OUR LADY OF FATIMA UNIVERSITY

College of Medicine
Valenzuela City

WRITTEN OUTPUT
ON
ALZHEIMER’S DISEASE
(Conference Topic)

Submitted by:
GROUP 7
Clemenia, Adnan
Collera, Charissa
Constantino, Venice
Cordova, Karla
Coronel, Romeo Jr.
Section A2
SPECIFIC OBJECTIVES OF THE REPORT:

1. To be able to define and characterize Alzheimer’s disease.

2. To determine the etiology and risk factors in the development of Alzheimer’s Disease, and to thoroughly
discuss its genetic determinants.

3. To determine the structural and biochemical changes during metabolism that result to the structural and
clinical abnormalities in Alzheimer’s Disease.

4. To discuss the Molecular Mechanisms and hypothesis, specifically the Amyloid Cascade Hypothesis in
the formation of Amyloid Plaques and Neurofibrillary Tangles and to differentiate them as to their type
of precursor proteins, role, site of formation and effect to neurons.

5. To be able to describe the imbalances of hormones and neurotransmitters involved in Alzheimer’s

Disease.

6. To be able to give the possible association of the following with Alzheimer’s:

a. lipoproteins and cholesterol.
b. inflammation and immune response
c. metal toxicity and free radicals
d. cigarette and tobacco smoking

7. To be able to give the management, preferably the treatment and prevention of Alzheimer’s Disease and
the rationale behind the use of different drugs.
CONTENTS:

I. INTRODUCTION
II. ETIOLOGY AND RISK FACTORS
III. MOLECULAR MECHANISMS AND HYPOTHESIS OF ALZHEIMER’S
DISEASE
A. CHOLINERGIC HYPOTHESIS
B. AMYLOID CASCADE HYPOTHESIS
C. TAU HYPOTHESIS
IV. HORMONES AND NEUROTRANSMITTERS INVOLVED
V. ASSOCIATION OF ALZHEIMER’S TO THE FOLLOWING:
A. LIPOPROTEINS AND CHOLESTEROL
B. INFLAMMATION AND IMMUNE RESPONSE
C. METAL TOXICITY AND FREE RADICALS
D. CIGARETTE AND TOBACCO SMOKING
VI. MANAGEMENT, TREATEMENT AND PREVENTION OF ALZHEIMER’S
DISEASE
I. INTRODUCTION

ALZHEIMER’S DISEASE

• It is a common isiduous and slowly progressive cerebral degeneration characterized by dementia.

• It was originally defined as pre-senile dementia, but it now appears that the same pathology underlies
the dementia irrespective of age onset.
• It is a progressive, degenerative disorder of uncertain cause, although abnormal metabolism and
deposition of amyloid beta protein appears to be closely linked to pathogenesis, the disease is defined by
characteristic histopathologic features especially neurofibrillary tangles and neuritic plaques.

SIGNS AND SYMPTOMS

 CONFUSION

 IRRITABILITY

 AGGRESSION

 MOOD SWINGS

 LANGUAGE BREAKDOWN

 LONG-TERM MEMORY LOSS

CLASSIFICATION:

1) PRE-DEMENTIA

- The first symptoms are often mistaken as related to aging or stress. The most noticeable deficit is
memory loss, which shows up as difficulty in remembering recently learned facts and inability to
acquire new information

2) EARLY DEMENTIA

• Increase impairment of learning and memory.

• Difficulties with language, executive functions, perception (agnosia), or execution of movements

(apraxia)

• Language and Writing Problems

3) MODERATE DEMENTIA

• Speech difficulties become evident due to an inability to recall vocabulary (PARAPRHASIA)

• Complex motor sequences become less coordinated

 • person may fail to recognize close relatives

• Long term memory impairment

• Neuropsychiatric manifestation such as wandering, irritability and labile affect, leading to crying,
outbursts of unpremeditated aggression, Sundowning, and delusion

• Urinary Incontinence

4) ADVANCED DEMENTIA

• completely dependent upon caregivers

• extreme apathy and exhaustion

• not be able to perform even the most simple tasks without assistance

• Muscle mass and mobility deteriorate

Neuritic Plaques – extracellular deposits that contain amyloid beta, presinilin1 and 2, alpha 1 antichemotrypsin,
apolipoprotein E and alpha2 macroglobulin and ubiquitin

Neurofibrillary Tangles – intracellular deposits containing hyperphosphorylated tau (microtubule-associated

protein) and ubiquitin.

II. ETIOLOGY AND RISK FACTORS

NOTATION CHROMOSOME GENE GENETICS AGE CLINICAL FEATURES

APP 21 Amyloid AD Early Rare but clinically stimulates
Precursor sporadic Alzheimer’s Disease
Protein
PS1 14 Presinilin 1 AD Early -as above-
PS2 1 Presinilin 2 AD Early -as above-
APO E 19 APOlipoprotein Haplotype Late Variants modify
susceptibility to typical AD
UBQLN 1 9 Ubiquitin SNP Late Familial Cases only
Trisomy 21 Amyloid Triploidy Middle AD is almost universal in
Precursor Age Down’s Syndrome
Protein
The cause of AD id still unknown. Links have been made to the genetic basis of AD. Alzheimer's Disease
(AD) can be divided into forms that run in families (genetically inherited) [known as Familial Alzheimer's
Disease (FAD)] and forms showing no clear inheritance pattern [known as Sporadic Alzheimer's Disease
(SAD)]. FAD accounts for only a small portion (less than 10%) of AD. All FAD is early-onset -- usually
occurring between ages 30 to 60 -- whereas SAD typically occurs after age 65. SAD affects roughly 2% of
those 65 years of age, with the incidence roughly doubling every 5 years up to age 90 at which the incidence is
over 50%. AD is much more prevalent in women than in men for any given age group.

All FADs can be cited as evidence of the amyloid cascade interpretation of AD causation -- against the
suggestion that NeuroFibrillary Tangles (NFTs) initiate AD. The gene that encodes tau-protein is located on
chromosome 17 and is not associated with any FAD. In fact, at least half of FAD cases can be accounted for by
the PS1 (Pre-Senilin 1) gene located on chromosome 14. PS1 is the predominant enzyme cleaving the gamma-
secretase site. PS1 resides within the endoplasmic reticulum/Golgi complex. Abnormal proteins from the PS1
and PS2 genes apparently influence gamma-secretase enzyme causing more Aß42 peptide formation. The
mutation on chromosome 21 (the chromosome that is present in triplicate in Down's Syndrome) is on the
Amyloid Precursor Protein (APP) gene itself, resulting in abnormal APP protein that is preferentially cleaved
by secretases to form more Aß42. (Down's Syndrome victims frequently develop AD if they reach age 40.)

III. MOLECULAR MECHANISMS AND HYPOTHESIS OF ALZHEIMER’S DISEASE

A. CHOLINERGIC HYPOTHESIS

The oldest hypothesis is the "cholinergic hypothesis". It states that Alzheimer's begins as a deficiency in
the production of acetylcholine, a vital neurotransmitter. Much early therapeutic research was based on this
hypothesis, including restoration of the "cholinergic nuclei". The possibility of cell-replacement therapy was
investigated on the basis of this hypothesis. All of the first-generation anti-Alzheimer's medications are based
on this hypothesis and work to preserve acetylcholine by inhibiting acetylcholinesterases (enzymes that break
down acetylcholine). These medications, though sometimes beneficial, have not led to a cure. In all cases, they
have served to only treat symptoms of the disease and have neither halted nor reversed it. These results and
other research have led to the conclusion that acetylcholine deficiencies may not be directly causal, but are a
result of widespread brain tissue damage, damage so widespread that cell-replacement therapies are likely to be
impractical. More recently, cholinergic effects have been proposed as a potential causative agent for the
formation of plaques and tangles[14] leading to generalized neuroinflammation.

B. AMYLOID CASCADE HYPOTHESIS

The molecular mechanisms and hypothesis of AD can be incredibly complex. A top down Cartoon-Like
overview followed by increasing depth and detail may be the best way to gain understanding.

1st sketch of Amyloid cascade Hypothesis

Aβ formation  Amyloid Plaques  Neuron Death  Dementia

The key event leading to Alzheimer’s Disease is the formation of a peptide known as Amyloid Beta.
Amyloid Beta clusters and forms into Amyloid Plaques (senile plaques). This aggregation would more or less
lead into neuron death.

2nd sketch of Amyloid cascade Hypothesis

APP  Aβ42  Fibrillary Aβ Amyloid plaques  inflammation  Neuron Death

 APP, Amyloid pre cursor Protein is a natural neuroprotective agent induced by neuronal stress or injury
which decreasescalcium concentration and protects neurons from glutamate excitotoxicity. Amyloid Beta
monomers are soluble an are normally ingested by surrounding microgliua. They contain short regions of beta-
sheets though they are largely alpha helical in membranes. However at sufficiently increased concentrations,
they undergo a dramatic conformational change from an alpha helical structure into a beta rich tertiary structure
that aggregates to form Amyloid Fibrils.
There are two types of Amyloid beta peptides. Amyliod Beta 42 (with 42 amino acid residues) are sticky
and hydrophobic and Amyloid Beta 40 (with 40 amino acid residues).
Amyloid Beta 42, because of its characteristic structure, is morelikely to form Fibrillary Amyloid Betas.
Both Amyloid Beta 40 and 42 are formed intracellularly but exert damaging effects when transported outside
the cell. Insulin accelerates extracellular transport, that may be the reason why DM type II patients have a
higher risk of developing AD.
These fibrillary Amyloid Betas clusters and forms Amyloid Plaques which then causes a a reactant
inflammation. Astrocytes are increased in the brain of people with AD. They are activated to produce
prostaglandin aand arachidonic acid to cause inflammation. Microglia, in the other hand, is the macrophages
present in the brain. They are also elevated and they produce damaging free radicals. Microglia multiply in
response tom injury and infection and are concentrated around Amyloid Plaques along with astrocytes.
Amyloid beta activation of Microglia produce Interleukin 1beta and Tumor necrosis factors as well as
NF-kB which increases cytokine production by neurons.

3RD Sketch of Amyloid Cascade Hypothesis

The process of Amyloid beta formation can now be described in more detail.

Enzymes that cleave APP are called secretatses, Alpha, Beta and Gamma.

1. 1. APP is digested by either beta or alpha secretase producing non toxic smaller products.
2. a. If beta secretase product is then cleaved by gamma secretatse it gives of 2 smaller products, an Amyloid
beta 42, with 42 amino acid residues, which is insoluble and toxic, and an amyloid beta 40 with 40 amino acid
residues which is more soluble and non-toxic.
b. If the alpha secretase product is the one cleaved by the gamma secretase, it would only give rise to a
single non-toxic product called P3.

Excess production of Amyloid Beta 42 is a key initiator of cellular damage in AD. Amyloid Beta clumps or
aggregates together and forms Amyloid Plaques outside the neurons.

C. TAU HYPOTHESIS
 TAU, Tubule Associated Units, are proteins that normally stabilizes the cell or neuron by stabilizing
cytoskeletal microtubules. They are mainly present in axons of neurons.

A NUMBER OF KINASES CAN PHOSPHORYLATE TAU BUT ONLY A FEW PHOSPHATASES

CAN DEPHOSPHORYLATE TAU.

Point of Comparison AMYLOID PLAQUES NEUROFIBRILLARY TANGLES

PRE-CURSOR PROTEINS AMYLOID PRECURSOR PROTEIN TUBULE ASSOCIATED PROTEIN

SITE OF FORMATION Extracellular; appear first at Intracellular; begins at the entorhinal

association areas of the cerebral cortex cortex, develop most frequently in
large pyramidal neurons with long
corticocortical connections

Associated with the areas of Associated with the cells of origin of

termination of corticocortical corticocortical projections
projections

Affects sensory and motor areas of

cerebral cortex as well as association
areas
Always a feature of AD
Insufficient to cause cell death
Restricted to association areas
Not always a feature of AD
Always associated with
neurodegeneration in AD

In cases where NFT is absent:

Cell death is invariably associated with Lewy Bodies of parkinsonism Dementia. Lewy Bodies are
similar to NFTs but are composed of Ubiquitin and Phosphorylated Neurofilament rather than TAU. They are
found in the Amygdala and Anterir Cingulate Cortex. NFTs are usually found at the entorhinal cortex and
hippocampus.

KINASE : MITOGEN-ACTIVATED PROTEIN KINASE – induced by fibrillar Amyliod Beta to produce NFT
via increased Calcium Influx into the cell.

MAPK Activity is crucial to T-cell activation; normally it declines with aging og immune system. But in AD,
there is an Aberrant increase in MAPK pathways.

PHOSPHATASE: PROTEIN PHOSPHATASE 2A (PP2A) – more responsible for hyperphosphorylation of

TAU than Kinases.

PIN1 Enxyme protects the brain from excessive Amyloid Beta production and excessive tau Phosphorylation.
Damage to Pin1 causes AD.
 In late stages, NFT become oxidized and glycated. NFTs bind to Proteosomes, inhibiting the organelle
to remove damaged proteins in the cell. This leads to accumulation of Amyloid Plaques and thus leads to AD.
Ubiquitin dependent degradation of Protein id inhibited by Amyloid Beta. Ubiquitin id concentrated in NFTs

Although little is known about the process of filament assembly, it has recently been shown that the
depletion of Prolyl Isomerase Protein in Parvaulin family accelerates the accumulation of TAU.

We now move on to the question whether the central mechanism of Ad neurogeneration is Amyloid
Beta or Neurofibrillary tangles of TAU Protein? These lead to the formation of religious wars between “tauists”
and “βaptists”. There are two theories postulated. The first theory states that Amyloid Plaque Formation
extracellulary is an early event while NFT formation is a late event. These two events were independent from
each other. While the second theory postulated that Amyloid Beat Formation lead to NFT Formation.
Some research literatures like NATURE 418:291(2002) AND CHEMICAL AND ENGINEERING
NEWS 80 (32); 31-34 (2002) stated that Amyloid Beta fibrils form pores in neurons leading to calcium influx
leading to activation on calcium activated kinases to excessively phosphorylate TAU, thus forming NFTS and
then leading to neuronal death in AD.

Choline Hypothesis
Acetylcholine ( ACh ), neurotransmitter can be found in the brain, neuromuscular junctions, spinal cord,
and in both the postganglionic terminal buttons of the parasympathetic division of the autonomic nervous
system and the ganglia of the autonomic nervous system. Acetylcholine ( ACh ) is synthesized from acetyl-
CoA and Choline. Chemical reactions in brain for the production of Acetylcholine ( ACh ).

One of the characteristic changes that occurs in Alzheimer's disease is the loss of memory
However, AChE activity is increased around amyloid plaques.
Marked reduction in choline acetyltranferase (ChAT) and acetylcholine (ACh) in the hipocompus and
the neocortex of the patients with Alzheimer’s disease. This loss of cholinergic synthetic capacity was attributed
to a reduction in the number of cells in the basal forebrain nuclei (nucleus basalis of Meynert), from which the
major portion of neocortical cholinergic terminals originate.
It was subsequently shown that projections from nucleus basalis provide the primary source of
neocortical acetylcholine. There are also cholinergic projections from the adjacent medial septum and diagonal
band of Broca to hippocampus. All these cholinergic projections together making up a wide source of
acetylcholine ( ACh ) in the brain. Acetylcholine (ACh ) role in learning and memory is on clear that most the
acetylcholine ( ACh ) in the neocortex originates in the basal forebrain, that cholinergic synapses themselves
were the sites for memory storage.
ACh receptors are one of the chief receptors for excitator neurotransmitters. The binding of
acetylcholine to ACh receptors results in a change in memprane potential of the target cell leading to an action
potential in the muscle cell. The acetylcholine is rapidly removed by enzymatic breakdown(acetyl
cholinesterase) so that when the presynaptic cell stops, the post synaptic cell will stop as well.

Acetylcholine

Acetylcholine is a neurotransmitter found in cholinergic synapses that provide a stimulatory transmission in the nervous
system. Acetylcholine (C01996) is synthesized from choline and acetyl-CoA by the enzymecholine acetyl transferase (EC 2.3.1.6) to form
acetylcholine, which is immediately stored in small vesicular compartments closely attached to the cytoplasmic side of presynaptic membranes.
Acetylcholine synthesis is a process that occurs only in the specialized region of neurons called synapses. The choline used for the synthesis of
acetylcholine is derived from the phospholipid phosphatidylcholine. Enzymes calledphospholipases catalyze the degradation of phosphatidylcholine
(PC).

Two independent pathways have been established for the release of choline. First, phospholipase D (EC 3.1.4.4) cleaves the phosphoester bond
towards the choline headgroup forming free choline and the membrane bound phosphatidic acid (PA). Phospholipase D is predominantly localized to
late endosomes and lysosomes (FEBS Lett 1999; 442(2-3):221-5). Choline is then covalently linked with an activated acetyl unit from acetyl-CoA to
form acetylcholine. This reaction is performed by choline-acetyl transferase (EC 2.3.1.6). Second, PC is degraded into its glycerol backbone and
fatty acid components by the sequential action of phospholipases A and B. Phospholipase A1 (EC 3.1.1.32) or Phospholipase A2 (EC 3.1.1.4)
removes the acyl chain from the C1 position forming a free fatty acid and lysophosphatidylcholine (lysolecithin). The second phospholipase B (EC
3.1.1.5) removes the C2 acyl residue to form glycerol-3-phospocholine and a fatty acid. Glycerol-3-phospocholine is hydrolyzed to glycerol-3-
phosphate (G3P) and choline.

Acetylcholine is then accumulated and stored in synaptic vesicles via a vesicular acetylcholine transporter. These vesicles are closely associated
with the cytoplasmic surface of the presynaptic membrane. Phospholipase D may play a role in guiding these acetylcholine loaded vesicle to the
membrane. This is based on evidence that phospholipase D activity is associated with control of membrane vesicular transport. This lipase may thus
provide a double mechanism for choline synthesis and the cytoplasmic transport of acetylcholine containing vesicles.

Upon a stimulus from an action potential and mediated by calcium induced membrane fusion (exocytosis), up to 300 vesicles per synapse release
their contents (acetylcholine) into the synaptic cleft, instantly providing a high concentration of neurotransmitters. Acetylcholine concentration
temporarily raises from 10nM to 0.5mM, a 50,000 fold increase occurring in about a millisecond. Acetylcholine rapidly diffuses across the cleft (20
to 50 nm) binding to nicotinic acetylcholine receptors located in the post-synaptic membranes found at neuro-muscular junctions. These receptors
initiate an action potential event in the muscle cell membrane causing a massive influx of extra-cellular calcium, thereby triggering muscle
contractions.

The exocytotic process of acetylcholine release can be inhibited by botulinum toxin. This potent toxin prevents the membrane fusion process and
causes muscle paralysis. Botulinum toxin is actually a mixture containing eight distinct proteins produced by the anaerobic bacteria Clostridium
botulinum. So called botulism is a major cause of food poisoning related to unrefrigerated meat.

Acetylcholine esterase (AChE)

Acetylcholine is rapidly removed by acetylcholine esterase (EC 3.1.1.7; AChE). The turnover rate of hydrolysis is 2.5x104 molecules per second.
This hydrolytic degradation ensures that the signal does not overstimulate the post-synaptic membrane. A molecular dynamics simulation published
in 1994 in the Journal 'Science' suggested that electrostatic fields funnel acetylcholine into the active site channel and release the hydrolysis products
through a 'back door' (Science, 1994, 263(6161)1276). The products choline and acetate are inactive molecules and are reabsorbed by the synapse
and recycled to replenish acetylcholine containing vesicles for subsequent chemical transmission. AChE is a serine esterase and has a catalytic triad
similar to that found in serine proteases trypsin and chymotrypsin. The triad consists of Ser200, His440, and Glu237 (note that serine proteases
contain a aspartate and not glutamate). The enzyme is located on the surface of the post-synaptic membrane and linked by a GPI anchor.

AChE can be inhibited resulting in the overstimulation of neuromuscular junctions. This leads to spasms and death by suffocation because the heart
muscles experience severe arrhythmia. AChE inhibitors have been used for a long time by the military as nerve gas. The most prominent
are tabun and sarin, which are specific for the human acetylcholine esterase. An insect specific AChE inhibitor, malathion, which does not bind to
the human isoform of the enzyme, is used by citrus crop producers to fight against Mediterranean fruit fly (Medfly; Ceratitis capitata) infestations.
 A. LIPOPROTEINS AND CHOLESTEROL

High levels of cholesterol are associated with increased risk of AD. Patients taking statins (a class of cholesterol-
lowering drugs) had a 60-73% lower prevalence of probable AD [ARCHIVES OF NEUROLOGY 57:1439-1443 (2000)].
Rabbits fed cholesterol showed twice the beta-amyloid in the hippocampal cortex as controls [ANNALS NEW YORK
ACADEMY OF SCIENCES 903:335-345 (2000)]. Cholesterol binds avidly to aggregated amyloid-beta, reducing
clearance and contributing to amyloid plaque [ANNALS NEW YORK ACADEMY OF SCIENCES 977:367-375 (2002)].
Atherosclerosis and AD are both particularly prevelant for the APOE4 genotype [LANCET 349:151-154 (1997)].

Apparently, the subcellular distribution of cholesterol affects amyloid-beta production. Beta-secretase activity occurs
in the trans-Golgi network & late endosome, whereas gamma-secretase release of beta-amyloid is thought to occur in the
endoplasmic reticulum [NEUROREPORT 10:1699-1705 (1999)]. Both beta-secretase & gamma-secretase activity
increases with elevated cholesterol, whereas the opposite effect is seen with alpha-secretase (which is more active with
lower cholesterol) [NEUROBIOLOGY OF DISEASE 9:11-23 (2002)]. APOE4 is associated with increased deposition of
Aß, but APOE4 has no effect on the rate of neurofibrillary tangle accumulation [ANNALS OF NEUROLOGY; Gomez-
Isla,T; 41(1):17-24 (1997)].

Cholesterol deposition on cerebral vessel walls can lead to ischemia. APOE4 genotype nearly triples the chance of
developing cerebral amyloid angiopathy (depositing of amyloid-beta on blood vessel walls) -- which can also lead to
ischemia. Ischemic release of calcium from the endoplasmic reticulum and disturbance of endoplasmic reticulum PS1
could be the ultimate cause of AD [NATURE MEDICINE 3(9):1016-1020 (1997)]. Alternatively, ischemic hypoperfusion
could be causing AD by the failure to eliminate amyloid-beta from the brain [ANNALS NEW YORK ACADEMY OF
SCIENCES 977:162-168(2002)]. Aß40 peptide has been shown to enhance cerebrovascular vasoconstriction and
hypoperfusion [ANNALS NEW YORK ACADEMY OF SCIENCES 826:35-46 (1997)]. An abnormal drop in endothelial
nitric oxide synthetase could promote inflammatory action by amyloid-beta [BRAIN RESEARCH REVIEWS 34:119-136
(2000)]. In any of these scenarios, AD is ultimately due to vascular disease.

B. INFLAMMATION AND IMMUNORESPONSE

The toxicity of Aß42 (amyloid-beta) is often attributed to the aggregation of this peptide into a ß-sheet structure of
ordered fibrils. Acidic conditions (such as exist in lysosomes and inflammation) enhance amyloid-beta aggregation.
Cross-linking with Advanced Glycation End-products (AGEs) stabilizes amyloid plaques and accelerates the formation of
ß-sheets. The Receptor for Advanced Glycation End-products (RAGE) may mediate the activation of microglia
potentiation of a positive feedback loop of immune/inflammatory activation.

RAGE can also act as a receptor for both AGEs and Aß. Activation of RAGEs by Aß and AGEs results in the
expression of more RAGEs, a feedback-loop that contributes to Aß toxicity Aß interaction with RAGEs on endothelial
cells leads to Aß transport across the blood brain barrier (BBB) as well as the expression of pro-inflammatory cytokines in
those cells.

Neurons in the brain are supported & nurtured by glial cells, classified as either macroglia (astrocytes &
oligodendrocytes) or microglia. The microglia of the brain serve a similar function as macrophages outside of the brain.
Normally the microglia are few in number, but they multiply in response to injury & infection and are concentrated
around amyloid plaques reactive astrocytes. Amyloid-beta activation of microglia causes them to produce inflammatory
cytokines like InterLeukin-1ß (IL-1ß) & Tumor Necrosis Factor alpha (TNF−α). Amyloid-beta also activates the
transcription factor NF−κB which increases cytokine production by neurons as well as by microglia [PROCEEDINGS OF
THE NATIONAL ACADEMY OF SCIENCES (USA); Kaltschmidt, B; 94(6):2642-2647 (1997)]. Microglia induces
enzymes such as nitric oxide synthetase -- generating nitric oxide leading to peroxynitrite and oxidative stress.

IL-1ß further aggravates the immune/inflammatory response by promoting more APP synthesis and by promoting
the production of more Aß-binding proteins by astrocytes. Over-expression of interleukin-1 near amyloid plaques may
promote the phosphorylation of tau protein, leading to the formation of NeuroFibrillary Tangles (NFTs) and neuron
death.

The idea that a positive feedback-loop of immune/inflammatory response is central to the damaging processes of
Alzheimer's Disease (AD) is reinforced by the fact that epidemiological studies have shown significant reductions in the
rate of AD among people taking anti-inflammatory drugs for conditions unrelated to AD. The relative protection from AD
seen from the anti-inflammatory drugs is in excess of 50% for persons taking the drugs for more than two
years [NEUROLOGY OF AGING 22:799-809 (2001)]. The effect is seen for the use of ibuprofen & indomethocin rather
than for glucocorticosteroids, which are normally seen as having more profound anti-inflammatory effect. Non Steroidal
Anti inflammatory Drugs seem to be more effective in preventing AD than in treating the disease. They act by reducing
inflammation by inhibition of the enzyme cyclooxygenase(COX). Although NSAIDs block both COX-1 & COX-2, the
beneficial effects are primarily attributed to inhibition of COX-1 in the microglia. Unfortunately, COX-1 inhibition is
associated with gastrointestinal bleeding. It has been suggested that NSAIDs directly decrease Aß 42 formation,
independent of COX inhibition [NATURE 414:212-216 (2001)], but neither naproxen nor aspirin lower Aß 42, yet both
have protective effects against AD.

C. METAL TOXICITY AND FREE RADICALS

Numerous epidemiological studies have indicated a correlation of aluminum in drinking water with the
prevalence of AD, whereas studies of aluminum occupational exposure and aluminum in antacids have shown no
correlation [BRAIN RESEARCH BULLETIN 55(2):187-196 (2001)]. Aluminum concentration is elevated in NFTs &
amyloid plaques, but this may be an effect of AD rather than a cause. Mercury is also elevated in the AD brain. Mercury
can bind to tubulin, the primary protein constituent of microtubule thereby interfering with microtubule assembly. Zinc &
selenium may protect against mercury neurotoxicity. The copper & iron in these plaques generate hydrogen peroxide
leading to oxidative damage. Zinc can initiate plaque formation by its ability to bind to Aß under non-acidic conditions
and by creating the inflammation which leads to acidity. Under acidic conditions -- such as exists in inflammed tissue.
Membranes containing oxidatively damaged phospholipids also promote amyloid ß-sheet formation [BIOCHEMISTRY
39(32):10011-10016 (2000)].

In its free state amyloid-beta has antioxidant properties which have beneficial effects for neurons. But amyloid-
beta aggregation by acidic conditions and by copper, iron, zinc & aluminum results in the highly toxic & pro-oxidant ß-
sheets. The binding is particularly strong for copper. Copper binds more strongly to Aß42 than to Aß40 and copper is a
greater catalyst of free radical formation than are the other metals [FREE RADICAL BIOLOGY & MEDICINE
31(9):1120-1121 (2001)]. Cu2+ bound to free Aß42 is reduced by O2 to produce H2O2 [JOURNAL OF BIOLOGICAL
CHEMISTRY; Opazo,C ; 277(43):40302-40308 (2002)]. Thus, copper, and to a lesser extent iron, appear to be the most
serious metal toxicities in AD.
 Polymerization of ß-amyloid peptide may be significantly accelerated by the presence of Advanced Glycation
End-products (AGEs) [BRAIN RESEARCH REVIEWS 23:134-143 (1997)]. AGEs are formed by glycation of proteins
by reducing sugars, followed by oxidation.

The most prominent marker of DNA free radical damage is 8-hydroxydeoxyguanosine (8-OHdG, equivalent to 8-
oxo-7,8-dihydroguanine, 8-oxoG). Levels of 8-OHdG are 18 times higher than normal in intact DNA from the
cerebrospinal fluid of Alzheimer's Disease patients [ARCHIVES OF NEUROLOGY 58:392-396 (2001)]. Tau-protein is
high in lysine, which would make tau highly susceptible to glycation [PROCEEDINGS OF THE NATIONAL
ACADEMY OF SCIENCES (USA); Yan,S; 91(16):7787-7791 (1994)]. Indeed, Advanced Glycation End-products
(AGEs) are intimately associated with NFTs and the resultant free radical generation undoubtedly makes a significant
contribution to neurodegeneration. In fact, it has been suggested that protein cross-linking associated with AGEs is more
critical to NFT formation than phosphorylation [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES
(USA); Smith,MA ; 91(12):5710-5714 (1994)]. Although Aß42 is most highly concentrated in neuritic plaques, Aß40 in the
soluble state may be the most toxic form of amyloid-beta [THE AMERICAN JOURNAL OF PATHOLOGY; Lue,L;
155(1):853-862 (1999)]. Nonetheless, both forms of amyloid-beta have been shown to cause neurotoxic oxidative
stress [JOURNAL OF STRUCTURAL BIOLOGY 130:184-208 (2000)].

D. CIGARETTE AND TOBACCO SMOKING

Several early epidemiological studies claimed that cigarette smoking has a protective effect against Alzheimer's
Disease [NEUROEPIDEMIOLOGY 13:131-144 (1992)]. Such studies have been criticized on many methodological
grounds, including survival bias & recall bias [ADDICTION 97:15-28 (2002)] and [BIOLOGICAL PSYCHIATRY
49:194-199 (2001)]. More nicotine receptors and fewer senile plaques are not surprising among autopies of smokers if
they are dying at a younger age than non-smokers.

More recent prospective (cohort) studies found opposite results from the earlier cross-sectional or prevalence
studies. A prospective Rotterdam Study found that the incidence of AD is more than double for smokers as compared to
non-smokers (smoking was not an additional risk factor for those having the APOE4 allele) [THE LANCET 351:1840-
1843 (1998)]. The Honolulu Heart Program (a longitudinal cohort study) also found more than twice the risk for AD
among medium & heavy smokers as compared to non-smokers [NEUROBIOLOGY OF AGING 24:589-596 (2003)].

M2 muscarinic receptors and nicotinic receptors are markedly decreased in AD. Nicotine administration to
transgenic mice has significantly reduced Aß42 plaques as compared to sucrose-administered controls [JOURNAL OF
NEUROCHEMISTRY 81:655-658 (2002)]. Nicotine administration into rat hippocampus produces lasting elevation of
Nerve Growth Factor (NGF), enhancing acetycholine production & release [BIOLOGICAL PSYCHIATRY 49:185-193
(2001)]. Studies of AD patients have shown beneficial effects of nicotine administration [BIOLOGICAL PSYCHIATRY
49:200-210 (2001)]. Nonetheless, a mouse model has shown a worsening of tau protein pathology (NFTs) due to nicotine
administration [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Oddo,S; 102(8):3046-3051
(2005)].

Tobacco smoke is a lethal substance, so claims of its possible benefits against AD should be viewed with caution. In a
40-year longitudinal study of tens of thousands of British Physicians, the death rate between the ages of 35 to 69 was only
20% for non-smokers as compared to 41% for smokers as a whole and 50% for those who smoked more than 25 cigarettes
per day. Of those who survived to age 70, nonsmokers had twice the chance of living to age 85 as smokers [BRITISH
JOURNAL OF MEDICINE 309:901-911 (1994)]. Even if nicotine is proven decisively to be of benefit in AD, it should
be administered as nicotine patches rather than as tobacco smoke -- which contains carbon monoxide, cadmium and
thousands of other toxins which may contribute to AD. If AD is a vascular disease, the damaging effects of the toxins in
tobacco smoke on the vasculature alone could easily outweigh possible increases in brain NGF. And if AD is not a
vascular disease, tobacco smoke certainly nonetheless contributes to vascular dementia.

I. TREATMENT AND PREVENTION MANAGEMENT

 A. DRUGS

1. DONEPEZIL- (Aricept) acting reversible acetylcholinesterase inhibitor. Selectively inhibits

acetylcholinesterase.

2. GALANTAMINE- (Razadyne) competitive and reversible cholinesterase inhibitor. It reduces the action of
AChE and therefore tends to increase the concentration of acetylcholine in the brain. It is hypothesized that
this action might relieve some symptoms of AD.

3. RIVASTIGMINE-(Exelon) parasymphatomimetic ang cholinergic agent. A cholinesterase that inhibits both

butrylcholinesterase and acetylcholinesterase.

4. MEMANTINE-It acts on the glutamergic system by blocking the NMDA receptors and inhibiting their
overstimulation by glutamate.

II. PREVENTION

There is no definite evidence to support that any particular measures is effective in preventing AD. However,
epidemiological studies have proposed relationships between certain modifiable factors such as:

1. Diet

2. Cardiovascular risk

3. Pharmaceutical products

4. Intellectual activities