Clinical definition
1. Dementia is a chronic progressive,
degenerative, cerebral disorder;
2. It affects higher cortical functions
including memory, thinking and
orientation;
3. Alzheimers disease (AD) is the most
common form of dementia.
4. AD owns characteristic neuropathological
and neurochemical features.
Clinical definition
1. People with Alzheimers disease lose the
ability to carry out routine daily activities
like dressing, toileting, travelling and
handling money;
2. Behavioural changes such as aggression
are particularly disturbing for carers.
Clinical definition
Non-cognitive symptoms in dementia include
agitation, behavioural disturbances (for
example, wandering and aggression),
depression, delusions and hallucinations.
Natural history of Alzheimer's disease
Onset gradual, probably imperceptible
Progression slow and gradual, but not linear; progressive amnesia
most common
Duration less than 10 years, on average, from diagnosis to death
Cognitive function
Alzheimers disease
Vascular dementia
Dementia with Lewy bodies
Time
The Alzheimers disease burden in the US
5.3 million people have Alzheimers disease.
$148 billion $ in annual costs.
9.9 million unpaid caregivers.
A new case every 70 seconds.
6th leading cause of death.
By 2050, the number of elderly subjects with
Alzheimers disease in the US is projected to be 11-16 million.
2009 Alzheimers Disease Facts and Figures report, March 24, 2009 2
Percentage changes in selected causes of death
between 2000 and 2006 in the US
2009 Alzheimers Disease Facts and Figures report, March 24, 2009 3
According to a recent European meta-
analysis, the annual costs for caregiving and
nursing demented patients in Austria are
around 1.1 billion Euro (Jnssn and Berr,
2005), 85% of which are paid by the patients
families; 75% are non-medical costs, while
only 6% are medical treatment costs.
History of Alzheimer s disease
Alzheimer made his greatest progress in
the area of the histopathology in
Kraepelins clinic in Munich. Kraepelin
fostered the view that psychiatric diseases
had a biological cause.
History of Alzheimer s disease
At the psychiatric clinic in Frankfurt/Main, he
examined Auguste D., a 51-year old woman with an
almost five year history of progressive memory
impairment, hallucinations, delusions, paranoid
ideas, apraxia, speech and severe social and
behavioural disorders, who died on April 8, 1906.
Photograph of Auguste D. in 1902
History of Alzheimer s disease
In her brain, in addition to severe
atrophy, using the silver
impregnation method developed
by Bielschowsky, he detected
neurofibrillary tangles in nerve
cells and deposits corresponding
to senile plaques all over the
cerebral cortex.
Neuropathology of Alzheimer s disease
The histopathology of AD is characterized
by gliosis and tissue atrophy caused
principally by synaptic loss which is most
pronounced in the frontal and temporal
cortices (Probst et al. 1991).
Neuropathology of Alzheimer s Disease
Cell loss, senile plaques, and
neurofibrillary tangles appear regularly in
the neocortex, hippocampus, amygdala, and
basal nucleus of Meynert.
Neuropathology of Alzheimer s Disease
After the importance of the hippocampus
and the cholinergic system for memory and
learning had been emphasized (Drachman
and Ommaya, 1964), the selective loss of
cholinergic neurons and their enzyme
activities in Alzheimer brain were reported
(Davies and Maloney, 1976), associated
with disorders of cortical cholinergic
innervation (Coyle et al., 1983).
Cholinergic System, an early target of disease
Jonathan Cooper Dept. Neuropathology, Kings College, London
Processing of amyloid precursor protein
A: amyloid- APP: amyloid precursor protein
APPs: soluble amyloid precursor protein- APPs: soluble amyloid precursor protein-
C83: carboxy-terminal fragment 83 C59: carboxy-terminal fragment 59
C99: carboxy-terminal fragment 99
De Strooper et al. Nat Rev Neurol 2010; 6: 99-107
Amyloid precursor protein processing
and -amyloid accumulation in the Alzheimer brain
Gandy. J Clin Invest 2005; 115: 1121-9
AD: formulation of a disease model
Blennow, Hampel et al. (2010) Nat Rev Neurol
Benilova et al. (2012) Nat Neurosci
Bringing it all together
5
Oxidative
damage
6
Inflammatory
response
Mutations in
APOE4
APP/PS-1
Increased A42 Tau phosphorylation Neuronal
Environment formation and and aggregation death
deposition
3
2 4
1
Age
Nistic et al, Mol Neurobiol 2012
Available treatments
At present, no treatment
can prevent or cure
Alzheimer s disease
Available treatments
The fact that Alzheimer s disease affects a
geriatric population complicates its
treatment. Older patients metabolize drugs
more slowly and are more vulnerable to
adverse effects; they are also likely to be
taking multiple medications, heightening the
risk of drug-drug interactions.
Available treatments
Figure 1. Approaches to treatment during different stages of
Alzheimer s Disease
Induction Latency Detection
Etiology Pathogenesis Symptoms Disease
Primary Secondary Symptomatic
prevention prevention treatment
(MCI) (cognitive,
behavioral)
MCI = mild cognitive impairment.
Correcting cholinergic loss in AD
4 3
Muscarinic receptor
Nicotinic receptor
1 Choline ACh
ACh metabolites
Lecithin Acetyl
CoA AChE
AChEIs 2
Current treatments for Alzheimer s Disease:
Cholinesterase Inhibitors
Acetylcholinesterase is a key inactivator of
neuronally released acetylcholine. It is
commonly understood that the inhibition
of the enzyme acetylcholinesterase can
boost the action of acetylcholine long
enough to enhance cognition in patients
suffering from Alzheimer s disease.
Available treatments
The 5 drugs approved for the treatment of
Alzheimer s disease are tacrine, donepezil,
galantamine and rivastigmine all of which
are cholinesterase inhibitors and memantine
which works through the glutamate system.
Available treatments
Donepezil inhibits acetylcholinesterase;
rivastigmine inhibits both
acetylcholinesterase and
butyrylcholinesterase; and galantamine
inhibits acetylcholinesterase while
allosterically modulating nicotinic
cholinergic receptors.
Tacrine
First AChEI to be approved for use in AD
Four times a day dosing
Most beneficial effects at high dosage
Effects on cognition seen within weeks
Severely limited by liver enzyme elevation in 1/3 of patients
Also has muscarinic and nicotinic receptor-binding properties
? Might be disease-modifying
? Might show an APOE-selective response
Donepezil
Reversible acetylcholinesterase (AChE) inhibitor
Half life < 70 hours
Once-daily dosing
Two doses: 5 mg/day and 10 mg/day
Greater efficacy at 10 mg/day
Subjected to Cochrane review
Evidence for improvement in cognition, global state and possibly
function
Side-effects similar to other AChEIs nausea and vomiting most
common
Side-effects often mild and attenuate with time
Nightmares may occur
Rivastigmine
Pseudo-irreversible acetylcholinesterase (AChE) inhibitor
Half life ~2 hours / effects on AChE ~10 hours
Twice-daily dosing
Dose-titration regimen
Greater efficacy (and more side-effects) at higher doses
Evidence for improvements in cognition, global state and possibly
function
Evidence for benefits in those with vascular risk factors
Side-effects similar to other AChEIs nausea and vomiting most
common
Few interactions with other drugs
Pharmacoeconomic modelling suggests modest cost savings
Galantamine
Competitive reversible acetylcholinesterase (AChE) inhibitor
Positive Allosteric modulator of nicotinic receptors
Half life ~2 hours / effects on AChE ~10 hours
Slow dose-titration reduces side-effects
Evidence for improvement in cognition, global state and
possibly function
No effect of APOE
Benefit maintained to 12 months
Side-effects similar to other AchEIs nausea and vomiting
most common
Available treatments
There are limitations to these medications,
however,there is typically only a modest
improvement from baseline. Additionally,
the effects are not sustained indefinitely,
and the disease continues to progress
even while patients are receiving treatment
with cholinesterase inhibitors.
Glutamatergic hypothesis of dementia
Glutamate is the main fast excitatory transmitter in regions
associated with cognition and memory
Cortical and subcortical structures that contain glutamatergic
receptors are structurally damaged in AD
Glutamate acts as an excitotoxin, causing neuronal death when
chronically released
Animal data suggest that NMDA-receptor antagonists provide
neuroprotection
Clinical signs of dementia correlate with deficits of glutamatergic
association fibres
Mechanism of action of memantine
Memantine is a partial agonist, allowing
the physiological activation of the
NMDA-receptor
Memantine does not leave the NMDA-
receptor channel following tonic low
level activation of NMDA-receptors
Available treatments
The myriad mood and behavioral
symptoms associated with Alzheimer s
disease pose further challenges to
treatment. Depression with Alzheimer s
disease may be treated with an
antidepressant that lacks substantial
anticholingeric effects.
Definition of symptomatic and
disease-modifying drugs in Alzheimers disease
Cognitive or Functional Performance
Time
Disease-modifying drugs
(anti-A compounds?)
Symptomatic drugs
(cholinesterase inhibitors,
memantine)
No treatment
Design to prove disease-modification
in Alzheimers disease
+ anti-Ab drug ?
Performance
stable dose of
donepezil
and/or
memantine
+ placebo
-16 0 Time (weeks) 78
Immunization
Inhibiting and secretase
Secretase
Amyloidogenic Non-amyloidogenic
cleavage cleavage
cleavage
Disease Protection
Fibrillogenesis
Enhancing -secretase
Secretase
Amyloidogenic Non-amyloidogenic
cleavage cleavage
cleavage
Disease Protection
Fibrillogenesis
Attacking amyloid
Secretase
Amyloidogenic Non-amyloidogenic
cleavage cleavage
cleavage
Disease Protection
Fibrillogenesis
Targeting tau
Phosphorylated tau Aggregated tau
GSK-3
Mutations
Tau Dysfunctional microtubules
Microtubules
Function Dementia
Drug development in Alzheimer's disease
Mangialasche et al. Lancet Neurol 2010
