a report on alzheimer’s disease and current research

8/14/2019 A Report on Alzheimers Disease and Current Research

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A Report on Alzheimers Disease

and Current Research

by Dr. Jack Diamond, Scientifc Director

Alzheimer Society of Canada


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2005 Alzheimer Society of CanadaRevised 2008


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A Report onAlzheimers Disease and Current Research

by Dr. Jack Diamond, Scientifc Director



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A Report on Alzheimers Disease and Current Research

Dr. Jack Diamond

Dr. Diamond is the Scientic Director ofthe Alzheimer Society of Canada. He wasformerly Associate Director for Scientic

Affairs at the Montreal Neurological Instituteat McGill University, and was the foundingChair of the original Department of

Neurosciences when the new medical school was establishedat McMaster University in Hamilton, Ontario. Dr. Diamondis also Professor Emeritus in the Department of Psychiatryand Behavioral Neurosciences at McMaster University, wherehe continues to run his laboratory research program witha special focus on diabetic neuropathy and on the apoE4risk factor for Alzheimers disease. Dr. Diamond is a long-

standing member of the grant review committees of theJuvenile Diabetes Research Foundation International, and healso served as a volunteer Scientic Committee reviewer andconference speaker for the ALS Society of Canada and theSpinal Cord Society.

Dr. Diamond received his PhD and subsequently his medicaldegree at the University of London, England, after which hedid two years of post-doctoral research at Harvard MedicalSchool, returning to a faculty position at University CollegeLondon. He is widely published, having written more than

70 papers in refereed journals, and 15 book chapters.

Te Alzheimer Society

The Alzheimer Society is a nationwide, not-for-prothealth organization dedicated to helping people affectedby Alzheimers disease. The Society consists of a national

ofce, 10 provincial organizations and more than 140local ofces across the country. The Society develops andprovides support and educational programs and informationfor people with the disease, their families, caregivers andmembers of the health-care team. The Society is a leadingfunder of Alzheimer research in Canada.


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able o Contents

Introduction

What is Alzheimers disease? .............................................................................................1

What causes Alzheimers disease? ....................................................................................2

Risk factors ............................................................................................................................3How can we reduce the risk of developing Alzheimers disease? ............................5

Four brain changes that occur with Alzheimers disease ...........................................6

i) The Plaques ..........................................................................................................7

ii) The Tangles ..........................................................................................................7

iii) Inammation of the brain ...............................................................................7

iv) Shrinkage and degeneration of nerve cells ................................................. 8

How is Alzheimers disease diagnosed? ..........................................................................8

Drug treatments ...................................................................................................................9

i) Aricept (donepezil), Exelon (rivastigmine), and Reminyl(galantamine) ........................................................................................................9

ii) Ebixa (memantine hydrochloride) .............................................................10

What other leads are being followed that could lead to earlier diagnosisor new treatments? ............................................................................................................ 10

i) Vaccines...............................................................................................................10

ii) MCI ......................................................................................................................11

iii) Statins .................................................................................................................11iv) Alzheimers disease and diabetes ..................................................................11

v) Anti-inammatory agents such as aspirin and other NSAIDs(nonsteroidal anti-inammatory drugs) ......................................................11

vi) Other drug therapies ......................................................................................12

vii) Early diagnosis by measuring chemical levels in tissues outsidethe brain ..............................................................................................................12

viii) Making new nerve cells from stem cells .....................................................12

ix) Promoting brain repair ....................................................................................14

A proposal: caregiving could be promoting brain repair ........................................15

Animal studies offer hope that lost long-term memories may be recoverable ...15

The Next Ten Years ..........................................................................................................16

Where does the Alzheimer Society come in? ..............................................................17


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Introduction

For the past few years Dr. Jack Diamond has

been making presentations on Alzheimers disease

research to various audiences across Canada and

internationally. From these presentations,A Report

on Alzheimers Disease and Current Researchhas been

created. The purpose of this report is to provide

people who are not scientists or clinicians with easy

to understand information on Alzheimers disease,

including risk factors, how researchers decide on the

most promising ways to search for new treatments

and where we stand in the search for a cure. To keep

pace with the rapid advances in research, this report

is updated periodically. This report focuses on the

advancements made in biomedical research. A new

companion report (in preparation) focuses on the

equally important Social/Psychological research,

which addresses the day-to-day issues that impact the

quality of life for people with Alzheimers disease,

their caregivers and their families. This companion

report will be available in the spring of 2008.


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What is Alzheimers disease?

Alzheimers disease is the most widespread of a large class ofdisorders which clinically are known as dementias, diseasescharacterized by a progressive deterioration of thinkingability and of memory. Alzheimers disease is a disease ofthe brain, in which nerve cells die and their connections withother nerve cells are lost. It was originally regarded as a purelybehavioral disorder, an inevitable decline in brain functionsas one aged, just like the deterioration of the body and itsability to undertake physical activities. For that reason it wasrst called senile dementia. This view changed however, or atleast began to change, when Dr. Alois Alzheimer publishedhis description of senile dementia over one hundred yearsago. After his female patient died in her early fties withsenile dementia he studied her brain tissue in the microscope,and observed the plaques and tangles which are nowaccepted as the hallmarks of the disease (well return to theselater). The plaques are sometimes referred to as amyloidplaques, senile plaques, and neurotic plaques. Some3-4 years later, in his honour, senile dementia was renamed

Alzheimers disease. Somewhat surprisingly it took morethan half a century for Dr. Alzheimers message to sink in

that senile dementia was a genuine disease, in which nervecells in the brain die due to the toxic effects of a number ofabnormal (pathological) changes that occur in the brain.

In most cases, the disease progresses slowly, but the rateof decline is extremely variable and changes from personto person. In many instances it may be preceded by a fewyears of Mild Cognitive Impairment (MCI), a condition in

which true dementia is absent, but nevertheless memory and

cognitive functions are detectably reduced (MCI is returned tolater). In Alzheimers disease, forgetfulness gradually increasesand in the later stages even close family members may fail tobe recognized. The ability to carry out normal activities suchas reading, driving, and cooking gradually decreases, as doesthe ability to make judgments and appropriate responses toeveryday issues. There can also be behavioural changes suchas agitation, aggression, depression, disturbances of balanceand movement, and an inability for people to nd their wayeven in familiar surroundings. In time the affected persons

become unable to look after themselves and caregiversbecome essential for all aspects of daily living. Alzheimersdisease is ultimately fatal, and death usually occurs withinseven to 10 years after diagnosis. The body is weakened byinactivity and muscle wasting, and a lowering of the bodysimmune functions makes bacterial and viral infections verycommon. This leads to the usual cause of death, pneumonia,hastened by the decreasing ability of the affected person tocough and generally to move about normally.


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It is important to know that Alzheimers disease is not a normal part ofaging. The decline in memory and thinking ability reect theprogressive death of brain cells caused by the disease process.

This is quite different from relatively minor brain cell loss thatmay occur naturally with aging, a loss which, until extreme

ages are reached may only marginally affect memory andcognitive ability.

New studies of the incidence of Alzheimers disease arein progress, but at present it appears that some 5-8% ofCanadians over the age of 65 have Alzheimers disease,rising to an alarming 30-50% of those over 85. While the

vast majority of Alzheimer cases are of the sporadic or lateonset form of Alzheimers disease, about 5 to 7 per cent ofthe Alzheimer population are in the category called Familial

Alzheimers disease (FAD), which traditionally used to be

called early onset Alzheimers disease (due to the fact thatpeople with FAD typically manifest symptoms earlier thanthose with sporadic Alzheimers disease). FAD is identicalto the sporadic form, but it is largely attributable to theinheritance of certain genes which at some point in thatfamily tree mutated. This means that they changed theirnormal character to an abnormal one that didnt functionproperly, and because they were inherited entire familiesbecame susceptible to Alzheimers disease. The discoveryof these mutated genes has been critically important in

furthering our understanding of all Alzheimers disease, andin allowing scientists at long last to create animal models ofthe disease upon which potential treatments can be tested.

Are we experiencing an epidemic of Alzheimers disease?Not really, but the numbers are increasing dramatically. Thisis attributable to the increasing ability of new diagnosticapproaches to reveal Alzheimers disease at earlier stages, toan aging Canadian population, and to the fact that the riskfactors for Alzheimers disease (see following) do genuinelyappear to be on the increase. While all this makes it appearas though a new type of early onset Alzheimers disease isappearing, this is not the case. The disease has not changedits character. It would be best to reserve the use of earlyand late onset Alzheimers disease simply to describe theindividual case, rather than the type of disease. Early onset

Alzheimers disease now should refer to people who developthe disease at ages signicantly younger than 65 years and

who are very likely to have the common sporadic form ofAlzheimers disease. Late onset Alzheimers disease generallyrefers to people who develop the disease at ages over 65.

What causes Alzheimers disease?

Its often stated that we dont know what causes Alzheimersdisease, but many are coming to the conclusion that in asense we actually do. All the organs of the body, including

the brain, have built-in self-repair mechanisms. Alzheimersdisease appears to develop when the combined effects of theknown and still to be identied inuences called risk factorscross a certain threshold. At this point they overwhelm thenatural self-repair and self-healing mechanisms in the brainthat normally maintain the nerve cells in a healthy state. If this

view is correct, then there is no specic cause of Alzheimersdisease, but rather it is the additive effects of multiple factors,

with aging heading the list.

Oxidative stress and Alzheimers disease

Oxidative stress refers to the threatening situation createdwhen small molecules known as reactive oxygen species(ROS) begin to accumulate faster than the body can get ridof them, allowing them to exert their adverse toxic effectson cells everywhere in the body, including the brain. ROSare normal products of metabolism, and can even be usedto benecial ends, for example by the immune system asone way to kill invading organisms. However, as ROS buildup they become damaging. Normally ROS are eliminatedby special enzymes made by the bodys cells, assisted by theintake in food of natural anti-oxidants such as vitamins Cand E. But environmental stress, many diseases, some drugs,the internal stress generated whenever a persons health and

well-being are threatened, probably most of the risk factorsdescribed below, and even A-beta itself (A-beta is the proteinregarded as the principal culprit in Alzheimers disease, as

will become evident in the following sections), all act toincrease the production of ROS, and to reduce the efciencyof their elimination by the body. This is oxidative stress. Itsan important contributor to the deterioration of the bodys

tissues and cells in aging, and its a major component ofAlzheimers disease. Oxidative stress, therefore, is a key targetof Alzheimer treatments, among which a healthy lifestyle isparamount.


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Risk Factors

These are characteristics of the person and the personslifestyle and environment that contribute to the likelihoodof getting the disease. While most risk factors are well

established, some are still controversial. Many of the riskfactors for Alzheimers disease, like high cholesterol levels orhigh blood pressure, are risk factors for many other diseasesas well. It is becoming increasingly recognised that most, ifnot all, of the risk factors help induce oxidative stress.

Aging

As indicated above, aging is the most important risk factor.Whatever other risk factors are present, Alzheimers diseasenever sets in until some minimum adult age is reached.

This age may be signicantly younger for a person withFAD. An important consequence of aging is deteriorationin the efciency of the bodys self-repair mechanisms. Thedeterioration occurs at different rates in different people,

which may also explain in part why some people are moresusceptible to getting Alzheimers disease than others.

While aging would appear to be the one risk factor that wecan do least about, this may not be so. A huge amount ofresearch is going into nding out what causes the progressivedeterioration in aging of tissues and organs that include thebrain (including the role of oxidative stress described above),and there is a genuine feeling among scientists that the answeris not beyond reach. There is solid evidence that in animalsa rigorously controlled caloric restricted diet (CR), beginningat weaning, dramatically slows the aging process. Whileinstituting an equivalent life-long CR in humans is just notpossible, the fact that body aging can be inuenced at all is a

very important stimulus to scientic research on aging. Theobjective is not so much to prolong life as to prevent the slowdecline in function during it. Everybody knows that someolder people seem to have remarkably young brains, while in

contrast, others seem to be old before their time. The pointhere is that from the perspective of Alzheimers disease, it isnot chronological age that matters but brain age, something

we can recognize but so far cannot control. One encouragingitem is that scientists are well on their way to understandingthe brains self-repair mechanisms, and are looking at ways toactivate them when they seem to be switching off, as in aging.

Genetic risk factors

Aside from the already mentioned mutated genes heavilyimplicated in FAD, the most important genetic risk factor forthe common sporadic Alzheimers disease is the apoE4gene. In contrast to the genes responsible for FAD, this geneis not an abnormal one, i.e. it has not undergone a mutationthat has impaired its ability to carry out its usual job. ApoE4 isone of the three variants of the apoE gene, the others beingthe benign apoE2 and apoE3 genes. Everybody has a doubleset of genes, one from each parent. If a persons pair of apoEgenes include one apoE4 (inherited from one parent), theyhave three times the normal risk of developing Alzheimersdisease. However, if they carry two apoE4 genes (meaningone from each parent) the risk increases to ten times. Thatsaid, it is important to note that people with no apoE4 genes

can still get Alzheimers disease, just as people with twoapoE4 genes can escape it. Having a parent or sibling with

Alzheimers disease increases ones risk two to three times,implying the likely involvement of genes not yet identied.Researchers are actively looking for evidence of other quitenormal genes that predispose one to Alzheimers disease,but it seems unlikely that these still to be discovered genes

will be as important a risk as the apoE4 one. To date, morethan a dozen gene variants have been identied that occurin people with Alzheimers disease to a greater extent than in

non-Alzheimer people, but as with the apoE4 gene, peoplecan have Alzheimers disease and not have these suspect

variant genes. Researchers are especially interested in theevidence that some variant genes (like the recently discoveredSORL1 gene) lead to a situation in the nerve cells thatfavors the production of the potentially dangerous A-betaprotein (also called beta amyloid), about which more willbe said later. Further research on these suspect genes couldproduce results that help chemists design drugs that wouldlessen the production of this threatening protein. Finally, a

newly identied gene (GAB2) in its healthy form appears toprotect the brain from developing tangles, but in a modiedform found in the Alzheimer brain seems to promote thedevelopment of tangles inside nerve cells. Again, futureresearch may be able to capitalize on these ndings to designdrugs that will oppose tangle formation.


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In addition to aging and to genetic factors, all the followinghave been documented as risk factors for Alzheimers disease:

Diabetes it has been known for some years that type2 (adult) diabetes is a risk factor for Alzheimers disease,in large part, it was assumed, because of the associatedblood vessel and heart disorders, and sometimes obesity,that are known risk factors for Alzheimers disease. Itsalso well established that glucose utilization is impaired inthe brains of people with Alzheimers disease, rather likethe situation in the bodies of people with diabetes. Newresearch techniques and brain imaging have now revealedthat the impairment in the Alzheimer brain is probablybecause the brain is itself in a sort of diabetic state, andit has even been suggested that Alzheimers disease becalled type 3 diabetes, even though the affected person

may not be diabetic in the ordinary sense. Its now knownthat in type 2 diabetic people, the toxic protein implicatedin plaques may be present in the pancreas (the organ thatnormally produces insulin), strengthening the suspectedlink between type 2 diabetes and Alzheimers disease.In any event, it seems that in the Alzheimer brain either(i) the production of insulin (known to occur in brains)is reduced for some reason, in this regard resemblingtype 1 (juvenile) diabetes and/or (ii) that the brain cellsare becoming insensitive to insulin, like the rest of the

bodys cells in type 2 diabetes. The outcome of thesediscoveries is that new anti-diabetic drugs which help thecells of people with type 2 diabetes respond to insulinare now being tested in people with Alzheimers disease

who are not diabetic to nd out if they can reducethe abnormalities in the brain. There are promisingindications of memory and cognitive improvement inthese people.

Head injury also know as traumatic brain injury,or TBI.

Strokes and Ministrokes the latter are very smallhemorrhages in the brain that seemed not to have causedany symptoms when they occurred, but evidence that

they did indeed occur is clearly visible when routinebrain imaging is done at later times. It is now known thatboth strokes and TBI cause increases in enzymes calledcaspases, which then, through a series of biochemicalsteps, allow other enzymes called BACE to build up inthe brain. This is bad news, because increased BACEactivity is partly responsible for the excessive formationof A-beta in Alzheimers disease.

High cholesterol levels

High blood pressure

Mild Cognitive Impairment (MCI) this importantrisk was mentioned earlier (What is Alzheimersdisease?). A diagnosis of MCI is commonly regardedas indicative of a high, but not certain, likelihood ofdeveloping the full-blown Alzheimers disease within thefollowing 10 years.

The post-menopausal state in women twice asmany women get Alzheimers disease than men. Thisis partly explained by their living longer than men on

average, partly because women are more prone thanmen to get diabetes, itself a risk factor, but in large partbecause in post-menopausal women there is a decline ofthe important hormone estrogen.

Downs Syndrome almost all with this disorderwho survive into their 40s or beyond will develop theabnormal brain changes that characterize the brain in

Alzheimers disease, but importantly, not all of these willactually develop dementia.

Chronic inammatory conditions , such as certain

forms of arthritis.A history of episodes of clinical depression

Stress

Lack of physical exercise

Inadequate exercising of the brain in a twin study,the ones doing more intellectually demanding work wereless likely to develop the disease than their identical twins.

Unhealthy eating habits

Obesity


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Low levels of formal education

Low socio-economic status

There are also risk factors that are not so rmly establishedsuch as smoking, excessive drinking, and taking drugs ofabuse. Researchers are still examining whether some peopleare at risk because their bodies have difculties in handlingfoods containing the metals copper, iron, and aluminum,although most researchers no longer regard aluminum as arisk factor for Alzheimers disease. Finally, some of the riskfactors, particularly the last two listed above (low educationand/or socio-economic status), may actually have beenidentied as such because persons in those categories areoften people exposed to risk factors such as inadequateexercising of the brain and of the body.

Always remember, however, that exposure to any or even to all ofthe known risk factors does not mean that a person will get Alzheimersdisease. Equally one may have limited exposure to the known risk

factors and yet still develop the disease.

How can we reduce the risk o developingAlzheimers disease?

Only the genetic risk factors and aging are currently beyondour control. Its important to understand that what matters isnot only how many risk factors a person might be exposed

to, but as already mentioned, how efciently the self-healingprocesses in his or her brain operate. It seems that thebrains ability to withstand risk factors and to preserve andeven enhance its healing capacity can be enormously helpedby adopting appropriate healthy lifestyles. These actuallyenhance the production in the brain of growth factors(more on these later), which promote the ability of braincells to maintain connections with each other and make newconnections. Recent discoveries suggest that healthy lifestylesmay even help in the creation of new nerve cells, which is

discussed later in the context of brain repair. The importanceof lifestyle can be appreciated from studies of identical twins,

who share the same genes. It turns out that about 60 percent of the overall risk factor for Alzheimers disease comesentirely from lifestyle and not genetic susceptibility. Healthylifestyles are often effective in reducing the Alzheimer riskindirectly, by reducing specic risk factors such as stress andobesity. Of obvious benet is the appropriate treatment ofmedical conditions such as diabetes, high cholesterol and highblood pressure levels.

Things that have been identied as helping reduce the risk of Alzheimers

disease, or to slow the disease progress once it has begun, include:

Healthy eating the focus here is on a Mediterraneantype diet, and especially on eating anti-oxidant rich foodssuch as blueberries and raspberries, and dark green leafy

vegetables such as spinach and collard greens. Alsorecommended by some are the anti-oxidants seleniumand folic acid. Folic acid, also called folates, is alsoreputed to help ward off heart disease. It occurs in a

wide variety of foods ranging from liver and fruits towhole wheat bread and lima beans, but like vitamin C isdestroyed by cooking or processing. Reduced blood levels

of both folate and vitamin B12 have been associatedwith increased levels of homocysteine in the blood andwith increased incidence of dementia, but the benetsof B12 supplementation have not been satisfactorilyestablished. Recently a benecial effect of fruit and

vegetable juices was reported (at least three glassesweekly) that appeared to be more related to the presencein the juices of antioxidants called polyphenols, ratherthan the presence of the antioxidant vitamins such as Eor C (different anti-oxidants target different members

of the reactive oxygen species category of substancedecribed earlier). Moderate intake of red wine has alsobeen promoted, particularly from French sources, asan approach to reducing the incidence of Alzheimersdisease. Similarly, certain spices used in curries, especiallycurcumin, have been implicated in the lower thanaverage incidence of Alzheimers disease in curry-eating populations, and research is actively underway toidentify drugs that would mimic the active ingredientsof the spices used. One important effect of curcumin


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is its ability to bind to A-beta and thereby prevent theindividual A-beta molecules from sticking together toform the toxic oligomers which are explained in theBrain changes section following. Finally, there is a newinterest in increasing ones intake of omega-3 fatty acids,found especially in cold water sh, ax and walnuts, afterndings that these fatty acids were low in people with

Alzheimers disease, and that in some studies (but notin all) their dietary supplementation improved cognitivefunctioning.

Aerobic exercising even the most modest levels arebenecial, such as a few daily walks up and down stairs.In one Canadian study people exercising three times a

week were 40 per cent less likely to develop Alzheimersdisease. Research indicates that exercise stimulates theproduction in the brain of the growth factors alreadymentioned, especially one known as BDNF, which bothpromote connectivity between nerve cells and helppreserve their health. Also, exercising almost certainlyhelps maintain a good blood supply and therefore oxygen

supply to the brain. This is particularly important becauseof the evidence that hypoxia, a reduced oxygen supply, ofthe brain promotes the production of the suspect proteinbeta amyloid, or A-beta.

Maintaining normal blood pressure

Keeping cholesterol levels at normal levels

An active social life including interactive and especiallyorganized social leisure activities, for example playing

cards or group theatre-going. Loneliness in seniors hasbeen linked to a higher risk for dementia, and clearlyincreased socialization would help here, including thingslike spending time with family.

Intellectual activity the use it or lose it principle,such as doing crossword puzzles, reading or playingchess. Interestingly, in a Swedish twins study, greaterparticipation in intellectual activities was associated withlower risk for Alzheimers disease for women, but not formen.

Protecting your head especially by wearing safetyhelmets during recreation and sporting activities to reducetraumatic head injury.

Hormone replacement therapy (HRT) despite

a recent large-scale clinical study on women whichrecommended discontinuation of HRT because it wasboth ineffective and had potentially dangerous sideeffects, a number of clinical researchers continue toregard it as worthy of further study, especially becauseof studies showing that estrogen treatment of post-menopausal women effectively reduced the incidencein them of Alzheimers disease. Animal studies are alsopointing to the possibility that testosterone treatmentcould benet men in this regard. Time will tell.

The accepted view today is that adopting a lifestyle that promotes a healthybrain, essentially much the same as one which promotes a healthy body, isthe most effective way of reducing ones chances of developing Alzheimersdisease, and of slowing down the progress of the disease in those that haveit. Adopting a lifestyle that ignores risk factors does not mean one willdevelop the disease, but it does increase the odds.

Four brain changes that occur with Alzheimersdisease

The major unknown in Alzheimer research is exactly howthe risk factors lead to the development of oxidative stressin the brain and to the production of the characteristicpathological changes, of which the most prominent are theloss of nerve cells, the appearance of plaques and tangles, andinammation. Once these are produced, however, their threatto the brain is beginning to be well understood, leading tothe rational design of drugs and the promotion of a healthylifestyle, all with the aim of reducing that threat.


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i) The plaques

These are made largely of the protein alreadymentioned, called beta amyloid, or A-beta, which isactually split off from a much larger protein moleculeknown as APP. Both APP and A-beta are presentin normal brains, but their function is still underinvestigation. The key problem in Alzheimers diseaseis that abnormally high amounts of A-beta accumulatein the brain, overwhelming the enzymes and othermolecules whose job it is to clear it away. As well, theclearing away process itself appears to be defective.

This applies even in the aging brain, in which at leasttwo of the enzymes that help eliminate A-beta becomeprogressively reduced whether Alzheimers diseaseis present or not. It is now accepted that the real

danger comes when the individual A-beta moleculesclump together to form small toxic aggregates calledoligomers. The continuing aggregation eventually leadsto the formation of the amyloid plaques. However,the oligomers are so toxic that by the time the plaquesappear the damage seen in the Alzheimer brain hasalready occurred.

ii) The tangles

The neurobrillary tangles, to give them their full

name, are made of a protein called tau, which, likeamyloid, occurs in normal nerve cells, but in Alzheimersdisease it becomes chemically altered and piles upas thread-like tangles, impairing taus key roles innerve cells. One of these roles is in nerve sprouting,an important feature of self-repair in the nervoussystem which is described later. Another tau role is inmaintaining a kind of railway track system inside nervecells that moves needed chemicals and tiny organellesup and down the nerve bres between the cell body and

the distant nerve endings. The cell body is the factoryand powerhouse for the entire nerve cell. This transportsystem is essential for the cell to work and survive, andthe tangles disrupt it and in a sense choke the cells todeath. The rst casualties of disrupted transport are thenerve endings, which contact the next cells in the circuit;these junctions are called synapses. Theyre vulnerablebecause theyre so far away from their cell bodies, thesource of their nutrients. Consequently the earliest signsof disturbed nerve cell function are seen at the synapses,

and in animal models of Alzheimers disease it is herethat researchers focus to see if future therapies areproving successful.

A controversy

Many researchers believe that the amyloid depositsnot only make the nerve cells sick, but they somehowpromote the development of tangles, and it is probablythese that actually kill the nerve cells. In keeping withthis cascade hypothesis, when mice models of

Alzheimers disease were immunized against A-beta, notonly the plaques but the tangles tended to disappear.Moreover tangles generally appear after the plaqueshave developed. In any event both plaques and tanglesare denitely implicated in Alzheimers disease. New

research is suggesting that a very early event is the entryof the accumulating A-beta molecules into the nervecells where the A-beta interacts with tau molecules thatmay be already altered, to form a deadly toxic productthat is responsible for the earliest degenerative changesin the nerve cells and synapses.

But the situation is complicated. The brains of somenormal elderly people have been found to have as manyamyloid plaques as in Alzheimer brains, but there wasno dementia! Nevertheless, most researchers still regard

A-beta as the main threat, and still direct their efforts toeliminating it. This laudable and necessary attempt tocure the disease may not, however, be enough. To curethe person with the disease needs more, as will be seenlater!

iii) Inammation of the brain

Whenever and wherever the body suffers trauma, oris attacked by some kind of potentially threateninginuence such as an infection or a toxin, it defends

itself in part by mounting an inammatory response.This, which is actually an immune response, alsooccurs in the Alzheimer brain. Unfortunately thedisease challenge is so great that the response becomesexcessive, and instead of helping it actually worsensthe situation. When the brains immune cells (calledmicroglia) become overactive they seem to overproducesubstances that are normally protective, to a level whichactually promotes death of cells. Moreover new resultsare suggesting that in Alzheimers disease the very early


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activation of these microglia actually helps trigger thechanges in the tau protein that result in the formationof tangles.

iv) Shrinkage and degeneration of nerve cells

As nerve cells die and disappear that part of the brainshrinks. This process, which rst begins in the partof the brain that deals with thinking and memory, isprogressive, eventually affecting all parts of the brain,

which consequently shrinks as a whole. The shrinkageis most marked, however, in the thinking and memoryregions, and this is very readily seen by brain imaging.

Dr. Alzheimer noted and described three of the abovepathological changes seen in the Alzheimer brain (i,ii, and iv). Its understandable that he missed number

(iii), inammation, since the recognition of immunecells in the brain and their functions had not yetentered medical science, nor had the concept and theimportance of oxidative stress.

How is Alzheimers disease diagnosed?

Although plaques and tangles are the distinguishingabnormal features that prove (in association with dementia,of course) the presence of Alzheimers disease, thesepathological appearances unfortunately have traditionally been

able to be identied only post mortem. Actually this situationis beginning to change, as will be seen below, but generallyspeaking this is still true. Nevertheless it is not a particularlyimportant item. In practice, the results of the tests doctors,along with their psychologist colleagues, make usually result in

a 90 to 95 per cent accurate diagnosis of Alzheimers disease.A number of approaches assist them in their diagnosis.First they have to eliminate other known conditions thatcan cause or mimic dementia, such as Parkinsons disease,thyroid problems, depression, vitamin deciencies, or excess

of alcohol. They also make a routine examination of thegeneral health of the person, including standard proceduressuch as blood pressure measurement and neurological testing(reexes, muscle strength, speech, sensation, etc). And nallycomes a battery of psychological and memory tests. Animportant one of these is the mini-mental state examination(MMSE), in which the person is presented with a seriesof questions designed to test a range of everyday mentalskills. Another popular test is the mini-cog, which involvesremembering the names of common objects, and drawing

the hour and minute hands in a face of a clock to show timesspecied by the examiner.

Brain imagingSometimes doubts or concerns exist that the doctor mightfeel require further tests to be sure of the diagnosis. Theperson is then referred to a specialist clinic. Some of theseuse more sophisticated psychological approaches, and some

will use brain imaging. Magnetic resonance imaging (MRI)and computed tomography (CT) give valuable informationabout the shape and volume of brain regions. The brains of

people with Alzheimers disease shrink signicantly as thedisease progresses (largely due to the loss of nerve cells), andshrinkage in specic regions of the brain may be an early signof the disease. Positron emission tomography (PET) andfunctional MRI (fMRI) reveal how well cells in various brainregions are actively using the sugar or oxygen brought by thebrains blood supply, functions which signicantly reducein Alzheimers disease. And nally, exciting new imagingtechniques are emerging that address the problem of learning

whats happening in regard to plaques during life rather than

post mortem. Special tracer compounds, chemicals thatshow up in the imaging process, are injected into the bloodcirculation and thereby reach the brain. These chemicalsattach to the A-beta proteins that form the plaques, whichare then visualized without any surgery or exposure of thebrain. One day this technique could become widely available,assisting not only in the diagnosis of Alzheimers disease, butalso helping to show whether treatments are working, sincethese treatments would be expected to signicantly reduce thenumber of plaques.


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Other diagnostic approachesA revised diagnostic testing protocol has been recentlyproposed which includes imaging evidence for shrinkage ofkey brain regions, evidence of reduced glucose utilization inthe brain, the presence in the cerebrospinal uid (the CSF, the

uid which bathes the brain and spinal cord) of abnormallevels of A-beta, evidence of the existence of a geneticmutation for Alzheimers disease within the immediate family,and of course indications of dementia. Discussion continueson whether this newly proposed set of criteria should becomethe universal standard.

It was recently reported that the steady weight loss normallyassociated with aging doubles in the year before even themildest Alzheimer-like symptoms become evident. This initself would make only a minor contribution to diagnosis, butit does support the quite common belief that Alzheimersdisease might be affecting body functions earlier than brainones. Findings like this, if true, support the endeavors ofresearchers who are continually looking at persons in theearliest stages of Alzheimers disease for unusual changesin easily examined tissues like the skin, blood, CSF, and theurine. The aim is to nd simple laboratory tests for earlydiagnosis, and some success is occurring here.

Drug treatments or Alzheimers disease

i) Aricept(donepezil), Exelon(rivastigmine) andReminyl(galantamine)

These drugs are cholinesterase inhibitors. They helppreserve the ability of sick nerve endings to transmit thenerve messages to the next cell in the chain. The rstof these drugs appeared in 1986, but wasnt consistentlyeffective until ten years later when along came the newgeneration of cholinesterase inhibitors, and their success

was rapidly recognized.

How they work makes a fascinating story. Nervemessages, or impulses, travel along nerve bres by anelectrical mechanism, but the electricity is inadequateto cross the junctions between the nerve and the nextcell. Nature invented a mechanism to deal with thisproblem: each arriving impulse releases a tiny blip ofa chemical called a neurotransmitter, which diffuses

very rapidly across the junction to stimulate the nextcell. For Alzheimers disease the most importantneurotransmitter is acetylcholine, the one used by

the nerve cells in the thinking and memory-makingparts of the brain. After the acetylcholine has carriedthe message across the junction its critical that itbe eliminated immediately, otherwise it would keepon stimulating the downstream cell. This could be

disastrous, leading to seizures for example. Naturedealt with this potential danger by ensuring that theacetylcholine is destroyed immediately after its deliveredthe message, and this is done by an enzyme calledcholinesterase.

Now, in Alzheimers disease the blip of acetylcholinethat is released by each arriving nerve impulse getsprogressively smaller and smaller as the nerve endingsget sicker and sicker, eventually becoming too small totransmit the message across the junction. Cholinesterase

inhibitors prevent cholinesterase from destroyingacetylcholine, and thus what little acetylcholine isreleased is preserved, building up to levels high enoughto get the message across to the next cell. And it works!However, eventually the sick nerve endings beginto degenerate and withdraw from the junctions andmessages can no longer be transferred across them.

To reach this point takes usually from two to threeyears (but sometimes much longer), which is whycholinesterase inhibitors usually work best in the short

term.

Remarkably, however, in some instances cholinesteraseinhibitors seem to have been effective for as long as8 to 10 years, and new research (including Canadianstudies) is nding that donepezil can continue to havebenecial effects in improving symptoms even in severe

Alzheimers disease. This nding ts in with otherevidence that another action of cholinesterase inhibitorsis somehow to protect nerve cells from damage byoxidative stress. It has to be acknowledged, though, thatthere is an unexplained variation among individuals asto how well they respond to cholinesterase inhibitors,and how badly they are affected by the side effects,

which include diarrhea, insomnia, nausea, infectionand bladder problems. To avoid side effects one drugcompany is trying a new method. The drug (Exelon)is not swallowed but is contained in a skin patch from

which it is absorbed directly into the body. The usualproblem of patch administration is knowing the exactdosage being taken in, but this appears to have been


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solved, and so this approach offers substantial promisefor eliminating the side effects of cholinesterase

inhibitors.

The consensus remains that, though not a cure,cholinesterase inhibitors are of benet to at leasta signicant proportion of those with diagnosed

Alzheimers disease, and a promising developmentdiscussed later is the use of cholinesterase inhibitors incombination with other drugs like Ebixa.

ii) Ebixa (memantine hydrochloride)

This story has to start by talking about another

neurotransmitter called glutamate. Unlike acetylcholine,glutamate is not destroyed by an enzyme after doingits job of conveying the message across the junctionsbetween nerve cells. Instead its taken back up intothe nerve endings from which it was released, or inother words, its recycled. This uptake requires thatthe glutamate combines rst with special receivingmolecules on the nerve endings called glutamatereceptors (known as NMDA receptors). However,theres a twist to the story here. All the cells of the body

contain a lot of glutamate because it has importantmetabolic roles aside from being a neurotransmitter.

When cells get sick, especially nerve cells, glutamateleaks out, and its concentrations outside the sick nervecells can be so high that the increased amount thatstaken back by way of the glutamate receptors is toxic,and indeed quite deadly. This is one of the reasonsnerve cells die in Alzheimers disease their sicknesscould be initially mild, but the massive glutamate leakageand re-uptake multiplies the threat.

Memantine acts by blocking the glutamate receptorsand preventing the re-uptake of the glutamate intothe nerve endings. The beauty of this approach is thatenough glutamate gets back into the sick nerve endingsto be used as a transmitter, but the massive uptake

that would be toxic is prevented. Since the glutamatethreat develops somewhat late in Alzheimers disease,memantine stands as one treatment that can be effectiveat moderate to advanced stages of the disease. Andthere is better news: ongoing research is nding thatcombining cholinesterase inhibitors together withmemantine seems to greatly improve the outcome,more than predicted from the sum of the effects ofeither drug alone. This combination therapy seems likelyto become an exciting therapeutic approach in

the future.

What other leads are being ollowed that couldlead to earlier diagnosis or new treatments?

i) Vaccines

There are promising developments here. Vaccinesbecame a real possibility when animal models of

Alzheimers disease were created (that is, geneticengineering was used to get the genes for familial

Alzheimers disease into mice). The brains of these micedevelop amyloid plaques and the mice are memory-impaired.

Researchers then designed a modied A-beta which,when it was injected into the mice, induced theirimmune systems to make antibodies against it.Because the modied A-beta was so like the normal

A-beta, the antibodies they generated also workedagainst the A-beta already in the brain, and the result

was a signicant reduction of the plaques and an

improvement in the cognitive abilities of the mice.Human trials were rapidly undertaken, only to bedramatically stopped in 2002 when some of theparticipants developed alarming brain inammation(this didnt happen with the mice).

So where do we stand? Well, new modied A-betavaccines are being vigorously sought and found that are predicted not to cause brain inammation.

Also, new mouse models are now being produced withneurobrillary tangles in the brain cells, and anti-tangle


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antibodies are being made and tested. In one newapproach the vaccine is given as a nasal spray, whichis claimed to stimulate the brains immune cells (themicroglia), which then will mop up the excess A-betamolecules. In another approach, instead of giving

substances which will stimulate the production ofantibodies (active immunization), already manufacturedantibodies are provided directly (made either in animalsor cultures of living cells). This approach, calledpassive immunization, bypasses the immune system ofthe body, hopefully thereby reducing the chances oftriggering adverse inammation of the brain. Finallya new experimental vaccine has been created whichtargets neither A-beta nor the tau protein of thetangles, but instead it targets one of the key enzymes

involved in splitting the toxic A-beta from its bigparent protein. While much remains to be found out,a number of these exciting animal studies have alreadybeen extended to human clinical trials, and the earlynews gives denite hope that within ve to seven years,there could well be a vaccination therapy that couldrevolutionize the treatment of Alzheimers disease.

ii) MCI

Some important developments relate to MCI, acondition that is being increasingly found in earlymiddle-aged and even young adults. MCI is clearly animportant risk factor for the disease. Brain imaging isshowing that abnormal changes almost certainly existin the brain even before MCI is diagnosed, and indeedeven in some totally non-MCI peoples brains that laterdeveloped symptoms of Alzheimers disease. Someresearchers believe that plaques may begin to appearas early as 5 to 10 years prior to any signs of dementia.Imaging approaches, added to psychological testing,should make it possible both to pick out the most at-riskMCI individuals, and to assist enormously in the earlydiagnosis of Alzheimers disease. This is important:earlier diagnosis means earlier treatment, and thesooner a therapy is started the better. Many (but not all)clinicians are now recommending that cholinesteraseinhibitors be given to people diagnosed with MCI

without waiting for signs of Alzheimers diseaseto appear.

iii) Statins

These cholesterol-reducing agents are being investigatedbecause the incidence of Alzheimers disease appearedto be less for people using these drugs to lower theircholesterol levels. At rst it was assumed that the benetof these statins came from their ability to reduce theincidence of cardiovascular disease (diseases affectingthe heart or blood vessels), which is a risk factor for

Alzheimers disease. However, we now know that statinsalso reduce the production of A-beta from APP, sohere is another promising future treatment strategy.Moreover, since cholesterol is a key component ofthe membranes that enclose nerve cells, abnormalcholesterol levels could seriously alter cell membranes,and the responses of nerve cells to substances such

as growth factors, hormones and of course drugs.Keeping cholesterol from rising above normal levels isclearly very important.

iv) Alzheimers disease and diabetes

As discussed in the section on Risk Factors, research onpeople with Alzheimers disease and on animal modelsof the disease is showing that, even when diabetes in theconventional sense is absent, anti-diabetic drugs calledglitazones can help maintain brain function and,

seen in the animal studies and assumed to occur also inpeople, reduce the development of brain plaques. Thisapproach is supported by the observation that insulinadministered through the nasal passage, which can getpreferentially to the brain without going through allthe rest of the body, improved memory and cognitionin some people a promise of future therapeuticmeasures.

v) Anti-inammatory agents such as aspirin and othe

NSAIDs (nonsteroidal anti-inammatory drugs)

Although not yet proven, there is intriguing evidencethat people routinely taking anti-inammatory agentsfor rheumatic and other conditions are at a decreasedrisk of getting Alzheimers disease, and this lead isbeing followed up. Cannabinoids (cannabis-derivedsubstances) have also been claimed to have anti-inammatory and other benets in Alzheimers disease,but at present the potential dangers associated with theirnumerous actions in the nervous system make their use

problematical.


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vi) Other drug therapies

Flurizan is an example of a new class of drugscurrently in clinical trials. Flurizan and other secretaseinhibitors work by blocking the process that splits off

A-beta from its big parent molecule, APP. This helpsto stop the dangerous accumulation of A-beta in thebrain. Other drugs, including cyclohexanehexol, a newagent discovered by Toronto reseachers, interact withthe A-beta molecules as they form, and prevent themfrom sticking together in small aggregates - aggregatesthat poison nerve cells and eventually deposit assolid plaques, but by the time they form most ofthe damage is already done. Alzhemed is anothersuch drug, but its initial promise was not supportedin expanded clinical trials, and it has now been

discontinued. Other treatments aim at encouraging themopping up of the A-beta before it reaches threateninglevels. Ubiquitin is a naturally-occurring chemical inthe brain that helps in this mopping up action, but itslevels are reduced in Alzheimer brains. When mice with

Alzheimers disease were given drugs that increasedtheir ubiquitin levels, their brain function improvedeven when the amyloid plaques persisted. Presumablythis was because the drug prevented the very smalltoxic aggregates of amyloid from developing. Iron,

zinc and copper, which are virtually impossible to avoidin normal diets, are needed for the A-beta moleculesto clump to form the toxic oligomers, and they havebeen suggested as risk factors for Alzheimers diseasein certain individuals. This possibility is being testedin trials of a drug called Clioquinol that helps removethe suspect metals from the body. Denitive results arenot yet in from these studies. Finally ginkgo biloba, aherbal supplement purported to improve memory, is inclinical trials to see if it affects the onset or severity of

Alzheimers disease.vii) Early diagnosis by measuring chemical levels in

tissues outside the brain

It has long been hoped that biological markers forAlzheimers disease would appear in various tissuesthat could be more easily accessed and studied thanthe brain itself. New ndings are offering hope thatearly diagnosis may become possible through suchbiological markers. Recent reports described two such

in the skin of people with Alzheimers disease, rstlyan abnormal inammatory chemical response that iseasy to detect, and secondly, the presence of abnormallevels of a number of proteins. Other studies on people

with Alzheimers disease are revealing alteration in their

CSF levels of A-beta and tau, the two proteins mostimplicated in Alzheimers disease. The search goeson for biological markers of Alzheimers disease, andscientists are hopeful.

viii) Making new nerve cells from stem cells:

Stem cells and their promise

Researchers are very excited at the prospect of replacinglost nerve cells in Alzheimer brains by using specialcells known as stem cells. These are immature cells that

have not yet developed to the stage when they showa recognizable mature identity, that is, one that wouldlabel them as nerve cells, heart cells, liver cells, and soon. Stem cells occur naturally in most of the bodystissues, such as bone marrow, skin, and also the brain,and apparently are used as a source of replacement cellsto be recruited whenever tissue degeneration occurs dueto disease or trauma (part of the bodys natural repairstrategy). There is evidence that the repair functionoffered by resident stem cells converting into nerve

cells can happen spontaneously after traumatic braininjury, and even in neurodegenerative conditions like

Alzheimers disease. The aim of Alzheimer researchersis to encourage this process, but even more so to obtaina reliable and abundant outside source of stem cellsand then to get them into the regions of the brain

where nerve cell degeneration has occurred. What arethe chances of achieving this aim?

Stem cells are multipotent, or pluripotent, meaningthat under appropriate conditions any stem cell can

transform into any particular adult cell types. Thistransformation is brought about in the body, and alsoin the experiments done by researchers, by exposingthe stem cells to trophic substances, also calledgrowth factors. These factors are natural nourishingmolecules made especially in the embryo to guide thedevelopment of stem cells along the road to becomingspecic mature cells, but trophic factors are also madecontinuously throughout life to help maintain the healthof virtually all the cells in the adult, including nerve cells.


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One of the most important of these trophic molecules,the rst such to be discovered actually, is called NerveGrowth Factor, or NGF for short. NGF is neededespecially to keep the brain cells involved in memoryand thinking alive and well, and therefore, as explained

following, is of special interest as a potential treatmentin Alzheimers disease. The stem cell replacementapproach is being very actively studied in experimentalanimals, and in some countries preliminary testshave begun in people with Alzheimers disease, withambiguous results.

Where will the stem cells come from?

A persisting problem has been how to obtain thesubstantial numbers of stem cells needed for their study,

and will certainly be needed if theyre going to replacecells lost in diseases like Alzheimers disease. In theorythis can be solved, once a source of stem cells has beenestablished, by transferring the cells to a special chambercontaining an appropriate nutrient broth in which theyare cultured, i.e. allowed to grow and divide, whichthey will do readily and apparently indenitely. Themost popular source of stem cells to date has beenembryos or fetuses, in which stem cells are abundant,and also from the amniotic uid that surrounds thefetus. There are, of course, ethical considerations inobtaining stem cells from human fetuses, and Canada,in common with many other countries, has importantlimitations on stem cell research in this regard. However,two recent research reports have cast an entirely newlight on the situation. Using a retrovirus as an infectingagent, certain molecules known as transcription factors

were introduced into fully developed human skin cells.Transcription factors regulate (or activate) genes.Using the virus, the researchers effectively shuttledup to four transcription factors into mature skin cells.

These factors were already known to be highly activein stem cells, but not in adult cells. The effect of thesetranscription factors was to activate genes that convertedthe adult skin cells back into an earlier and moreprimitive state, into cells in fact that closely resemblednormal embryo-derived stem cells. In the jargon, theskin cells were reprogrammed; their original adultcharacter was lost, and instead they looked and behavedlike normal immature stem cells. The excitement

generated by these two reports was not just because ofthe discovery of how to transform normal adult cellsinto stem cells, but because of the implication that stemcells could now be obtained without the involvement ofhuman fetuses. So the question becomes how near are

we to using stem cells reliably and safely as replacementnerve cells in people with Alzheimers disease?

Pluses and minuses of stem cells as potential replacement cells:

Some big pluses When any foreign tissue or cellsare transplanted into a person, their immune systemimmediately starts to work to get rid of what it viewsas potentially harmful invaders. This is called rejection,and to prevent it the host recipient has to be givenimmune-suppressants. This is hazardous, because

now the body is being deprived of its most importantdefense against dangerous threats such as infection andthe development of tumors. A wonderful advantageof using skin as a source of stem cells is the possibilityof using the skin of the person him or herself, therebyallowing for a replacement cell strategy without thecomplication of rejection. This reasoning is a powerfulplus in favor of creating a skin-derived stem cellindustry. Moreover, because of the immortality ofstem cells already referred to, once they are obtained in alaboratory setting they constitute a persisting source ofcontinuously dividing stem cells that needs no renewal.


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Are there drawbacks? Indeed yes - there always have beenproblems associated with the idea of a stem cell therapy whateverthe source of the cells.

i) the genetic make-up of the stem cells created usingretroviral infection of adult skin cells described inthe new reports mentioned above was not identicalto that of conventional embryonic stem cells. Itsnot yet known how abnormal the consequencesof these genetic differences might be. One majorconcern is that the use of a retrovirus mightintroduce the potential for initiating tumors inthe host body, or of causing undesirable geneticmutations in neighboring cells. Moreover,reprogrammed adult skin cells might still containDNA abnormalities caused by earlier exposure

to sunlight or environmental toxins, hazards thatcould carry over to the newly created stem cellpopulation.

ii) There is other evidence that laboratory culturedstem cells are not guaranteed to convert into totallynormal adult cells. In some earlier Canadian studiesstem cells (actually obtained from adult skin) weretransformed into what looked like perfectly normalnerve cells, but it turned out that some criticallyimportant mechanisms required for the cells toproduce nerve impulses (messages) were missing--an important defect by any standards!

iii) To promote useful functions any nerve cellsimplanted into the brain have to become correctlyintegrated into the existing neuronal circuitry. Theimplanted material has to be positioned at theright anatomical sites, the new nerve cells have tobe recognized by other nerve cells as appropriatetargets with which to make new connections, and

they themselves have to grow out nerve bres thatwill make connections with the correct receivingnerve cells.

What are the chances of these circuitry needs being successfullyaccomplished?

Daunting though these problems may seem, thereis an unexpected kind of evidence which supportsthe possibility of implanted nerve cells becomingappropriately integrated into the host nervous system.

It seems that cues exist, even in adult nervoussystems, which help guide newly-growing nervebres to correct destinations. Apparently some of themechanisms that operate during early development, toensure that the correct connectivity is achieved, survive

into adulthood. That such mechanisms were once thereis clear. Were they absent, and supposing that trial anderror were ultimately responsible for ending up withthe correct connectivity in the brain, this would takeliterally hundreds of years to achieve rather than themonths of fetal brain development. So, provided thatneuroscientists are able to implant stem cells, or stemcells already transformed into adult nerve cells, into therequired brain locations, it could be that enough newconnectivity would spontaneously develop to maintain

or restore functions threatened by disease or trauma.In the case of Alzheimers disease, the brain regionsinvolved in memory and cognitive functions would bethe prime ones to receive such implantations.

How long before we have a viable stem cell replacementtherapy? The best guess of this writer is decades atthe very least. This is not to deny the potential ofsuch therapy, which offers a direct solution to the lossof nerve cells in the brain. But while we await thisdesirable result, its encouraging to know about the other

promising treatments that are on the horizon.

ix) Promoting brain repair: The special importance ofstem cell studies and others now to be mentioned is thatthey address the problem of brain repair. If the brainfunctions that are lost in Alzheimers disease are to berestored, the brain damage must eventually be reversed.Even when a truly successful treatment for Alzheimersdisease appears, i.e. one that actually stops the disease inits tracks so that theres no further brain degeneration,there will still be the need to deal with the damage thatsalready happened. We have to cure the person as wellas the disease! Of great importance here are the growthfactors such as NGF described earlier. Growth factorsalso stimulate nerve cells to sprout new branches andmake new connections to make up for those lost asneighbouring nerve cells die. This compensatory nervesprouting helps recovery after stroke and brain trauma,for example. Unfortunately it doesnt occur so readilyin aging, and it is also reduced by some of the knownrisk factors for Alzheimers disease. Scientists are now


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implanting genetically engineered cells that make NGFinto the brains of animal models of Alzheimers disease,and in one study NGF-producing cells were implanteddirectly into the brains of people with Alzheimersdisease. Initial results show promise both for keeping

nerve cells from dying and in improving cognition andmemory.

It is certain that the three approaches, delivery ofgrowth factors, delivery of stem cells, and mobilizingstem cells already resident in the brain, will one daypay off as a way of reversing the damage caused by

Alzheimers disease. However, all of this will take quite afew years. Another more immediate and quite different

way of promoting brain repair is described in thefollowing section.

A proposal: caregiving could be promotingbrain repair

Nerve sprouting from surviving nerve cells is a key feature ofrepair in the diseased or damaged nervous system. The newsprouts make connections with other surviving nerve cells,compensating for the connections lost when nerve cells died.Nerve sprouting is induced by growth factors among whichNGF is very important. However, there is another way toinduce nerve sprouting; this is by initiating impulses (nervemessages) in the nerve cells. Experimentally this driving, asits called, is done either by electrically stimulating the nervecells, or by increasing the sensory input, that is by providingincreased sensory stimulation such as light, touch, sound, andso on. Now in the parts of the brain that control feeling andthinking, the input that matters most is that from the socialenvironment from people talking and touching or caressing,physically and emotionally interacting with the individual.

This means that the more of this social stimulation a personwith Alzheimers disease gets, the more likely it is that theirsurviving brain cells will be induced to sprout and restorelost connections. Not only that, but research is showing thatin mouse models of Alzheimers disease, environmentalenrichment, which is a form of increased social stimulation,actually reduces the levels of A-beta and the amyloid deposits.

Also, in normal mice, environmental enrichment promotedsprouting and increased connectivity between brain cells.

The caregiver, family member or anyone else involvedwith the person with Alzheimers disease has a critical role

here. We should never be put off by absence of immediateresponse because nerve sprouting and the subsequentmaking of connections with other nerve cells can take manymonths. Now this proposal has obviously not been provenexperimentally in humans, but a lot of animal research would

support it, and anecdotal accounts from caregivers support ittoo. The emotional benets of maintaining contact betweenpeople with Alzheimers disease and their caregivers andfamily members can only be guessed at, but the bottomline is keep trying to communicate, keep talking, and keepon showing affection like holding and caressing (withoutoverdoing it of course, which could cause distress to bothsides). The thing to avoid at all costs is social isolation.

Animal studies ofer hope that lost long-term

memories may be recoverableIn this work two genes were studied in mice. One gene, whenactivated by appropriate drugs, caused nerve cells to die justas in Alzheimers disease, and as in Alzheimers disease, long-term memory was lost. The rst, truly exciting result wasthat when put into an enriched environment, the long-termmemory eventually reappeared, despite the loss of nervecells. Thus the memories were there, but couldnt be accesseduntil new connections were made by the surviving cells. Sothe message in the preceding section gains more support:

socialization and stimulation can eventually help restorememory in a damaged brain.

The second gene the researchers studied is involved in theformation of long-term memories (probably by sproutingnew connections). Unexpectedly, a protein that occursnormally in the body was found to suppress this gene,so interfering with long-term memory production. Theresearchers were able to oppose the action of this suppressorprotein with another drug, and in these mice long-termmemory formation was facilitated, even in brain-damagedanimals.

Now all this is a long way from the human situation, but themessage is critically important. Lost memories may not havedisappeared forever. Even after nerve cells have died, therecovery of these memories may still be possible, providednew connectivity among nerve cells can be achieved. And thisis possible, both by environmental stimulation, and one dayby drug treatments.


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Te Next en Years

These could be even more exciting than the last decade. Lets look at some of the developments that seem mostlikely to pay off within ten years. Clinical trials (many already begun and some well advanced) will test the following,

and hopefully within the next ve to seven years the most promising of them will be approved for people withAlzheimers disease:

Drugs that block the enzymes that split off the toxic1.A-beta from APP (secretases inhibitors).

Drugs that prevent the threatening clumping together of2.newly formed A-beta molecules.

Drugs (like Neprilysin) that help clear away the3.accumulating A-beta molecules before they begin

clumping together.Neuroprotective drugs (like the growth factors) that4.increase the ability of threatened nerve cells to stay alive.

Drugs that will prevent the chemical modication of tau5.protein, and so prevent tangles.

New vaccines that will eliminate both the production and6.the accumulation of amyloid (A-beta) but not have thedangerous side effects of the rst vaccines.

New vaccines that will eliminate tangles.7.

Improved techniques to implant genetically engineered8.living cells into the brain for delivery of growth factorsand other drugs to counteract the development ofplaques and tangles.

New anti-diabetic drugs that will correct glucose9.

metabolism in the brains of people with Alzheimersdisease.

New drug delivery techniques which will ensure that10.drugs get to the regions of the brain where they areneeded.

Improved availability of non-invasive imaging techniques11.that will reveal plaques and tangles even before dementiadevelops. These techniques would use special chemicalsinjected into the blood, that reach the brain and attach to

plaques, and are visualized by imaging, so facilitating earlydiagnosis and revealing whether treatment strategies arereducing the brain abnormalities.

New biological markers for Alzheimers disease that can12.be measured in the blood, in the CSF, in urine, and inthe skin, to help in early diagnosis, and in evaluation oftreatment therapies.

Early diagnosis based on the pattern of brain waves13.(EEG).

New cognitive training regimens that will help slow down14.the decline in brain functioning without the use of drugs.

Delivery of therapeutic agents via the nose, in some15.instances associated with harmless viruses calledphages.


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Where does the Alzheimer Society come in?

Canadian scientists rank among the top Alzheimer scientistsin the world. To support these scientists, the AlzheimerSociety is a leading funder of Alzheimer research and research

training in Canada. In 2007, the Society (with our partners)funded 22 new grants and training awards, amounting to $2million. The funding for the research program comes fromprovincial and local Alzheimer Societies across Canada, andfrom the generosity of individuals and corporations. The

Alzheimer Society of Canada (ASC) administers the researchprogram. The research applications received for the annualcompetition are reviewed through an extensive peer reviewprocess, and the funding is divided equally between thebiomedical and the social/psychological elds. ASC seeks out

partnerships to enhance the impact of its research funding.Our current partners include:

Provincial Alzheimer Societies and local Chapters acrossCanada

Canadian Institutes of Health Research (CIHR)

Canadian Nurses Foundation (CNF)

Pzer Canada Inc.

Institute of Aging (CIHR)

Institute of Gender and Health (CIHR)

Fonds de la recherche en sant du Qubec (FRSQ)

Alzheimer Society Of Saskatchewan (supports YoungInvestigator Grants)

The Alzheimer Society Research Program supports biomedical researchprojects in essentially all the areas discussed in this Research Report.

While Canadian scientists rank among the top Alzheimerscientists in the world, the fact remains that there is currentlyno cure for Alzheimers disease. Research remains the keyto nding a cure, and if a cure is to be found, Alzheimerresearch must be made a higher priority in Canada, and morefunding must be given in support of Canadas world classresearchers.

This report focuses on biomedical advancements. Acompanion report is in development that will address theequally important Social/Psychological research. Thiscompanion report will be available in 2008.

The contents of this document are provided for information purposes only and do not represent advice, an endorsement or a recommendation, with respect to any product, service or

enterprise, and/or the claims and properties thereof, by the Alzheimer Society of Canada. The information contained in this report was current at the time of printing.


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