1. Update on Alzheimer’s Research and Clinical Trials
Dr Cathy Short
Neurologist
CALHN Memory Service
Department of Neurology
The Queen Elizabeth Hospital
September 2017
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2. INTRODUCTION > 342,800 Australians living with dementia
Will approach 1 million by 2050 unless significant breakthrough in treatment
As of million people with dementia worldwide
Expected to double every 20 years to approx.
74.7 million in 2030
131.5 million in 2050
Total estimated worldwide cost of dementia in → US$818 billion
Cost has increased by 35% since last estimated in 2010
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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. How long does it take to market a new drug?

5. Clinical Trial phases

6. Current medication for AD
Benefits of Acetylcholinesterase Inhibitors (AChEI’s) first described 24 years ago
Still only symptomatic therapies for AD.
Only 4 drugs available for AD: donepezil, galantamine, rivastigmine and memantine
No new drug has been marketed for nearly 20 years
lack of understanding as to exactly what causes AD – major problem in finding treatment

7. Alzheimer’s Disease Theories
Several theories proposed to explain the cause of AD but so far, no one theory can adequately explain all aspects of the disease
Precise mechanisms for AD progression are also unclear
3 major theories (Cholinergic, Amyloid, Tau) currently regarded as the most likely explanation for AD
being used as the basis for therapeutic development

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

9. Amyloid Cascade Hypothesis
Main focus of research to date
Beta-amyloid (Aβ) is the main component of amyloid plaques (pathological hallmark of AD)
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

10. Aβ cascade hypothesis
Postulated that after amyloid plaques are deposited a cascade follows
Causes inflammation and ultimately formation of neurofibrillary tangles (NFT’s) (hallmark of AD)
Problems with neurotransmitters and neuronal function in the brain and ultimately neurone death

11. New theories about AD Pathology
We now know that tau accumulates in the medial temporal lobes of the brain during normal ageing
Tau doesn’t extend beyond the MTL until Aβ is present in the cortex
Tau PET scanning has allowed us to potentially stage AD in vivo
Amount of tau in the brain correlates very closely with degree of cognitive impairment

12. Anti-Amyloid strategies - Immunotherapy
Initial studies - injecting animals with Aβ → good ab response →cleared amyloid plaques from brains
Human studies prematurely ceased (2002) →development of brain inflammation (meningoencephalitis) in 6%
BUT -evidence that treatment had removed amyloid plaque from the brain
Idea of active immunisation not abandoned – several pharmaceutical companies early phases of developing new active vaccines

13. Anti-amyloid strategies - immunotherapy
Alternative to actively immunising with Aβ, is “passive immunisation”
Bypasses the need to respond to an antigen
Passive immunotherapy leading approach today for disease–modifying treatments
Monoclonal antibodies target various domains of the Aβ peptide to prevent aggregation or speed up removal

14. Monoclonal antibodies
Several monoclonal antibodies have been studied in clinical trials including bapineuzumab and gantenerumab
Stopped prematurely due to lack of perceived efficacy
Subgroups did show benefits leading to further studies
Lack of efficacy thought to be due to underdosing.
Recently restarted studies with Gantenerumab in the same patient group but using larger doses

15. Monoclonal antibodies
Several active ongoing studies
Some early positive results– solanezumab, crenezumab and adecanumab – we await the outcomes of these studies in MCI/mild AD
Phase 3 Solanezumab: failed to meet primary endpoints and slow cognitive decline in AD patients. Trials of this drug are now continuing in prodromal AD patients (the A4 study) – higher doses extending for 3 years.
Phase 3 Adecanumab studies will run until 2022
Phase 3 Crenezumab studies are still recruiting worldwide

16. Anti-amyloid strategies – reducing production
Another approach to reducing the amount of amyloid in the brain is to reduce the production
Inhibiting enzymes that help produce Aβ means less is produced
BACE inhibitors specifically inhibit the beta- secretase enzyme in the amyloid cascade.
There are a number of studies in progress (at TQEH and RAH) looking at the benefits of BACE inhibition in mild AD

17. Anti-amyloid strategies – reducing production
Other drugs inhibit gamma-secretase – the other main enzyme involved in Aβ production
Problems with unwanted side-effects – skin cancer, rash and hair discolouration
Semagacestat showed promise in early trials but failed to show benefit in phase 3 trials
2 other gamma-secretase inhibitors have also failed to show benefit
Scientists are still developing more highly selective gamma-secretase inhibitors with less side effects and more effective inhibition of Aβ production.

18. Anti-amyloid strategies – stopping aggregation
Curcumin (a substance in the spice Turmeric) – anti-oxidant, anti-inflammatory and anti- aggregation properties
It binds Aβ and reduces amyloid plaque burden in mice
Preliminary results show reduced rate of cognitive decline in normal healthy elderly receiving curcumin compared to placebo – only short time frame (6 months) and small numbers – larger studies needed.
Limited studies in AD patients have so far failed to show any benefit clinically.

19. Tau Far fewer drug trials have focussed on tau
No luck so far with anti-Aβ treatments → greater interest in tau
Mouse and primate models of AD show amyloid plaques that respond to anti-amyloid therapy but no tau pathology like human AD
Aged dogs develop AD-like disorder with Aβ and NFT’s
Treatment of these animals with anti-Aβ therapies reduces plaque load but no change in cognition or tau pathology
There is a very robust correlation between tau pathology and clinical measures of dementia

20. Methylthioninium Chloride (Methylene Blue)
First drug targeting tau
Derived from the dye used to stain NFT’s in neuropathological studies
Inhibits tau aggregation
Phase 2 study showed cognitive benefits
Phase 3 trial for mild-moderate AD (both TQEH and RAH) finished February 2016– failed to slow cognitive or functional decline in mild-moderate AD
30% drop-out due to side-effects
2nd generation compound (TRx0237) currently in Phase 3 trials for AD and FTD

21. 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 ↓ risk of developing AD
Lithium inhibits chemical changes in tau that causes formation of NFT’s
Studies on Lithium have been mixed – some have shown benefit with very low doses in MCI, others →worsening confusion – further studies are needed

22. 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
Small number of tau immunotherapies currently in phase 1 and 2 testing.
Initial reports are there are no serious adverse effects but still very early

23. Neurotransmitters and Receptors
5HT6 (serotonin) receptor →promising drug target for Alzheimer’s Disease
Good evidence it’s involved in memory and learning
Antagonism of this receptor→ increase in ACh.
Phase 2 trials showed improved cognition with 5HT rec. antagonist in moderate AD patients already on donepezil
Phase III studies failed to reproduce this result.
Ongoing studies looking at lower doses and giving different AChEI’s

24. Inflammation in Alzheimer's Disease
All chronic neurodegenerative disorders and ageing involve inflammation, oxidative stress and cellular dysfunction
→impaired function and loss of brain cells
Brain cells no longer able to participate in neuronal networks needed for cognitive, behavioural and motor function
→self-perpetuating cycle of cell injury and ↑ likelihood of more damage
Some research suggests that these inflammatory processes →Aβ and tau accumulation and AD.

25. 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

26. Anti-Inflammatory Therapy
Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) → primary prevention study 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

27. Anavex 2-73 Media-hype about this trial drug last year
Effects sigma-1 receptors – involved in multiple cellular pathways and physiological processes.
Studies in mice → memory-preserving and neuroprotective effects.
32 patients, phase 2, 52 week study (Melbourne only) mild-moderate AD → improvements in psychomotor function, attention and working memory. Also improved mood, decreased agitation
Phase 3 double-blind, placebo controlled trial CALHN memory Trials late 2017

28. Vitamins and Anti-oxidants – B12 and Folate
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

29. Vitamins and Anti-oxidants- Vitamin D
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
Early laboratory evidence that Vitamin D receptor may help regulate clearance of Aβ from the brain
No firm scientific evidence yet that Vitamin D supplementation will have positive effect on cognition

30. Vitamins and Anti-oxidants- E,C,A
Vitamins E, C and beta-carotene (pre-cursor for Vitamin A) – all powerful anti-oxidants
Epidemiological studies show that low intake ↑ 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

31. Vitamins and Anti-oxidants- Ginkgo Biloba
Ginkgo biloba has been studied in trials with mixed results.
Some studies have suggested it improves cognitive performance in MCI
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

32. Vitamins and Anti-oxidants- Fish oil
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

33. Mediterranean diet
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

34. Diet in AD 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)

35. Diet in Alzheimer’s Disease
Those who strictly followed any of these 3 diets had ↓ risk of AD
Even modest adoption of MIND diet approach eg. 2 vegetable servings/week, 2 berry servings/week, 1 x fish meal/week → ↓ risk of AD
Researchers believe making healthy food choices →improved cholesterol and blood sugar levels, better overall vessel health →reduced risk of MCI and AD
Another theory →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

36. Souvenaid
Medical nutrition supplement specifically for Mild AD→ Omega-3 polyunsaturated FA’s, Uridine, monophosphate, choline, B vitamins and a range of other nutrients
Supports neurones and connections in the early stages of AD
Studies →modest benefits on cognition, memory and daily function in subset of patients in earliest stages of AD
Also delayed shrinkage of hippocampus (important in STM)

37. “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
Combining mental, social and physical activity in leisure activities are best for reducing dementia risk
dedicated computerised brain training activities →modest effect at improving cognitive performance in healthy older adults
Can intensive computerised training stop progress of cognitive decline and onset of dementia? studies ongoing

38. Physical Activity
Research into potential for physical exercise to reduce the risk of dementia is continuing
Still no randomised trials available yet –several studies have found that physical activity in early, mid and later life is associated with ↓ risk of cognitive decline and dementia
Other studies found people who exercise have slower loss of brain tissue as they age.
People who exercise regularly are less likely to have vascular disease which ↑’s risk of AD

39. Physical Activity Also beneficial in patients that have dementia
Helps prevent muscle weakness, mobility problems and other health complications associated with inactivity
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

40. Physical Activity
If an exercise program is incorporated in the early stages of dementia it is more likely to be maintained as the condition progresses
Exercise needs to be continued on a regular basis, long term to see benefits on cognition.
Regular aerobic type exercise confers the most benefit for delaying cognitive decline and slowing brain atrophy

41. 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 how brain cells use sugar and produce energy
Researchers have been studying diabetic medications such as pioglitazone which also has potent anti-inflammatory effects

42. Insulin resistance
Preliminary studies with pioglitazone have had mixed results but there is a worldwide 5 year phase 3 study underway (site in Melbourne)
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
This study is ongoing and we await the results

43. Vascular disease and Alzheimer’s
Vascular risk factors including
hypertension
heart disease
smoking
high cholesterol
obesity
stroke
diabetes
are also risk factors for Alzheimer's disease.
Relationship between vascular disease and AD is complex and not fully understood
vascular disease in the brain thought to lower threshold for clinical expression of AD pathology

44. Vascular disease and Alzheimer’s
Observational studies→ rate of cognitive decline in AD ↓ if vascular risk factors better managed but results inconsistent
Larger, longer randomised controlled trials needed to determine effectiveness of treatment of vascular risk factors in AD
Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER study) →preventative study
→ combination of diet, exercise, cognitive training and vascular risk factor monitoring in an “at risk” population.
Early 2 year results look promising
Now expanding to UK, Singapore, China and USA

45. Research in Familial Alzheimers Disease
3 known mutations that cause FAD – accounts for less < 5% of all cases of AD
Several new studies looking at anti-amyloid drugs in asymptomatic patients with either:
one of the known rare genetic mutations OR
strong FHx of AD
will give us more insight into whether treatment at the asymptomatic stage will prevent development of AD

46. Alzheimers Prevention Initiative
Alzheimer’s Prevention Initiative (API) international consortium established to conduct research into an extended family (5000 members) in Colombia South America
Family carry the presenilin 1 (PS1) mutation- effects 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

47. Dominantly Inherited Alzheimer Network (DIAN)
International initiative funded by the National Institute on Ageing (NIA) in US.
Tracks individuals from families with known AD mutations
Are there physical or mental changes that distinguish those with mutation from those without?
DIAN-TU study- asymptomatic patients with
known mutation or
very high risk of developing AD
Treatment either:
solanezumab or ganteneurumab vs. placebo
Still recruiting (one site in Australia at the Austin Hospital) - due for completion end 2019

48. Biomarkers Diagnosing AD is still essentially clinical
Diagnosis - straight forward if clinically obvious but is challenging when atypical or in very early stages
Diagnostic biomarker would avoid uncertainty and allow definitive diagnosis.
Several clinical trials in progress examining:
brain imaging techniques (eg. Aβ and tau PET)
biomarkers in CSF and blood
Retinal scanning techniques (OCT, angiography)

49. Biomarkers
Access to biomarker →definitive Dx of AD in earliest and most treatable stage
Dx in pre-symptomatic phase would be best outcome → starting treatment before irreversible neurodegeneration has occurred
Pathological changes of AD ( on Aβ PET scans) can be seen up to 20 years before cognitive symptoms appear
Maybe why many trials done in mild-moderate AD have not been effective
Biomarkers may also eventually offer better ways of monitoring response to treatment

50. Outlook
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:
understanding of pathophysiology, range of causes and how AD progresses from pre- clinical to advanced disease still limited.
too much 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

51. 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

52. 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

53. Clinical Trials in AD
RAH and TQEH– have combined their clinical trials units and is now the CALHN Memory Trials Unit.
Majority of trials now focus on treatment in the early stages of AD
Trials are currently based across 2 sites – TQEH and nRAH within the next month.
We are hopeful for a presence at SAHMRI 2 in the next few years
Clinical trials are co-located with the Central Adelaide Local Health Network (CALHN) Memory service (CMS) also based at TQEH.

54. Current recruiting AD trials
EARLY study –cognitively normal prevention study, first degree relative with AD ideal but not necessary. BACE inhibitor
CREAD II – prodromal/mild AD, monoclonal ab (Crenezumab) (MMSE 22-30). First stage finished recruiting – will restart late 2017.
(Hopefully Anavex will start recruiting later this year)

55. Clinical Trials in progress
ROCHE (Marguerite Rd and Scarlett Rd) – Gantenerumab (monoclonal ab) in mild AD – Open label extension
MERCK - prodromal AD – BACE inhibitor
AMARANTH – prodromal/mild AD – BACE inhibitor – 2 years

56. DON’T JUST HOPE FOR A CURE… HELP US FIND ONE!
Patient and carer support for clinical trials is an important part of finding a cure for AD For any new referrals for diagnosis, treatment or involvement in clinical trials Please contact: CALHN Memory Service and CALHN Memory Trials Ph: , Fax:

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