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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

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