1. Update on Alzheimer’s Research and Clinical Trials
Dr Cathy Short
Neurologist
Memory Disorders Unit
Department of Neurology
The Queen Elizabeth Hospital
September 2015

2. 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 million people in 2030 and 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

3. 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)

4. 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

5. 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

6. AD Pathology
Histopathologically, when we examine brain tissue under a microscope the 2 hallmarks of Alzheimer’s disease are extracellular amyloid plaques and intra- neuronal neurofibrillary tangles (NFTs) composed of tau
Described in 1907 by Alois Alzheimer they remain the major pathological abnormalities seen in AD

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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 beta- secretase 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

13. 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

14. Anti-amyloid strategies – inhibiting aggregation
Curcumin (a substance in the spice Turmeric) – has anti-oxidant, anti-inflammatory and anti- aggregation 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

15. Tau Far fewer drug trials have focussed on tau
Interest has grown recently because of difficulties with anti- Aβ 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

16. 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

17. 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

18. 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

19. 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)

20. 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

21. 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 ( ) incl: Ibuprofen, indomethacin, naproxen, celecoxib ,rofecoxib and other anti – inflammatory meds such as prednisolone
All were negative

22. Anti-Inflammatory Therapy
Primary prevention study (Alzheimer’s Disease Anti- inflammatory 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

23. 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

24. Vitamins and Anti-oxidants
Vitamin D – primarily has functions in bone health and metabolism but may also have anti- oxidant 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

25. 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

26. 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

27. 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

28. 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

29. 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)

30. 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

31. “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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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 anti- amyloid 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

39. 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

40. 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

41. 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

42. 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

43. 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 pre- clinical 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

44. Outlook
In the future, AD may be treated like other chronic diseases- with 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

45. 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

46. 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 Multi- disciplinary 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.

47. 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

48. 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

49. THANK YOU
Please contact TQEH Memory Disorders Unit and Clinical Trials Ph: , Fax: Or RAH Clinical trials centre Ph : Fax : 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!