Pharmacotherapy of Alzheimer's disease
Introduction
History
Risk factors
Pathophysiology
Symptoms
Diagnosis
Non pharmacological treatment
Drugs used in treatment of Alzheimer`s
Recent advances
Screening methods
Summary
References
2. CASE STUDY
A 75-year-old man was brought with a h/o progressive
functional decline, so much so that he now needs to be
looked-after all the time. He misplaces his daily need
articles, forgets what he said few minutes ago, is unable
to perform simple calculations, mixes up what
happened today and what happened yesterday, has
poor control of emotions, but vision, hearing and other
sensations are well preserved, and there is no gross
ataxia.
3. OBJECTIVES
Introduction
History
Risk factors
Pathophysiology
Symptoms
Diagnosis
Non pharmacological treatment
Drugs used in treatment of Alzheimer`s
Recent advances
Screening methods
Summary
References
4. INTRODUCTION
Alzheimer's disease (AD) is a progressive, neurodegenerative disorder in elderly (≥ 60
years)
Characterized by
Memory loss (92%)
Confusion (71%)
Short attention span (63%)
Declining sense of direction (53%)
Personality changes (31%)
≈1 in 8 > 65 years
7. Prevalence of Alzheimer`s Disease
INDIA
> 4 million people (3rd Highest case load in the World)
China > U.S > India
India's dementia and Alzheimer's ≈ 7.5 million by the end of 2030
9. HISTORY
Alzheimers disease was first described by German Physician Dr Alois
Alzheimer in 1906
Alois Alzheimer Auguste Deter
10. HISTORY
Alois Alzheimer
First reported
pathologically
documented
Emil Kraepelin
Named the disease
Schottyky J
The first reported
kindred with
pathologically
documented AD
1906 1910 1984
Glenner & Wong
Amyloid β protein
identified from
Plaques
1986
Goate et al.
Misense mutation in
APP gene identified
1932 1987 1991
Tau protein
Identified in
Neurofibrillary
Tangles
1992
Tacrine
First Alzheimer’s
Drug Trial
Amyloid
cascade hypothesis
11. HISTORY
PSEN1 E280A
Mutation
reported
PSEN1 E280A
Increases Aβ42
deposition
Clinical Features of
EOAD pE280A
Presenilin-1
mutation
1995 1996 1999
Alzheimer’s vaccine
successful in mice
PSEN-1 is catalytic
unit of γ-Secretase
20001997 2002
Aβ25-35 induces
apoptosis via OS
mechanism
DNA Damage does
not correlate with
Aβ/ NFT in E280A
FAD
12. HISTORY
Proposed Clinical stages
Asymptomatic MCI
Symptomatic MCI
MCI
Dementia
Fibrillar Aβ begins
to accumulate in
carriers at a mean
age of 28 years
2011 2012 2014
Passive Aβ
immunization
started
API
Alzheimer’s
Prevention
Initiative Launched
MRI anomalies &
Aβ1-42
overproduction in
CSF & plasma
CA 1 neuronal loss
related with
epilepsy
2004
13. Histological Hallmarks of AD
SENILE PLAQUES NEUROFIBRILLARY TANGLES
SP Neocortex, Hippocampus & in several Subcortical areas
NFT density correlates with disease duration and severity of dementia
SENILE PLAQUES
16. Vulnerable Neurons in AD
• Basal forebrain cholinergic system (Nucleus basalis)
• Monoaminergic system
• Hippocampus (CA1 and CA2 pyramidal cells)
• Amygdala
• Entorhinal cortex
• Neocortex
17. Effects of neuronal death in AD
• Hippocampus & Enthorhinal cortex Memory and learning
• Cortex & Basal forebrain cholinergic systems Memory and attention
• Amygdala & other deep nuclei Behavior and emotions
18. • Onset age: < 65 years
• ≈ 5%
• Genes: APP,PSEN1,PSEN2
Early onset
AD
• Onset age: > 60-65 y
• ≈ 90-95%
• Genes: APOE
Late Onset
AD
Categories of Alzheimer's Disease
19. Risk Factors for Alzheimer`s Disease
1) AGE
2) SEX
Females are more effected
< 65
65-75
> 85
75-84
20. Risk Factors for Alzheimer`s Disease
3) HEREDITY
EARLY ONSET
Alterations on chromosome 1, 14 and 21
Mutation on chromosome 14 PRESENILIN 1 (PSEN1)
Mutation on chromosome 1 PRESENILIN 2 (PSEN2)
PSEN1 & 2 encode for membrane protein involved for APP
Mutations activity of γ-secretase βAP formation
APP is encoded on chromosome 21
Mutation on APP gene overproduction of βAP
21. Risk Factors for Alzheimer`s Disease
3) HEREDITY
LATE ONSET
Due to apo-lipoprotein E (apoE) gene
Gene responsible for production of apoE gene – chromosome 19
Inheritance of apoE4 allele posses genetic risk
Degree of risk depends on:
Number of copies of apoE4 genes
Age
Ethnicity
22.
23.
24. Risk Factors for Alzheimer`s Disease
4) Race & Ethnicity
African-Americans: 2 times greater risk
Hispanics: 1.5 times greater risk
Cardiovascular risk factors more common
Lower levels of education, socioeconomic status
47. Pathogenesis of Alzheimer’s Disease
INFLAMMATORY MEDIATORS:
Brain amyloid deposition is associated with local inflammatory and
immunologic alleviations.
It is associated with release of Nitric oxide, cytokines, other radical species &
complement factors that injure neurons and promote inflammation.
CHOLINERGIC HYPOTHESIS:
Loss of cholinergic activity correlates with AD severity.
In late AD, number of cholinergic neurons are decreased, loss of nicotinic
receptors in hippocampus and cortex.
48. Pathogenesis of Alzheimer’s Disease
OTHER NEUROTRANSMITTER ABNORMALITIES:
Glutamate & other excitatory amino acid NTs act as potential neurotoxins for AD
If glutamate remains in synapse for a long period of timedestroys nerve cells
Blocking of NMDA receptors decreases the glutamate activity in synapse –
decreases cellular injury in AD
49. Pathogenesis of Alzheimer’s Disease
BRAIN VASCULAR DISEASE & HIGH CHOLESTROL:
ApoE lipoprotein carries cholesterol in blood through brain.
ApoE4 is associated with increased deposition of βAP.
Increased cholesterol in brain neurons alter membrane functioning leads
to plaque formation Alzheimer’s disease.
57. Stages of Alzheimer’s Disease
Stages Mild Moderate Severe
Symptoms • Recent memory loss
• Language problems
• Mood and
personality changes
• Diminished
Judgment
• Increased memory loss
• Behavioral &
personality changes
• Unable to learn or
recall new information
• Wandering, Agitation &
Aggression
• Confusion about time &
place
• Require assistance
with ADLs
• Loss of recognition of
familiar people or places
• Total loss of verbal skills
• Unstable gait
• Incontinence
• Motor disturbances
• Bedridden
• Dysphagia
• Poor / No ADLs
• LTC placement
ADL = Activities of Daily Living
LTC = Long-Term Care
58. Death due to Alzheimer’s disease
Life expectancy Reduced
Following diagnosis 3 – 10 years
< 3% of people live > 14 years
Pneumonia & Dehydration Death
59. Diagnosis of Alzheimer’s Disease
Cognitive testing:
Mini- Mental Status Examination
Cutoff = 24/30
SCORE DIAGNOSIS
27 – 30 Normal
21 – 26 Mild cognitive impairment
11 – 20 Moderate cognitive impairment
0 – 10 Severe
66. Brain Training
Crosswords
Learning a new language
Reading a book
Undertaking further education
Can intensive computerised training stop progress of cognitive decline and
onset of dementia? Studies ongoing
67. Physical Activity
Still no randomised trials available yet
People who exercise Slower loss of brain tissue
People who exercise regularly are less likely to have vascular disease
which ↑’s risk of AD
Reduce - stress, anxiety and depression
3 types of exercise program – sustained aerobic exercise, weight training
and flexibility and balance training
68. Diet in AD
A recent study looked at 3 different diets:
1. Mediterranean diet
2. DASH diet (Dietary Approaches to Stop Hypertension)
3. MIND diet (Mediterranean-DASH Intervention for Neurodegenerative Delay)
Natural plant-based foods, berries and green leafy vegetables, limited
saturated fats Benefit brain health
75. Cholinergic Hypothesis
Role
– Ach is an important neurotransmitter in brain Memory
Impact
– Loss of ACh in AD Impairment of memory
Treatment approach
– Enhancement of cholinergic function may stabilize or improve cognitive
function Behavior and daily functioning
78. Donepezil
• Long t ½ – 70 hrs
• Dose = 5 -10 mg daily
• Several controlled trials modest benefits in cognition and behaviour
• Not hepatotoxic
• Adverse effects: Nausea, diarrhoea, vomiting, fatigue, muscle cramps, bradycardia
• Generally safe & well tolerated
79. Rivastigmine
• Inhibits both AChE & BChE
• Higher affinity for brain AChE than peripheral
• Half-life of 2 hours
• Dosing BD of 3 - 12 mg/day
• Patch 9.5 mg/24 hr available
• Metabolism independent of hepatic CYP450 system
• GI adverse events are common, including weight loss
80. Galantamine
• Galantamine has a dual mechanism of action
– Competitive inhibition of AChE
– Allosteric modulation of presynaptic and postsynaptic nicotinic receptors
• Galantamine improves major aspects of AD
(eg: cognition, behavior, function)
• Generally safe and well tolerated
81. Dual Mechanism of Action
Postsynaptic
nerve terminal
M receptor N receptor
Presynaptic nerve
terminal
Galantamine
ACh and other
neurotransmitters
M receptor N receptor
ACh
• Choline
• Acetic acid
Galantamine
N = nicotinic
M = muscarinic
ACh = acetylcholine
83. NMDA receptor antagonists
Glutamate Excitatory
neurotransmitter in brain
Acts on post synaptic NMDA receptors
Glutaminergic overstimulation may
result in neuronal damage
(excitotoxicity)
Dementia and pathogenesis of
Alzheimer`s disease
84.
85. Memantine
• NMDA receptor antagonist approved Moderate to severe AD
• Uncompetitive
• Low affinity
• Voltage dependent
• Interacts with Mg2+ binding site of channel to prevent excessive
excitation while sparing normal functions
86. Memantine (Pharmacokinetics)
• 100 % bioavailability
• T ½ = 60-80 hrs
• Rapidly crosses BBB
• Little metabolism, 75% -90% excreted unchanged in urine
• Minimal drug interactions and food interaction
• Starting dose – 5 mg OD , recommended target dose is 20 mg/day
90. GAMMA SECRETASE INHIBITORS
SEMAGACESTAT Candidate drug
↓ Plasma and CSF A- Concentration
IDENTITY -1 Trial Phase 3 started in March 2008
Interrupting Alzheimer's Dementia By Evaluating Treatment Of Amyloid
Pathology
91. GAMMA SECRETASE INHIBITORS
IDENTITY - 2 trial started in September 2008
Did not slow disease progression
Worsened cognition and the ability to perform ADL
↑ risk of skin cancer, rash and hair discolouration
Eli Lily halted the development
92. ANTIOXIDANTS
Recent research Link between antioxidant intake and decreased
incidence of Alzheimers
Curcumin
Ginko biloba
Vitamins
Green tea
93. Curcumin (Turmeric)
Anti-oxidant, anti-inflammatory & anti-aggregation
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.
94. GINKO BILOBA
Ancient use in China and Japan as a tonic
Poor circulation
Inner ear disorders
Absent-mindedness
Dementia
Depression
Hypertension in the elderly
Impotence in men
Chinese used leaves and nuts
96. Physiologic Mode of Action Cont’d
Acts by releasing NO & PGI2
↑ blood flow ↑oxygen & nutrient delivery tissues Brain
↓ blood viscosity
↑ in the release of neurotransmitters
Antioxidant activity
Prevention of free radical damage
97. Side effects
Hemorrhage
Hematoma
Hyphema (bleeding in eye)
In all trials < 0.5% reported minor
side effects including headaches, GI
distress and allergic skin reactions.
98. Vitamins
Insufficient evidence low levels of vit 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 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
99. Vitamins
Vitamin D Anti-oxidant and anti-inflammatory properties
not clear Vit D deficiency Cognition
Early laboratory evidence that Vitamin D receptor may help regulate
clearance of Aβ from the brain
No firm scientific evidence yet that Vit D supplementation will have
positive effect on cognition
100. Vitamins E, C & A – all powerful anti-oxidants
Epidemiological studies low intake ↑ dementia risk, but inconsistent
association
Multiple clinical trials Did not alter cognitive outcomes in MCI, AD or
healthy elderly but results still debated
Vitamins
101. Fish oil
Omega-3 fatty acids found in fish oil and nuts – Neuroprotective
Studies have failed to show any improvement in cognition
In elderly without AD – inconclusive evidence
Further large –scale studies needed
103. Statins
Higher Cholesterol risk factor for AD
Lovastatin prevented death of nerve cells in animal experiments
Results of various studies not promising
No difference between drug and control in terms of dementia,
cognitive function and neuropsychological tests
104. Estrogens
AD more common in postmenopausal women
Estrogen
Modulate ApoE gene
↑ APP metabolism
Protects against oxidative stress
↑Cerebral blood flow
Prevent neuronal atrophy
Clinical trials are inconclusive
105. NSAIDS
Inhibit COX enzymes
↓Production of cytokines & microglial activation
↓ Platelet aggregation
↓ iNOS
↓ Beta secretase
Large number of therapeutic trials of NSAID’s in AD (1993-2004)
Ibuprofen, Indomethacin, Naproxen, Celecoxib , Rofecoxib & Prednisolone
All were negative
106. Heavy metal chelators
Amyloid beta plaques bind copper and zinc & removal of these metal
ions promotes dissolution of Plaques
Levels of iron & zinc abnormally ↑ in brain in AD
Desferrioxamine : ↓ dementia in a trial
Clioquinal: Regression of Amyloid plaques in animal models of AD
107. Nicotinic receptor agonists
α4β2 & 7 nAChR types localized in areas of brain
Long term memory & Learning
7 nAChR agonist :
4 OH-GTS21
Protective action on cholinergic neurons
Antiamnestic effect
EVP-6124: Currently in phase2
108. 5-HT6 receptor antagonists
5HT6 receptor (functionally excitatory) Co-localized with GABAergic
neurons overall inhibition of brain activity
In parallel with this, 5HT6 antagonists are hypothesized to improve
cognition, learning, and memory
Latrepirdine, Idalopirdine & Intepirdine Novel treatments for AD
Phase III trials have failed to demonstrate efficacy
Reduce appetite & produce weight loss
112. Immunization For Alzheimers Disease?
Transgenic animals were immunized with A42
Either before the onset of AD-type neuropathologies (at 6 weeks of
age) or at an older age (11 months)
When amyloid- déposition and several of the subsequent
neuropathological changes were well established
113. Immunization for Alzheimers disease?
Immunization of the Young animals essentially prevented the
development of -amyloid plaque formation, neuritic dystrophy and
astrogliosis.
Treatment of the older animals also markedly reduced the extent and
progression of these AD-like neuropathologies.
Hence the possibilty that immunization with amyloid-b may be effective
in preventing and treating AD
115. Anti-Amyloid strategies - Immunotherapy
Initial studies - Injecting animals with Aβ → good Ab response → cleared amyloid
plaques from brain
Human studies prematurely ceased (2002) → development of brain inflammation
(Meningoencephalitis) in 6%
BUT- Evidence Removed amyloid plaque from the brain
Idea of active immunisation not abandoned – several pharmaceutical companies
early phases of developing new active vaccines
118. Monoclonal antibodies
Several mAb’s have been studied Bapineuzumab and Gantenerumab
Stopped prematurely Lack of perceived efficacy
Subgroups did show benefits leading to further studies
Lack of efficacy Underdosing
Recently restarted studies Gantenerumab in the same patient group
Larger doses
119. Monoclonal antibodies
Several active ongoing studies
Some early positive results– Solanezumab, Crenezumab & Adecanumab
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
120. Most patients reported Adverse Effects
94 % Bapineuzumab
90 % Placebo
90 % mild to moderate
in severity
Back pain 12.1% vs 5.5% Weight loss 6.5% vs 1.8%
Anxiety 11.3% vs 3.6% Paranoia 6.5% vs 0.9%
Vomiting 9.7% vs 3.6% Skin laceration 5.6 % vs 2.7%
Vasogenic Edema 9.7% vs 0% Gait disturbance 5.6% vs 1.8%
Hypertension 8.1% vs 3.6% Muscle spasms 5.6 % vs 0.9%
AEs >2 times as often as placebo rate and seen in >5% of bapineuzumab patients
Safety Results
122. Methylthioninium Chloride (Methylene Blue)
First drug targeting Tau
Derived from the dye used to stain NFT’s
Inhibits Tau aggregation
Phase 2 study showed cognitive benefits
Phase 3 trial for mild-moderate AD - finished February 2016 – failed to slow cognitive or
functional
30% drop-out due to side-effects
2nd generation compound (TRx0237) currently in Phase 3 trials for AD
123. Tau Therapies
Mouse and primate models of AD show amyloid plaques
Respond to anti-amyloid therapy
But no tau pathology like human AD
Aged dogs develop AD Aβ and NFT’s
Tau immunisations Animal models Reduction Tau & clinical benefits
Small number of Tau immunotherapies phase 1 and 2 testing
Initial reports No serious adverse effects (still very early)
124. Tau Therapies
Mouse and primate models of AD show amyloid plaques
Respond to anti-amyloid therapy
But no tau pathology like human AD
Aged dogs develop AD Aβ and NFT’s
Tau immunisations Animal models Reduction Tau & clinical benefits
Small number of Tau immunotherapies phase 1 and 2 testing
Initial reports No serious adverse effects (still very early)
125. Tau Therapies
• Lithium inhibits chemical changes in Tau NFT’s
• Studies on Lithium (Mixed) Benefit with very low doses in MCI
Worsening confusion (Studies needed)
External Ca2+ ER Ca2+
Lithium Lithium
NMDA
antagonism
IMP
inhibition
Lowered Intracellular
Ca2+ intrusion from
External stores
Reduced IP3
Lowered Intracellular
Ca2+ intrusion from
Internal stores
126. Vascular disease and Alzheimer’s
Larger, longer randomised controlled trials
Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability
(FINGER study) →preventive 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
127. Alzheimer’s Prevention Initiative (API) international consortium
Research in 5000 members Colombia,South America
Study on asymptomatic individuals carry the PS1 mutation
Using the monoclonal antibody Crenezumab vs. placebo
This is a five year study and is still recruiting
128. Glycogen synthase kinase 3 beta (GSK3β) GSK3β activity
increased Aβ production & deposits,
Tau hyperphosphorylation
synaptic damage in AD patients & animal models
(VDAC- Voltage-dependent anion-selective channel)
GSK3β INHIBITORS
129. Glycogen synthase kinase 3 beta (GSK3β) GSK3β activity
increased Aβ production & deposits,
Tau hyperphosphorylation
synaptic damage in AD patients & animal models
(VDAC- Voltage-dependent anion-selective channel)
GSK3β INHIBITORS
130. Screening in Alzheimer’s Disease
Passive Avoidance Methods
Active Avoidance Methods
Discrimination Learning
Conditioned Response
a) Step down test in Mice & Rat
b) Step through test in rodents
c) Uphill avoidance tests in rats
d) Scopalamine induced amnesia in mice
e) Ibotenic acid-induced impairment of
memory
a) Runway avoidance in rats & mice
b) Shuttle box avoidance test
c) Jumping avoidance test
a) Spatial habituation learning
b) Spatial discrimination test in rodents
c) Spatial learning test in water maze
d) Olfactory learning in rats
a) Conditioned nictitating
membrane response in
rabbits
131. SUMMARY
AD - Most debilitating diseases affecting the old age.
Pathology - Amyloid beta protein & Tau protein.
No cure – Delay progression
Approved drugs – AChE & NMDA receptor inhibitors.