M ECHANISMS OF DEMENTIA AND
OUTLOOK ON NOVEL TREATMENTS
by
Dr Sveinung Lillehaug MD PhD
a trial lecture for the degree of doctor philosophiea
| Concept artwork by Lightspring via Shutterstock.com
I NTRODUCTION
AGENDA
▪ INTRODUCTION
▪ TYPES OF DEMENTIA
▪ ALZHEIMER’S DISEASE
▪
PATHOPHYSIOLOGY
▪
PHARMACOLOGICAL TREATMENT
▪ OUTLOOK ON NOVEL TREATMENT
I NTRODUCTION
DEMENTIA IN NUMBERS
• Affects around 50 million people
• Projected to double every 20 years
• Annual cost around US $1000 billion
Dementia is public health priority
| GLOBAL IMPACT OF DEMENTIA: WORLD ALZHEIMER REPORT 2015 – estimates for 2018 | World Health Organization 2019
I NTRODUCTION
DEFINITION
Dementia is a syndrome
• Cognitive, behavioural and psychological
symptoms
• Biological changes in the brain
• So far no specific treatments
| Alzheimer's Association 2020
TYPES OF DEMENTIA
FRONTOTEMPORAL DEMENTIA (FTD)
Frontal
Lobe
Degeneration of:
• Frontal lobe: Judgement, reasoning, personality
• Temporal lobe: Speech, memory, hearing
Temporal Lobe
Cause unknown (but hereditary component)
| National Institute of Neurological Disorders and Stroke. Retrieved January 2020| illustration by thebrainclinic.com
TYPES OF DEMENTIA
LEWY BODY DEMENTIA
• Visual hallucinations, changes in attention and motor symptoms
• Unknown cause
• Deposits of alpha-synuclein protein in nerve cells (Lewy bodies)
Dendrite
Heathy
nerve cell
Sick
nerve cell
Lewy Body
| National Institute of Neurological Disorders and Stroke. Retrieved January 2020 | Histology: unknown source
TYPES OF DEMENTIA
VASCULAR DEMENTIA (VASCULAR COGNITIVE IMPAIRMENT)
Vascular disorder: Impaired brain blood flow
• Stroke
• Multi-infarct dementia
• Damaged small vessels in the brain
Treatment of underlying condition(s)
• Lower blood pressure
• Reduce cholesterol
• Anticoagulation
• Diabetic control
| National Institute of Neurological Disorders and Stroke. Retrieved January 2020
May slow
progression
TYPES OF DEMENTIA
OTHER CONDITIONS ASSOCIATED WITH DEMENTIA
• Parkinson’s disease
• Huntington’s disease
Neurodegeneration
• Creutzfeldt-Jakob disease (prion disease)
• Multiple Sclerosis (late stage)
Direct damage
• Head injury (“punch drunk syndrome”)
| Alzheimer’s Association - alz.org
TYPES OF DEMENTIA
ALZHEIMER’S DISEASE (AD)
• Most common form of dementia
• Target of most pharmacological research
| Concept art by dreamstime.com
ALZHEIMER ’S D ISEASE
ORIGIN
•
Dr. Alois Alzheimer
Named after Dr. Alois Alzheimer
ALZHEIMER ’S D ISEASE
ORIGIN
•
Named after Dr. Alois Alzheimer
•
In 1901 he started treating Auguste Deter
•
Her symptoms included memory loss, language
problems and unpredictable behaviour
•
When she died in 1906, post mortem
examination revealed many abnormalities:
Auguste Deter. First Alzheimer’s patient
ALZHEIMER ’S D ISEASE
ORIGIN
Healthy Brain
Severe Alzheimer’s
Severely Enlarged
Ventricles
Extreme
cortical
shrinkage
Cerebral
Cortex
Ventricles
•
Named after Dr. Alois Alzheimer
•
In 1901 he started treating Auguste Deter
•
Her symptoms included memory loss, language
problems and unpredictable behaviour
•
When she died in 1906, post mortem
examination revealed many abnormalities:
-
Hippocampus
(extreme shrinkage)
Hippocampus
Entorhinal
Cortex
Entorhinal Cortex
(extreme
shrinkage)
| Illustration adapted from NIH – National institute of Aging
Shrinking of brain tissue
ALZHEIMER ’S D ISEASE
ORIGIN
•
Named after Dr. Alois Alzheimer
•
In 1901 he started treating Auguste Deter
•
Her symptoms included memory loss, language
problems and unpredictable behaviour
•
When she died in 1906, post mortem
examination revealed many abnormalities:
Amyloid
Plaque
Neurofibrillary tangle
(Tau tangle)
-
Shrinking of brain tissue
-
Abnormal clumps
(now called amyloid plaques)
-
Tangled fibres
(now called neurofibrillary tangles/ tau
tangles)
| Silver stain histology as originally used by dr. Alzheimer
ALZHEIMER ’S D ISEASE - PATHOPHYSIOLOGY
MAIN HYPOTHESES
Amyloid cascade hypothesis:
(Amyloid hypothesis)
β-amyloid (Aβ) is the main
causative agent is Alzheimer’s
disease
Tau hypothesis:
Abnormal tau protein is the
main causative agent in
Alzheimer’s disease
| Illustration from National Institute on Aging, NIH
ALZHEIMER ’S D ISEASE - PATHOPHYSIOLOGY
AMYLOID HYPOTHESIS
• Main component in plaques is β-amyloid 1
• Derived from amyloid precursor protein (APP)
• Enzymes cut APP in two places, creating a β-amyloid peptide
β-amyloid peptides
(36–43 amino acids)
Amyloid Precursor
Proteine (APP)
| Illustration adapted from Chen et al (2017) | 1: Glenner GG & Wong CW (1984
1984
ALZHEIMER ’S D ISEASE - PATHOPHYSIOLOGY
AMYLOID HYPOTHESIS
• Discovery of inherited mutations causing familial Alzheimer’s disease 1,2
• Cause longer amyloid-β peptides that clump together
Longer
β-amyloid
β-amyloid
peptidespeptides
(Mainly
Aβ42) acids)
(36–43 amino
APP
mutation
PSEN1/ PSEN2
mutations
Amyloid Precursor
Proteine (APP)
| Illustration adapted from Chen et al (2017) | 1: Goate et al (1991) Nature | 2: Sherrington et al (1995) Nature
19911995
ALZHEIMER ’S D ISEASE - PATHOPHYSIOLOGY
AMYLOID HYPOTHESIS
• Discovery of inherited mutations causing familial Alzheimer’s disease 1,2
• Cause longer amyloid-β peptides that clump together
• Accumulation produces insoluble fibrils which form plaques
Insoluble
Soluble
Aggregated
Monomer
Oligomer
Fibril
Amyloid
plaque
Postulated as causative agents of Alzheimer’s disease
The exact relevant pathological form(s) of Aβ remains elusive
| Illustration adapted from Chen et al (2017) | 1: Goate et al (1991) Nature | 2: Sherrington et al (1995) Nature
ALZHEIMER ’S D ISEASE - PATHOPHYSIOLOGY
AMYLOID HYPOTHESIS
~3%
<65 yrs
Familial
Alzheimer’s disease
Sporadic (late-onset)
Alzheimer’s disease
Mutations in APP or PES genes
Genetic and environmental
risk factors + aging
Lifelong increase in
Aβ production
Increased Aβ production and/ or
reduced clearance
~97%
>65 yrs
Aβ accumulation and
oligomerization
Gradual deposition of Aβ
oligomers as diffuse plaques
Microglia and astrocyte
activation and inflammation
Neuronal degeneration
and cell death
Altered ionic homeostasis and
oxidative stress
Neuronal dysfunction with
transmitter defects
Altered kinase/
phosphatase activity
CLINICAL DEMENTIA
Neurofibrillary tangles
| Blennow K (2006) Alzheimer's disease The Lancet
Secondary tau
pathology
ALZHEIMER ’S D ISEASE - PATHOPHYSIOLOGY
THE AMYLOID HYPOTHESIS ON TRIAL 1
• Many elderly people without dementia have plaques
• Many failed clinical trials targeting β-amyloid
• Dementia symptoms linked more closely to the number and
2016
location of tau tangles 2
| 1: Mankin S (2018) The amyloid hypothesis on trial Nature Outlook
| 1: Brier M et al. (2016) Tau and Aβ imaging in Alzheimer’s disease. SCIENCE Translational medicine
ALZHEIMER ’S D ISEASE - PATHOPHYSIOLOGY
TAU HYPOTHESIS1,2
Normal tau protein:
• Stabilizes cytoskeleton
• Regulates intracellular transport
Stabilized microtubule
Tau
protein
Illustration adapted Hervy et al. (2019) | 1: Li H et al (2018) | 2: Kametani F & Hasegawa M (2018)
ALZHEIMER ’S D ISEASE - PATHOPHYSIOLOGY
TAU HYPOTHESIS1,2
Alzheimer’s disease: Abnormal tau protein
• Unstable cytoskeleton and impaired intracellular transport
• Recruits normal tau and other proteins forming tangles
Amyloid pathology develops secondary
Normal tau
Clinical Dementia
Illustration adapted from Meier S et al (2016) | 1: Li H et al (2018) | 2: Kametani F & Hasegawa M (2018)
ALZHEIMER ’S D ISEASE - PATHOPHYSIOLOGY
TAU PROPAGATION HYPOTHESIS
SYNAPSE
Tau pathology spreads from
nerve cell to nerve cell
throughout the brain
Tangles mainly in the
entorhinal region of
the brain
Involvement of limbic
regions such as the
hippocampus
Extensive neocortical
involvement
| 1: de Calignon et al. (2012) | 2: Liu et al (2012) | 4: Mudher et al (2017) What is the evidence that tau pathology spreads through prion-like
propagation? Acta neuropathol commun
ALZHEIMER ’S D ISEASE - PATHOPHYSIOLOGY
CURRENT STATUS: AMYLOID VS TAU 1, 2
Maybe both?
Or something else?
| 1: Liu P et al. (2019) | 2: Mankin S (2018) The amyloid hypothesis on trial. Nature Outlook
ALZHEIMER ’S D ISEASE - PATHOPHYSIOLOGY
CURRENT UNDERSTANDING: RISK FACTORS AND THEORIES
Risk factors:
Explanatory Hypotheses:
Aging
β-amyloid
Smoking
Genotype
Tau
Head Injury
Chronic Inflammation
Alcoholism
Cell-cycle regulation
Menopause
Mitochondria dysfunction
Diabetes
Calcium metabolism
Stroke
Neurodegeneration
Chronic infection
Depression
Dementia
Adapted from Senanarong V (2019) Novel Immunotherapy in Alzheimer Disease [Lecture]
ALZHEIMER ’S D ISEASE - TREATMENT
IS THERE A CURE?
| concept illustration from lakeside.org
ALZHEIMER ’S D ISEASE - TREATMENT
TABLOID MEDIA
| Source: World wide tabloid media
ALZHEIMER ’S D ISEASE - TREATMENT
HEALTH JOURNALISM
“Our experiments were able to identify various
substances that start the process of Mitophagy. The
experiments were carried out on mice, a type of
roundworm and brain tissue in the laboratory. When
we introduced the various substances to the animals, it
started the cleansing process of dysfunctional
mitochondria in brain cells. Consequently, the animals’
memory loss was considerably reduced, Lautrup says.
The group at UiO and Ahus is part of an international
team of researchers from the USA, the UK, Denmark
and Greece respectively. They are now moving forward
with clinical trials, which will test the findings on
humans”
| Source: Institute of Clinical Medicine - Faculty of Medicine web-page: UiO |Fang EF et al (2019) Nature Neuroscience
ALZHEIMER ’S D ISEASE - TREATMENT
HEALTH JOURNALISM
“Our experiments were able to identify various
substances that start the process of Mitophagy. The
experiments were carried out on mice, a type of
roundworm and brain tissue in the laboratory. When
we introduced the various substances to the animals, it
started the cleansing process of dysfunctional
mitochondria in brain cells. Consequently, the animals’
memory loss was considerably reduced, Lautrup says.
The group at UiO and Ahus is part of an international
team of researchers from the USA, the UK, Denmark
and Greece respectively. They are now moving forward
with clinical trials, which will test the findings on
humans”
| Source: Institute of Clinical Medicine - Faculty of Medicine web-page: UiO |Fang EF et al (2019) Nature Neuroscience
ALZHEIMER ’S D ISEASE - TREATMENT
HEALTH JOURNALISM
“Our experiments were able to identify various
substances that start the process of Mitophagy. The
experiments were carried out on mice, a type of
roundworm and brain tissue in the laboratory. When
we introduced the various substances to the animals, it
started the cleansing process of dysfunctional
mitochondria in brain cells. Consequently, the animals’
memory loss was considerably reduced, Lautrup says.
The group at UiO and Ahus is part of an international
team of researchers from the USA, the UK, Denmark
and Greece respectively. They are now moving forward
with clinical trials, which will test the findings on
humans”
| Source: Institute of Clinical Medicine - Faculty of Medicine web-page: UiO |Fang EF et al (2019) Nature Neuroscience
ALZHEIMER ’S D ISEASE - TREATMENT
OUTLOOK ON NOVEL TREATMENT - THE BIG PICTURE
Trial phase:
Preclinical
Safety in humans
I
Effectiveness
Safety and side effects
II
Placebo controlled
Large scale effect and safety
Clinical
Approval
Laboratory studies
Animal testing
III
Long term safety
IV
Illustration adapted from favpng.com
ALZHEIMER ’S D ISEASE - TREATMENT
CURRENTLY APPROVED PHARMACOLOGICAL TREATMENT IN NORWAY
Cholinesterase inhibitors:
Donepezil (Aricept®, Donepezil®)
Rivastigmin (Exelon®, Rivastigmin®)
Modifies signalling in the brain
Galantamin (Galantamin®)
May slightly improve symptoms
Effect only in some patients
NMDA-receptor antagonist:
Memantin (Ebixa®, Memantin®, Nemdatine®)
May improve symptoms – Do not halter disease progression
| Norsk Legemiddelhåndbok / Felleskatalogen (2019)
ALZHEIMER ’S D ISEASE - TREATMENT
OUTLOOK ON NOVEL TREATMENT - THE BIG PICTURE
June 2019:
132 agents in clinical trials
(clinicaltrials.gov)
β-amyloid
Tau
Others
| Cummings J et al. (2019) Alzheimer's disease drug development pipeline: 2019 Alzheimer's Dement
ALZHEIMER ’S D ISEASE - TREATMENT
OUTLOOK ON NOVEL TREATMENT - THE BIG PICTURE
| Cummings J et al. (2019) Alzheimer's disease drug development pipeline: 2019 Alzheimers Dement
ALZHEIMER ’S D ISEASE – TREATMENT APPROACHES
ACTIVE IMMUNIZATION (β-AMYLOID)
Hypothesis: Activate the body’s own immune system to produce antibodies against
β-amyloid
▪ The first trial was stopped in 2002 when 6% of participants developed
inflammation in the brain 1
▪ One drug reached phase 3: 2
• Safe in humans 3
• Antibody formation in 82% of patients 3
• Study running until 2025 4
| 1: Orgogozo et al (2003) |2: Mo et al. (2017) | 3: Vandenberghe et al. (2016) | 4: alzheimersnewstoday.com/cad106/ (2019)
ALZHEIMER ’S D ISEASE – TREATMENT APPROACHES
PASSIVE IMMUNIZATION (β-AMYLOID)
Hypothesis: Antibodies bind β-amyloid and initiates clearance
| Illustration adapted from: Alves et al. (2014)
ALZHEIMER ’S D ISEASE – TREATMENT APPROACHES
PASSIVE IMMUNIZATION (β-AMYLOID)
Antibodies recruit immune cells 1
control
Glia cells (“first responders”)
|1: Sevigny J et al. (2016) The antibody aducunamuab reduces Aβ plaques in Alzheimer’s disease Nature
treatment
ALZHEIMER ’S D ISEASE – TREATMENT APPROACHES
PASSIVE IMMUNIZATION (β-AMYLOID)
Status of clinical trials (Jan 2020) 1,2
Aducanumab
BAN2401
Gantenerumab
Crenezumab
MEDI-1814
LY3002813
Bapineuzumab
Solanezumab
Phase 2
complete
Phase 3
(until 2024)
Discontinued
Phase 1
Partially
discontinued
Discontinued
Partially
discontinued
Current
Status
Phase 3 Halted
Re-evaluation)
Origin
Moving forward in phase 3
|1: Data from Alzforum.com therapeutics database | 2: Vander Zanden CM et al. (2020)
ALZHEIMER ’S D ISEASE – TREATMENT APPROACHES
ENZYME INHIBITION (β-AMYLOID)
Hypothesis: Inhibit enzymes that cleaves APP into β-amyloid
Non-pathological
peptides
Amyloid precursor
protein (APP)
| Burki T (2018) Alzheimer's disease research: the future of BACE inhibitors The Lancet
ALZHEIMER ’S D ISEASE – TREATMENT APPROACHES
ENZYME INHIBITION (β-AMYLOID)
Hypothesis: Inhibit enzymes that cleaves APP into β-amyloid
Phase 3 enzyme inhibitors:
•
Verubecestat
•
RG7129
•
NJ-54861911/ atabacestat
•
LY2886721
•
Elenbecestat
2017:
Treatment worse than placebo
2017-2019:
Liver toxicity
▪ No cognitive improvement 1
Data from Alzforum.com database | 1: Burki T (2018) Alzheimer's disease research: the future of BACE inhibitors The Lancet
ALZHEIMER ’S D ISEASE – TREATMENT APPROACHES
IMMUNIZATION (TAU)
Passive immunization:1
LY3303560 (Lilly)
RO7105705 (Genentech /AC Immune SA)
• Phase 1 or 2
JNJ-63733657 (Janssen Pharmaceutica)
• Well tolerated
• Efficacy data not ready
Active immunization:2
AADvac1 3
|1: Vander Zanden et al. (2020) Passive Immunotherapies Targeting Amyloid Beta and Tau Oligomers in Alzheimer’s Disease
|2: Shahpasand et al (2018) Tau immunotherapy: Hopes and hindrances. Hum Vaccin Immunother | 3: alzforum.org news: AADvac1
ALZHEIMER ’S D ISEASE – TREATMENT APPROACHES
ANTI TAU AGGREGATION
Hypothesis: Reduce formation of tau-tangles
LMTX-target
•
Only phase 3 drug is LMTX (LMTM/ methylthioninium chloride (MTC), TauRX,
Singapore)
•
Mixed results so far 1,2
|1: Gauthier S et al (2016) The Lancet | 2: Wilcock GK et al (2018) Journal of Alzheimer’s Disease
ALZHEIMER ’S D ISEASE – TREATMENT APPROACHES
SUMMARY
Disease Modifying drugs
Anti β-amyloid:
Passive immunization
Active Immunization
Many failed or cancelled trials
Enzyme inhibition
Anti Tau:
Passive Immunization
Active Immunization
Anti-Aggregation
Failed trials or early phase
Under re-evaluation
Other drugs:
Anti-inflammation
Neuroprotection
No convincing evidence in
Antibiotic
clinical trials yet
etc…
ALZHEIMER ’S D ISEASE - TREATMENT
LOST IN TRANSLATION 1
0 substances demonstrated to slow down or improve Alzheimer’s disease pathology in humans
Over 1000 substances demonstrated to improve Alzheimer’s disease in mouse models
Why?
- Dr Man, I see that vitamin B6, propranolol and insulin
cures dementia. Should my father take everything at once?
Mice are not men
– models do not fully replicate human disease
Wrong study population?
- findings from studies using models with genes associated
with familial AD extrapolated to late-onset disease
Wrong target?
- exact pathophysiology still unknown
No precise surrogate outcome measures
- such as e.g. HBA1c in diabetes research
Intervention starting too late?
- no way to diagnose presymptomatic AD
|1: Quinn JF (2018). Lost in Translation? Finding Our Way To Effective Alzheimer's Disease Therapies. Journal of Alzheimer's disease
ALZHEIMER ’S D ISEASE – TREATMENT
IS THERE HOPE?
ALZHEIMER ’S D ISEASE – TREATMENT
IS THERE HOPE?
• NIH budget for AD research is now $3 billion 1
• 12,000 papers on Alzheimer’s disease in 2019 2
• Progress in blood tests 3 and brain imaging 4 for early detection
• Hopefully better animal models and better data from these models 5
• Still many anti amyloid/ tau drugs in clinical trials 6,7
• Some drugs besides anti β-amyloid/ tau have promising results 8
1: Alzforum.org (2019)—A Year of Hope for Alzheimer's Research | 2: PubMed 3:Beach (2017) | 4: Shimizu et al. (2018) | 5: Lillehaug (2019) Thesis
6: Hovakimyan et al. (2019) | 7: Cummings et al. (2019) | 8: Alzforum.org (2019) - Early Failures and Hints of Success from Small Trials
ALZHEIMER ’S D ISEASE - TREATMENT
DEMENTIA IS NOT JUST BIOCHEMISTRY
New law from January 2020: 1
Norwegian muncipalities are obliged
to provide daytime activities for
persons with dementia living at
home
| 1: Norsk Lovtidende (July2019)
ALZHEIMER ’S D ISEASE - TREATMENT
DEMENTIA IS NOT JUST BIOCHEMISTRY
THANK YOU FOR YOUR
KIND ATTENTION
QUESTIONS?
| The purple ribbon that symbolizes Alzheimer's Awareness
th
February
February 11
11th 2020
2020
ALZHEIMER ’S D ISEASE - TREATMENT
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ALZHEIMER ’S D ISEASE - TREATMENT
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ALZHEIMER ’S D ISEASE - TREATMENT
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