Australians living with dementia
• This number is likely to approach 1 million by 2050 unless
there is a significant breakthrough in treatment
• As of 2015, there are 46.8 million people with dementia
worldwide
• This number is expected to double every 20 years to approx.
74.7 million people in 2030 and 131.5 million in 2050
• Total estimated worldwide cost of dementia as of 2015 is
US$818 billion
• This cost has increased by 35% since it was last estimated in
2010
AD Research
AD research continues both here and internationally in many different
areas
We will review some of the following:
• treatment - drugs
- non- pharmacological therapies
• prevention - epidemiology
- risk factors
• diagnosis - Genetics
- biomarkers (imaging, CSF, serum)
Current medication for AD
• 24 years after the first descriptions of the therapeutic
benefits of tacrine ( one of the first AChEI’s) we still only
have symptomatic therapies for AD.
• Only 4 drugs are regularly used for AD: donepezil,
galantamine, rivastigmine and memantine.
• No new drug has been marketed for nearly 20 years
• One of the major obstacles to progress in this field is a
lack of understanding as to exactly what causes AD
Alzheimer’s Disease Theories
• A number of theories have been proposed to explain the
cause of AD but to date, no one theory can adequately
explain all aspects of the disease
• Precise mechanisms for AD progression are also unclear
• There are 3 major theories (Cholinergic, Amyloid, Tau)
that are currently regarded as the most likely explanation
for AD
• They are being used as the basis for therapeutic
development
AD Pathology
• Histopathologically, when we examine brain tissue
under a microscope the 2 hallmarks of Alzheimer’s
disease are extracellular amyloid plaques and intraneuronal neurofibrillary tangles (NFTs) composed
of tau
• Described in 1907 by Alois Alzheimer they remain
the major pathological abnormalities seen in AD
Amyloid Cascade Hypothesis
• This has been the main focus of research to date
• Beta-amyloid (Aβ) is the main component of
amyloid plaques (one of the pathological hallmarks
of AD)
• Scientists now have a detailed understanding of how
this protein fragment is clipped from it’s parent
compound amyloid precursor protein (APP) by two
enzymes – beta-secretase and gamma-secretase
• Researchers are developing medications aimed at
every point in the amyloid processing pathway
• It has been postulated that after the deposition
of amyloid plaques that a cascade ensues
• This leads to inflammation and ultimately
formation of neurofibrillary tangles (NFT’s) –
the other major hallmark of AD
• This causes problems with neurotransmitters
and neuronal function in the brain and
ultimately neurone death
Anti-Amyloid strategies Immunotherapy
• Initial studies showed that injecting animals with
beta-amyloid lead to a good antibody response and
clearing of the amyloid plaques from their brains
• Subsequent human studies were prematurely ceased
(2002) due to development of brain inflammation
(meningoencephalitis) in 6%
• However, there was evidence that the treatment had
removed amyloid plaque
• The concept of active immunisation hasn’t been
abandoned yet – several pharmaceutical companies
are in the early phases of developing new active
vaccines
Anti-amyloid strategies immunotherapy
• As an alternative to actively immunising with
beta-amyloid, the next studies looked at “passive
immunisation”
• This bypasses the need to respond to an antigen
• Passive immunotherapy remains the leading
approach today to disease–modifying treatment
for AD
• These monoclonal antibodies target various
domains of the beta-amyloid peptide and
prevent aggregation or speed up removal
Monoclonal antibodies
• To date, a number of monoclonal antibodies have
been studied in clinical trials including
bapinezumab and gantenerumab but were stopped
prematurely due to lack of perceived efficacy
• However analyses of some subgroups have shown
benefits that have lead to further studies
• There are still a number of other monoclonal
antibodies that are being actively studied and some
are showing early positive results– solanezumab,
crenezumab and adecanumab – we await the
outcomes of these studies
Anti-amyloid strategies
– reducing production
• Another approach to reducing the amount of
amyloid in the brain is to reduce the production
• Inhibiting the enzymes that help produce
amyloid-beta will lead to less being produced
• BACE inhibitors specifically inhibit the betasecretase enzyme involved in the amyloid
cascade.
• There are a number of studies in progress (at
TQEH and RAH) at the moment looking at the
benefits of BACE inhibition in AD
Anti-amyloid strategies
– reducing production
• Drugs have also been developed to inhibit gamma-secretase – the
other main enzyme involved in producing beta-amyloid
• There have been problems with unwanted side-effects from these
agents – skin cancer, rash and hair discolouration
• Semagacestat showed promise in early trials but failed to show
benefit in phase 3 trials
• Two other gamma-secretase inhibitors have also failed to show
benefit
• Pharmaceutical companies are currently working on developing
more highly selective gamma-secretase inhibitors that will cause
less side effects and inhibit beta-amyloid production more
effectively
Anti-amyloid strategies – inhibiting
aggregation
• Curcumin (a substance in the spice Turmeric) –
has anti-oxidant, anti-inflammatory and antiaggregation properties
• It binds beta-amyloid and reduces amyloid
plaque burden in mice
• Phase 2 trial is ongoing – if effective – it may be
a favoured therapy as toxicity is low
Tau
• Far fewer drug trials have focussed on tau
• Interest has grown recently because of difficulties with antiAβ treatments
• Mouse and primate models of AD show amyloid plaques that
respond to anti-amyloid therapy but these animal models
don’t replicate the tau pathology seen in human AD
• Aged dogs develop an AD-like disorder with amyloid and
NFT’s
• Treatment of these animals with anti-amyloid therapies
reduces plaque load but doesn’t alter cognition or change tau
pathology
• There is a very robust correlation between tau pathology and
clinical measures of dementia
Methylthioninium Chloride
(Methylene Blue)
• First drug targeting tau
• Drug is derived from the dye used to stain NFT’s
in neuropathological studies
• Primarily inhibits tau aggregation
• Phase 2 study showed cognitive benefits
• SPECT and FDG-PET results also encouraging
• Phase 3 trial for mild-moderate AD (both TQEH
and RAH finished recruiting) will be finished
February 2016
Other tau therapies
• Several other drugs that inhibit the development of
tau have been studied
• Observational studies in geriatric patients taking
chronic lithium for BPAD were found to have
reduced risk of developing AD
• Lithium inhibits chemical changes in tau that leads
to formation of NFT’s
• Studies on Lithium have been mixed – some have
shown benefit with very low doses in mild cognitive
impairment, others have shown worsening
confusion – further studies are needed
Other tau therapies
• Tau immunisations have been studied in animal
models and have shown a reduction in the
amount of tau and also clinical benefits
– Phase I trials are beginning
Neurotransmitters and Receptors
• 5HT6 (serotonergic) receptor in the brain is a
promising drug target for Alzheimer’s Disease
• There is good evidence that this receptor is involved
in memory and learning
• Antagonism of this receptor causes modulation of a
number of other neurotransmitters (DA, ACh, NAd)
and pathways in the brain
• Phase II trials showed improved cognition with the
addition of a 5HT rec. antagonist in moderate AD
patients already on donepezil
• Phase III trials are currently underway – recruiting
at TQEH (for patients on any AD treatment)
Inflammation in Alzheimer's
Disease
• All chronic neurodegenerative disorders and aging
involve inflammation, oxidative stress and cellular
dysfunction
• Leads to impaired function and loss of brain cells
• These brain cells are no longer able to participate in
neuronal networks needed for cognitive, behavioural
and motor function
• Leads to self-perpetuating cycle of cellular injury
and predisposition to further insults
• Some research suggests that these inflammatory
processes are the underlying cause of AD and that it
leads to Aβ and tau accumulation
Anti-inflammatory therapies
• Markers of inflammation have been recognised
in AD for a long time
• Large epidemiological studies have
demonstrated a lower prevalence of AD in long
term users of NSAID’s
• Large number of therapeutic trials of NSAID’s in
AD (1993-2004) incl: Ibuprofen, indomethacin,
naproxen, celecoxib ,rofecoxib and other anti –
inflammatory meds such as prednisolone
• All were negative
Anti-Inflammatory Therapy
• Primary prevention study (Alzheimer’s Disease Antiinflammatory Prevention Trial or ADAPT) of naproxen,
celecoxib and placebo in cognitively normal elderly with
a first degree relative with dementia
• prematurely suspended -↑ cardiac and cerebrovascular
events
• Both drugs failed to ↓ incidence of AD after 2 years of
treatment
• 4 year follow-up found those exposed to naproxen were
protected from onset of AD by 67% c/w placebo
• NSAID’s not considered to be practical treatment option
for AD – tolerability and safety issues
Vitamins and Anti-oxidants
• To date there has been insufficient evidence that low
levels of vitamin B12 in elderly ↑ risk for dementia or
that supplements improve performance
• Again, studies looking at folate supplementation
have been inconsistent
• In 2014 a group of Oxford University researchers
assembled all the best clinical trial data involving
22,000 people and concluded that taking B vitamins
and folate doesn’t slow mental decline as we age, nor
is it likely to prevent AD
Vitamins and Anti-oxidants
• Vitamin D – primarily has functions in bone
health and metabolism but may also have antioxidant and anti-inflammatory properties
• not clear whether Vitamin D deficiency is
causally related to cognition or is a marker for
another process
• not confirmed that Vitamin D supplementation
will have positive effect on cognition
Vitamins and Anti-oxidants
• Vitamins E, C and beta-carotene (pre-cursor for
Vitamin A) – all powerful anti-oxidants
• Epidemiological studies show that low intake is
associated with ↑ dementia risk but association
remains inconsistent
• Multiple clinical trials provide evidence that
supplements with these compounds did not alter
cognitive outcomes in MCI, AD or healthy elderly
but results still debated
• Concern about cardiovascular risk of Vitamin E are
likely to prevent further studies of this in AD
Vitamins and Anti-oxidants
• Ginkgo-biloba has been studied in trials
• Reasonably firm evidence that it does not alter
the risk of dementia or improve cognitive
performance in healthy elderly
• Potential side-effects of bleeding tendency and
drug interactions
Vitamins and Anti-oxidants
• Omega-3 fatty acids found in fish oil and nuts –
thought to be neuroprotective
• Studies have failed to show any improvement in
cognition in AD patients
• In elderly without AD – inconclusive evidence
that they may slow cognitive decline
• Further large –scale studies needed
Mediterranean diet
• This diet is rich in fruits, vegetables, olive oil,
legumes, whole grains and fish
• Studies have shown that people that closely follow a
Mediterranean diet are less likely to have AD than
those who don’t
• Research suggests that a Mediterranean diet may –
-slow cognitive decline in older adults
-reduce the risk of MCI progressing to AD
-slow the progression of AD and
prevent disease-related deaths
Diet in Alzheimer’s Disease
• A recent study looked at 3 different diets:
1. Mediterranean diet
2. DASH diet (designed to treat hypertension –
low salt and sugar)
3. MIND diet (Combination of the above 2 diets)emphasizes natural plant-based foods, limited
saturated fats, encourages consumption of berries
and green leafy vegetables (known to specifically
benefit brain health)
Diet in Alzheimer’s Disease
• People that strictly followed any of these 3 diets had a lower
risk of AD
• Even a modest adoption of the MIND diet approach such as
eating 2 vegetable servings per week, 2 berry servings per
week and one fish meal per week appeared to lower the risk of
AD
• Researchers speculate that making healthy food choices may
improve cholesterol and blood sugar levels and overall vessel
health which may in turn reduce risk of MCI and AD
• Another theory is that a Mediterranean diet may help prevent
brain tissue loss
• More studies are needed to know to what degree this diet
prevents AD or slows cognitive decline
“Brain Training”
• This is quite broad and can include a range of structured
mentally stimulating activities such as:
 crosswords
 learning a new language
 reading a book
 undertaking further education
 dedicated computerised brain training activities that focus on
memory, attention or other cognitive functions
• Recent studies have found that “computerised brain training”
is only modestly effective at improving cognitive performance
in healthy older adults
• Further studies are about to start to see whether intensive
computerised training can stop the progress of cognitive
decline and the onset of dementia
Physical Activity
• Research into potential for physical exercise to
reduce the risk of dementia is continuing
• There are still no randomised trials available yet –
several studies have found that physical activity in
early, mid and later life is associated with lower risk
of cognitive decline and dementia
• Other studies have found that people who exercise
experience a slower loss of brain tissue as they age.
• In addition people who exercise regularly are less
likely to have cerebro- and cardio-vascular disease
which is associated with increased risk of AD
Physical Activity
• It is also beneficial in patients that have dementia
• It can help prevent muscle weakness, mobility
problems and other health complications associated
with inactivity
• It also helps reduce symptoms of stress, anxiety
and depression
• 3 types of exercise should be included in the
program– sustained aerobic exercise, weight
training and flexibility and balance training
• If an exercise program is incorporated in the early
stages of dementia it is more likely to be maintained
as the condition progresses
Insulin Resistance
• Insulin resistance and the way the brain
processes insulin may be linked to AD
• Researchers are exploring the role of insulin in
the brain and closely related questions of how
brain cells use sugar and produce energy
• Researchers have been studying diabetic
medications such as pioglitazone which also has
potent anti-inflammatory effects
Insulin resistance
• Preliminary studies with pioglitazone have had
mixed results but there is a worldwide phase 3
study underway (site in Melbourne)
• The study is looking at cognitively normal
patients who are considered at risk of developing
AD and giving either pioglitazone or placebo and
giving placebo to those considered low risk
• We await the results
Vascular disease and Alzheimer’s
• It is well known now that vascular risk factors
including hypertension, heart disease, smoking,
high cholesterol, obesity, stroke and diabetes are
also risk factors for Alzheimer's disease.
• The relationship between vascular disease and
AD is complex and still not fully understood
• It is likely that vascular disease in the brain
lowers the threshold for the clinical expression
of AD pathology
Vascular disease and Alzheimer’s
• Some observational studies have shown that the rate of
cognitive decline in AD is reduced with better
management of vascular risk factors but results have
been inconsistent
• Larger randomised controlled trials are needed over
longer periods of time to determine effectiveness of
treatment of vascular risk factors in AD
• The Finnish Geriatric Intervention Study to Prevent
Cognitive Impairment and Disability (FINGER study) is
one such study that is showing promising preliminary
results at 2 years
• Preventative study looking at benefits of a combination
of diet, exercise, cognitive training and vascular risk
factor monitoring in an “at risk” population
Research in Familial Alzheimers
Disease
• There are 3 known mutations that cause FAD – this
accounts for less than 5% of all cases of AD
• There are several new studies looking at antiamyloid drugs in asymptomatic patients who either
have one of the known rare genetic mutations or are
at very high risk of developing AD based on their
family history
• It is hoped that these studies will give us more
insight into whether treatment at the asymptomatic
stage will prevent later development of AD
Alzheimers Prevention Initiative
• The Alzheimers Prevention Initiative (API) is an
international consortium established to conduct
research into an extended family (5000
members) in Colombia South America
• This family carry the presenilin 1 mutation that
affects amyloid processing
• API are performing a study on asymptomatic
individuals that carry the PS1 mutation using the
monoclonal antibody crenezumab vs. placebo
• This is a five year study and is still recruiting
Dominantly Inherited Alzheimer
Network (DIAN)
• DIAN is an international initiative funded by the
National Institute on Ageing (NIA) in the USA.
• The network tracks individuals from families in whom
an AD mutation has been identified
• One of their goals is to detect physical or mental changes
that distinguish those who inherit a mutation from those
who do not.
• The DIAN-TU study is looking at asymptomatic patients
with a known mutation or at very high risk of developing
AD and treating them with one of 2 monoclonal
antibodies (solanezumab and gantenerumab) vs. placebo
• This study is still recruiting (one site in Australia at the
Austin Hospital) and is due for completion end 2019
Biomarkers
• Making a diagnosis of Alzheimers disease is still
essentially a clinical diagnosis
• It is not a difficult diagnosis to make when the disease is
clinically obvious but it can be challenging when the
disease presentation is atypical or a patient presents at a
very early stage
• Having a diagnostic biomarker available would avoid any
uncertainty and allow a definitive diagnosis to be made.
• In addition to investigating experimental drugs, there
are a range of clinical trials in progress examining
various brain imaging techniques (eg. amyloid and tau
PET) as well as the testing of a range of potential
biomarkers in CSF and blood
Biomarkers
• Researchers hope that these techniques will one day
provide methods to definitively diagnose AD in it’s
earliest and most treatable stages
• Ideally we could diagnose before symptoms appear and
start treatment in this asymptomatic phase before
significant neurodegeneration has occurred
• We now know that the pathological changes of AD (seen
on amyloid PET scans) can start up to 20 years before
cognitive symptoms appear
• This is perhaps why many trials done later in the disease
have not been effective
• Biomarkers may also eventually offer better methods to
monitor response to treatment
Outlook
• There are often no simple solutions to complex
problems and AD is a good case in point
• Clinical trial results to date have been disappointing
for several reasons:
 our understanding of the pathophysiology , the
range of causes and how AD progresses from preclinical to advanced disease is still limited.
 too great a focus on amyloid-directed therapy –
need to look at non-amyloid targets such as tau,
antioxidants/neuroprotectants and others
 giving treatment too late in the disease process
Outlook
• In the future, AD may be treated like other chronic diseaseswith a mixture of disease-modifying and symptomatic
therapies used in combination and in sequence
• Likely scenario could be:
 Start AChEI
 Add a disease-modifying drug eg. monoclonal ab
 Change to another disease-modifying drug if disease
progresses
 Consider changing/ adding another agent such as a BACE
inhibitor or 5HT receptor antagonist
• Limitations will be adverse effects and affordability
Outlook
• Although there have been many obstacles and
setbacks along the way to developing treatment
for AD – the future still looks promising
• We are hopeful that an effective treatment will
become available in the near future
• Trials of several promising agents are in
progress here and internationally
Clinical Trials in AD
• RAH and TQEH currently both have AD clinical
trials centres
• Soon we will be combining to one large AD trials
centre based at TQEH
• Clinical trials will be co-located with a large Multidisciplinary Memory Service
• This will be known as the Central Adelaide Local
Health Network (CALHN) Memory Service and will
provide a multi-disciplinary approach to diagnosing
and managing dementia with ongoing support for
patients and their carers through a case manager.
Current RAH AD trials
• Merck – mild to moderate AD – BACE inhibitor
– 2 years plus extension study
• Merck –prodromal AD – BACE inhibitor – 2
years plus extension study
• Marguerite road study – mild AD –monoclonal
antibody (Gantenerumab)– 2 years
• AMARANTH – prodromal/mild AD – BACE
inhibitor – 2 years
• AZTherapies – prodromal AD -cromolyn sodium
(intal) / ibruprofen (brufen) – 2 years
Clinical Trials at TQEH
• Merck – mild to moderate AD – BACE inhibitor – 2
years plus extension study
• Lundbeck- moderate AD (MMSE 12-22) – 5HT
receptor antagonist (Idalopiridine) -6 months actively recruiting
• Marguerite Road – mild AD – monoclonal antibody
(Gantenerumab) – 2 years
• Roche – monoclonal antibody (Crenezumab) – in
planning stages – to start Dec 2015/Jan 2016
THANK YOU
Please contact TQEH Memory Disorders Unit and
Clinical Trials
Ph: 82226748, Fax: 82226435
Or RAH Clinical trials centre
Ph : 8222 2798 Fax :8222 2799
Any new referrals for diagnosis, treatment or
involvement in clinical trials
Patient and carer support for clinical trials is an
important part of finding a cure for AD!