ALZHEIMER DISEASE

FAREEHA ANWAR
 Drugs Used in Alzheimer's Disease
• Pharmacologic intervention for Alzheimer's disease
is only palliative and provides modest short-term
benefit. None of the currently available therapeutic
agents have been shown to alter the underlying
neurodegenerative process. Dementia of the
Alzheimer's type has three distinguishing features:
• 1) accumulation of senile plaques (beta-amyloid
accumulations),
• 2) formation of numerous neurofibrillary tangles,
and
• 3) loss of cortical neurons particularly cholinergic
 Tau Hypothesis
• Tau protein, a member of the microtubule-associated
protein, is also a functional monomeric and unfolded cell
membrane protein, located within the cytosol of a
neuron and very crucial in tubulin stabilization. In
addition, tau is known to control neurite growth and
have a role in axonal guidance, thus enhancing the
normal function of neurons. In humans, tau protein is
only found in trace levels in non-neuronal cells. Tau goes
through various post-translational changes, especially
hyper phosphorylation, a process which acts as a
significant factor in influencing the stability of
microtubules, thereby leading to tau protein
accumulation in AD.
 Amyloid Hypothesis
• Ab peptide is a derivative of Amyloid β -
precursor protein (AβPP), also an intrinsic type
I glycoprotein
• Proteolytic series of events taking place around and in
the APP transmembrane sphere yield a better
expression for the production of toxic Aβ 42 protein, and
eventually for AD pathogenesis. Three different divisions
release the APP from the membrane. These divisions
have been confirmed to α-secretase split (which
separates Aβ-domain and inhibits Aβ-development- by
generating amyloidogenic substance- due to the
incapability of developing pathogenic Ab ), β -secretase
cleavage (the segment produced from α-secretase,
while the β–secretase segments remains connected to
the membrane; following further conversion by γ-
secretase it becomes weakened), and Aβ-protein (Ab 42)
breakage (whose aggregation is thought to cause AD
due to the presence of toxic and fibril aggregates)
 Cholinergic Hypothesis
• Acetylcholine (ACh) is a neurotransmitter
utilized by cholinergic neurons and is crucial for
physiological processes like attention, learning,
memory, stress response, wakefulness, and
sleep, as well as sensory information. Damage
to cholinergic neurons was observed as an
important pathological alteration which
corresponds with cognitive destruction seen in
AD.
 DSM-IV and DSM-5 criteria for dementia
(Diagnostic and Statistical Manual of Mental
disorders)

• https://www.uptodate.com/contents/image?
imageKey=NEURO%2F91276#!
• DSM IV. Diagnostic criteria for dementia of the Alzheimer's
type.
• Diagnostic criteria (DSM IV) for Dementia of the
Alzheimer's Type
• A. The development of multiple cognitive deficits manifested
by both (1) memory impairment (impaired ability to learn
new information or to recall previously learned information)
(2) one (or more) of the following cognitive disturbances:
• (a) aphasia (language disturbance)
(b) apraxia (impaired ability to carry out motor activities
despite intact motor function)
(c) agnosia (failure to recognize or identify objects despite
intact sensory function)
(d) disturbance in executive functioning (i.e., planning,
organizing, sequencing, abstracting)
• B. The cognitive deficits in Criteria A1 and A2 each cause significant impairment
in social or occupational functioning and represent a significant decline from a
previous level of functioning.

C. The course is characterized by gradual onset and continuing cognitive decline.

D. The cognitive deficits in Criteria A1 and A2 are not due to any of the
following:
• 1. Other central nervous system conditions that cause progressive deficits in
memory and cognition (e.g., cerebrovascular disease, Parkinson's disease,
Huntington's disease, subdural hematoma, normal-pressure hydrocephalus,
brain tumor)
• 2. Systemic conditions that are known to cause dementia (e.g., hypothyroidism,
vitamin B or folic acid deficiency, niacin deficiency, hypercalcemia, neurosyphilis,
HIV infection)
• 3. Substance-induced conditions
• E. The deficits do not occur exclusively during the course of a delirium.

F. The disturbance is not better accounted for by another Axis I disorder (e.g.,
 Case Study
• http://www.stacommunications.com/
customcomm/Back-issue_pages/AD_Review/
adPDFs/march1998/18.pdf
Chemicals used to induced AD
• Current therapies are aimed at either
improving cholinergic transmission within the
CNS or preventing excitotoxic actions
resulting from overstimulation of N-methyl-D-
aspartic acid (NMDA)-glutamate receptors in
selected brain areas.
 Acetylcholinesterase inhibitors
• Numerous studies have linked the progressive loss
of cholinergic neurons and, presumably, cholinergic
transmission within the cortex to the memory loss
that is a hallmark symptom of Alzheimer's disease. It
is postulated that inhibition of acetylcholinesterase
(AChE) within the CNS will improve cholinergic
transmission, at least at those neurons that are still
functioning. Currently, four reversible AChE
inhibitors are approved for the treatment of mild to
moderate Alzheimer's disease. They are donepezil,
galantamine, rivastigmine, and tacrine.
• Except for galantamine, which is competitive,
all are uncompetitive inhibitors of AChE and
appear to have some selectivity for AChE in
the CNS as compared to the periphery.
Galantamine may also be acting as an
allosteric modulator of the nicotinic receptor in
the CNS and, therefore, secondarily increase
cholinergic neurotransmission through a
separate mechanism. At best, these compounds
provide a modest reduction in the rate of loss
of cognitive functioning in Alzheimer's
patients.
• Rivastigmine is hydrolyzed by AChE to a
carbamylate metabolite and has no interactions
with drugs that alter the activity of P450-
dependent enzymes. The other agents are
substrates for P450 and have a potential for such
interactions. Common adverse effects include
nausea, diarrhea, vomiting, anorexia, tremors,
bradycardia, and muscle cramps all of which are
predicted by the actions of the drugs to enhance
cholinergic neurotransmission. Unlike the
others, tacrine is associated with hepatotoxicity.
 NMDA-receptor antagonist

• Stimulation of glutamate receptors in the CNS

appears to be critical for the formation of certain
memories; however, overstimulation of glutamate
receptors, particularly of the NMDA type, has been
shown to result in excitotoxic effects on neurons and
is suggested as a mechanism for neurodegenerative
or apoptotic (programmed cell death) processes.
Binding of glutamate to the NMDA receptor assists
in the opening of an associated ion channel that
allows Na+ and, particularly, Ca2+ to enter the
neuron.
• Unfortunately, excess intracellular Ca 2+ can
activate a number of processes that ultimately
damage neurons and lead to apoptosis.
Antagonists of the NMDA-glutamate receptor
are often neuroprotective, preventing the loss of
neurons following ischemic and other injuries.
Memantine is a dimethyl adamantane
derivative. Memantine acts by physically
blocking the NMDA receptor–associated ion
channel, but at therapeutic doses, only a
fraction of these channels are actually blocked.
• This partial blockade may allow memantine to
limit Ca2+ influx into the neuron such that toxic
intracellular levels are not achieved during
NMDA receptor overstimulation, while still
permitting sufficient Ca2+ flow through
unblocked channels to preserve other vital
processes that depend on Ca2+ (or Na+) influx
through these channels. This is in contrast to
psychotoxic agents such as phencyclidine, which
occupy and block nearly all of these channels.
• In short term studies, memantine has been
shown to slow the rate of memory loss in both
vascular-associated and Alzheimer's dementia
in patients with moderate to severe cognitive
losses.
• However, there is no evidence that memantine
prevents or slows the neurodegeneration in
patients with Alzheimer's disease or is more
effective than the AChE inhibitors. Memantine
is well tolerated, with few dose-dependent
adverse events.
• Expected side effects, such as confusion,
agitation, and restlessness, are
indistinguishable from the symptoms of
Alzheimer's disease. Given it's different
mechanism of action and possible
neuroprotective effects, memantine is often
given in combination with an AChE inhibitor.
Long-term data showing a significant effect of
this combination is not available.