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UnravelingtheMystery ALZHEIMER’S DISEASE National Institute on Aging National Institutes of Health
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UnravelingtheMysteryALZHEIMER’S DISEASE

National Institute on AgingNational Institutes of Health

National Institute on AgingNational Institutes of Health

UnravelingtheMysteryALZHEIMER’S DISEASE

Alzheimer’s Disease: Unraveling the Mystery2

Over the past few decades, Alzheimer’s diseasehas emerged from obscurity. Once considereda rare disorder, it is now seen as a major publichealth problem that has a severe impact onmillions of older Americans and their families.Research on Alzheimer’s disease has grown

accordingly. The small group of pioneers whoconducted research on the disease in the 1970shas expanded to thousands of scientists in lab-oratories and institutions all over the world.

The lead agency for Alzheimer’s research atthe National Institutes of Health (NIH) is theNational Institute on Aging (NIA), whichlaunched its Alzheimer’s disease program in1978. Since then, the study of this disease hasbecome one of NIA’s top priorities. Severalother NIH institutes also conduct and sponsorstudies on Alzheimer’s disease, including theNational Institute of Neurological Disordersand Stroke, the National Institute of MentalHealth, and the National Institute of NursingResearch.

In the private sector, the Alzheimer’sAssociation, other voluntary organizations,and private industry are also working to com-bat this disease. They fund research, con-tribute to public policy decisions, inform andeducate the public, and provide critical servic-es to people with Alzheimer’s disease and theirfamilies. Their support for research is criticalin the effort to understand and defeat this dis-order.

Thanks to these many groups, the study ofAlzheimer’s disease is moving ahead rapidly.This booklet explains what Alzheimer’s diseaseis, describes what we have learned to date, andprovides a glimpse into future directions forresearch.

Preface

Alzheimer’s Disease: Unraveling the Mystery 3

Table of Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4The Impact of Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6Unraveling the Mystery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8

Part 1: A Walking Tour Through the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10Inside the Human Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11Neurons and Their Jobs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16Plaques and Tangles: The Hallmarks of AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20The Changing Brain in Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24

Part 2: AD Research — Finding New Answers and Asking Better Questions . . . . . . . . . . . . . .30The Search for Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31

Genetic Factors at Work in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31Genes and Early-onset Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33A Different Genetic Story in Late-onset Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . .33

Other Factors at Work in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34Beta-amyloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34Tau . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35Cardiovascular Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35Oxidative Damage from Free Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36Brain Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36

New Techniques Help in Diagnosing AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37

The Search for New Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42Helping People with AD Maintain Their Mental Functioning . . . . . . . . . . . . . . . . . . . . . . . . .42Slowing, Delaying, or Preventing Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43Managing Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45

Improving Support for Families and Other Caregivers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54For More Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57

Alzheimer’s Disease: Unraveling the Mystery4

Often, Mary was afraid, a nameless, shapeless fear. Her impaired mindcould not put a name or an explanation to her fear. People came,memories came, and then they slipped away. She could not tell what

was reality and what was memory of people past. The bathroom was notwhere it was yesterday. Dressing became an insurmountable ordeal....Marygradually lost the ability to make sense out of what her eyes and ears toldher....She worried about her things: a chair, and the china that had belongedto her mother. They said they had told her over and over, but she could notremember where her things had gone. Perhaps someone had stolen them. Shehad lost so much....

Mary was glad when her family came to visit. Sometimes she rememberedtheir names; more often she did not. She never remembered that they hadcome last week, so she regularly scolded them for abandoning her....She wasglad when they didn’t try to remind her of what she had just said or that theyhad come last week, or ask her if she remembered this person or that one. Sheliked it best when they just held her and loved her.

Introduction

This excerpt from The 36-Hour Day, a bookfor families and caregivers of people withAlzheimer’s disease (AD) and other similardiseases, gives a glimpse into what anAlzheimer’s patient might be thinking andfeeling. The gradual slipping away of mindand memory is frightening and frustrating,both for the person with the disease and forfamily and friends. Not so long ago, we couldn’t do much for Mary or others like her. Happily, that situation is changing.Thousands of scientists, voluntary organiza-tions, health care professionals, and familiesare working hard to learn more about

Alzheimer’s. They are also finding ways tomanage, treat, and eventually perhaps, preventthis terrible disease.

Alzheimer’s is an irreversible, progressivebrain disease that slowly destroys memory andthinking skills, eventually even the ability tocarry out the simplest tasks. Although the riskof developing AD increases with age – in mostpeople with AD, symptoms first appear afterage 60 – AD is not a part of normal aging. Itis caused by a disease that affects the brain. Inthe absence of disease, the human brain oftencan function well into the tenth decade of life.

O

Alzheimer’s Disease: Unraveling the Mystery 5

Alzheimer’s Disease: Unraveling the Mystery6

Introduction

The Impact ofAlzheimer’s Disease

AD is the most common cause of dementiaamong people age 65 and older. Dementia isthe loss of memory, reason, judgment, and language to such an extent that it interferes

with a person’s daily life andactivities. It is not a diseaseitself, but a group of symp-toms that often accompaniesa disease or condition.

AD is a major publichealth problem for theUnited States because it hassuch a huge impact on indi-

viduals, families, the health care system, andsociety. Scientists estimate that up to 4 mil-lion people now have AD. For every 5-yearage group beyond 65, the percentage of peoplewith AD doubles.

More than 34 million people are now age65 or older. This number is 13 percent of thetotal population of the U.S. The percentageof people over age 65 will increase rapidly overthe next few years as the “baby boom” genera-tion reaches 65. In addition, the group of peo-ple over 85 – the group with the highest risk ofAlzheimer’s disease – is the fastest growing seg-ment of the population. By 2050, 14 millionolder Americans are expected to haveAlzheimer’s disease if the current numbershold and no preventive treatments becomeavailable.

Slightly more than half of those with AD arecared for at home, while the rest are in differ-ent kinds of care facilities. A recent study esti-mated that the annual cost of caring for oneperson with AD in 1996 was between $18,400and $36,100, depending on how advanced thedisease was and whether or not the person wasat home. The cost of care has been steadilyrising since then. The national cost of caringfor people with AD is now thought to be about$100 billion every year.

The cost of care is not only financial.Families, friends, and caregivers struggle withgreat emotional and physical stress as theycope with the physical and mental changes intheir loved ones. Caregivers must juggle manyresponsibilities and adjust to new and chang-ing roles. As the disease gets worse and caringat home becomes increasingly difficult, familymembers face difficult decisions about long-term care. The number of caregivers – andtheir needs – will steadily grow as our popula-tion ages and the number of people with ADincreases.

How Many New Cases of AD Were There in 1995?How Many New Cases May Occur in the Future?

Researchers recently projected the number of new cases of AD that couldoccur every year over the next 50 years if current population trends continueand no preventive treatments emerge. They estimate that the number of newcases every year will double between 1995 and 2050 – from 377,000 to959,000. Two factors will combine to cause this large increase:

● The fact that the risk of AD increases as people get older.● The growing numbers of older people, especially those over 85.

The annual number of new cases will begin to climb sharply around the year2040, when all the baby boomers will be over 65.

Source: Hebert et al. (2001). Alzheimer Dis Assoc Disord, 15(4), 169-173.

Estimated Number of New AD Cases, in Thousands

Alzheimer’s Disease: Unraveling the Mystery 7

Alzheimer’s Disease: Unraveling the Mystery8

Introduction

Unraveling the Mystery

Thinking about Alzheimer’s disease leads toquestions such as: Will I get it? What causesit? What can be done to cure it or prevent it?Scientists ask the same types of questions, andthis booklet describes their search for answers.It is written for people with AD, their familymembers, friends, and caregivers, and anyoneelse interested in AD.

Unraveling the Mystery has two sections. Part1 gives readers the basics – it’s a “walking tour”through the brain. Illustrations with text showwhat a healthy brain looks like and how itworks, and what happens in a brain affected byAD. Part 2 talks about current research andthe advances that are bringing us closer toways of managing, and eventually defeating,AD. Throughout, terms in bold are defined ina glossary at the end of the booklet.

The end of the booklet also includes a list ofpublications and resources that family mem-bers and caregivers may find useful as they liveday-to-day with the disease.

A booklet like this would not have beenpossible 25 years ago. Other than some basics,we knew very little about AD. We did noteven know it was a distinct disease, differentfrom normal aging. Today, we know muchmore about Alzheimer’s disease – what it is,who gets it, how it develops, and what courseit follows. We are better able to diagnose itearly and accurately. We even have somepromising leads on possible treatments.Recent studies are also beginning to focus onfactors that might be used to reduce a person’srisk of developing AD in the future. Researchconducted over the last two decades has deep-ened our understanding of this devastating dis-ease. It also has expanded our knowledge ofbrain function in healthy older people andidentified ways we might lessen normal age-related declines in mental function.

Where Are People with Alzheimer’sDisease Cared For?

● Home● Assisted living facilities (those in the early stages) ● Nursing homes● Special care units

Alzheimer’s Disease: Unraveling the Mystery 9

The brain is a remarkable organ. Seeminglywithout any effort, it allows us to carry out

every element of our daily lives. It managesmany of the body functions that happen with-out our knowledge or direction, such as breath-ing, blood circulation, and digestion. It alsodirects all the functions we carry out conscious-ly. We can speak, move, see, remember, feelemotions, and make decisions because of thecomplicated mix of chemical and electricalprocesses that take place in our brains.

Our brains are made of nerve cells and lots ofother cell types. Nerve cells are also calledneurons. The neurons of all animals functionin basically the same way, even though animalscan be very different from each other. Whatsets people apart from other animals is the hugenumber of nerve cells we have in the cerebralcortex, regions of which are proportionallymuch larger in humans than in any other ani-mals. These regions are the parts of the brainwhere cognitive functions, like thinking, learn-ing, speaking, remembering, and making deci-sions, take place. The many interconnectionsamong the nerve cells in these regions alsomake us different from other animals.

To understand Alzheimer’s disease, it’s impor-tant to know a bit about the brain. Part 1 ofUnraveling the Mystery first gives an inside viewof the normal brain, how it works, and whathappens during aging. Then, it shows whathappens to the brain in Alzheimer’s and howthe disease slowly destroys a person’s mentaland physical capacities.

Part1 A Walking Tour Through the Brain

the Brain’s Vital Statistics

● Adult weight: about 3 pounds● Adult size: a medium cauliflower● Number of neurons: 100,000,000,000 (100 billion)● Number of synapses (the gap between neurons):

100,000,000,000,000 (100 trillion)

Alzheimer’s Disease: Unraveling the Mystery 10

Alzheimer’s Disease: Unraveling the Mystery11

InsidetheHumanBrain

The Three Main Players

● The cerebral hemispheres accounts for 85percent of the brain’s weight. The billions ofneurons in the two hemispheres are connectedby a thick bundle of nerves called the corpuscallosum. Scientists now think that the twohemispheres differ not so much in what theyfocus on (the “logical versus artistic” notion),but how they process information. The lefthemisphere appears to focus on the details(such as recognizing a particular face in acrowd). The right hemisphere focuses on thebroad background (such as understanding therelative position of objects in a space). Thecerebral hemispheres have an outer layercalled the cerebral cortex. This is where thebrain processes sensory information receivedfrom the outside world, controls voluntarymovement, and regulates conscious thoughtand mental activity.

● The cerebellum takes up a little more than10 percent of the brain. It’s in charge of bal-ance and coordination. The cerebellum alsohas two hemispheres. They are always receiv-ing information from the eyes, ears, and mus-cles and joints about the body’s movementsand position. Once the cerebellum processesthe information, it works through the rest ofthe brain and spinal cord to send out instruc-tions to the body. The cerebellum’s workallows us to walk smoothly, maintain our bal-ance, and turn around without even thinkingabout it.

Hypothalamus

HippocampusBrain Stem

Side View of the Brain

Cerebellum

Cerebral CortexCorpus Callosum

Thalamus

Alzheimer’s Disease: Unraveling the Mystery 13

Other Crucial Parts

Several other essential parts of the brain liedeep inside the cerebral hemispheres:

● The limbic system links the brain stemwith the higher reasoning elements of thecerebral cortex. It controls emotions andinstinctive behavior. This is also where thesense of smell is located.

● The hippocampus is important for learningand short-term memory. This part of the brainis considered to be the site where short-termmemories are converted into long-term memo-ries for storage in other brain areas.

● The thalamus receives sensory and limbicinformation, processes it, and then sends it tothe cerebral cortex.

● The hypothalamus is a structure under thethalamus that monitors activities like bodytemperature and food intake. It issues instruc-tions to correct any imbalances. The hypo-thalamus also controls the body’s internalclock.

● The brain stem sits at the base of the brain. It connects the spinal cord with therest of the brain. Even though it’s the smallestof the three main players, its functions are cru-cial to survival. The brain stem controls thefunctions that happen automatically to keepus alive – our heart rate, blood pressure, andbreathing. It also relays information betweenthe brain and the spinal cord, which thensends out messages to the muscles, skin, andother organs. Sleep and dreaming are alsocontrolled by the brain stem.

Alzheimer’s Disease: Unraveling the Mystery14

The Brain in Action

New imaging techniques allow scientists tomonitor brain function in living people. Thisis opening up worlds of knowledge about nor-mal brain function and how it changes withage or disease.

One of these techniques is called positronemission tomography, or PET scanning. PETscans measure blood flow and glucose metabo-lism throughout the brain. (For more onmetabolism see Neurons and Their Jobs on p. 16.) When nerve cells in a region of thebrain become active, blood flow and metabo-lism in that region increase. These increasesare usually shown as red and yellow colors on aPET scan. Shades of blue and black indicatedecreased or no activity within a brain region.In essence, a PET scan produces a “map” ofthe active brain.

Scientists use PET scans to see what happensin the brain when a person is engaged in aphysical or mental activity, at rest, or evensleeping or dreaming. Scientists can alsoinject chemicals tagged with a tracer that will“light up” on PET scans. These tracers cantrack the activity of brain chemicals, for exam-ple neurotransmitters such as dopamine andserotonin. Some of these neurotransmittersare altered with age, disease, and drug treatment.

Hearing Words

Speaking Words

Thinking about Words

Seeing Words

InsidetheHumanBrain

PET Scan of 80-year-old BrainPET Scan of 20-year-old Brain

The Aging Brain

As a person gets older, changes occur in allparts of the body, including the brain:

● Some neurons shrink, especially large onesin areas important to learning, memory, plan-ning, and other complex mental activities.

● Tangles and plaques develop in neurons and surrounding areas, though in much smalleramounts than in AD (see p. 20 for more onplaques and tangles).

● Damage by free radicals increases (free radicals are a kind of molecule that reacts easi-ly with other molecules; see p. 36 for more onthese molecules).

What is the impact of these changes?Healthy older people may notice a modestdecline in their ability to learn new things andretrieve information, such as rememberingnames. They may perform worse on complextasks of attention, learning, and memory.However, if given enough time to perform thetask, the scores of healthy people in their 70sand 80s are often the same as those of youngadults. As they age, adults also often improvetheir vocabulary and other forms of verbalknowledge.

Alzheimer’s Disease: Unraveling the Mystery 15

Alzheimer’s Disease: Unraveling the Mystery16

NeuronsandTheirJobs

The human brain is made up of billions ofneurons. Each has a cell body, an axon,

and many dendrites. The cell body contains anucleus, which controls all of the cell’s activi-ties, and several other structures that performspecific functions. The axon, which is much,much narrower than the width of a humanhair, extends out from the cell body and trans-mits messages to other neurons. Sometimes,the messages have to travel over very long dis-tances (even up to 5 feet!). Dendrites alsobranch out from the cell body. They receivemessages from the axons of other nerve cells.Each nerve cell is connected to thousands ofother nerve cells through its axon and den-drites. Neurons are surrounded by glial cells,which support, protect, and nourish them.

Groups of neurons in the brain have specialjobs. For example, some are involved withthinking, learning, and memory. Others areresponsible for receiving sensory information.Still others communicate with muscles, stimu-lating them into action.

Several processes all have to work smoothlytogether for neurons to survive and stayhealthy. These processes are communication,metabolism, and repair.

Communication: Sending Millions ofMessages a Second

Imagine the telecommunication cables thatrun under our streets. All day and night, mil-lions of telephone calls are flashing down fiberoptic cables at incredible speeds, letting peoplestrike deals, give instructions, share a laugh, orlearn some news. Multiply that many-fold andthat’s the brain. Neurons are the great com-municators, always in touch with their neigh-bors.

As a neuron receives messages from sur-rounding cells, an electrical charge, or nerveimpulse, builds up. This charge travels downthe axon until it reaches the end. Here, ittriggers the release of chemical messengerscalled neurotransmitters, which move from the axon across a tiny gap to the dendrites orcell bodies of other neurons. The typical neuron has up to 15,000 of these tiny gaps, orsynapses. After they move across the synapse,neurotransmitters bind to specific receptorsites on the receiving end of dendrites of thenearby neurons. They can also bind directlyto cell bodies.

Once the receptors are activated, they openchannels through the cell membrane into thereceiving nerve cell’s interior or start otherprocesses that determine what the receivingnerve cell will do. Some neurotransmittersinhibit nerve cell function (that is, they makeit less likely that the nerve cell will send an

electrical signal down its axon). Other neuro-transmitters stimulate nerve cells; they primethe receiving cell to become active or send anelectrical signal down the axon to more neu-rons in the pathway.

During any one moment, millions of thesesignals are speeding through pathways in thebrain, allowing it to receive andprocess information, makeadjustments, and send outinstructions to variousparts of the body. Ifneurons are discon-nected, they becomesick and may die.

Neuron

Dendrites

Axon

Electrical Im

pulses

NeurotransmitterMolecules

ReceptorSynapse

}

NeuronsandTheirJobs

Alzheimer’s Disease: Unraveling the Mystery18

You

ng

Rat

sA

ged

Rat

s

REST

0

0.1

0.2

0.35

0.6

1.35

40

CalciumLevels

SHORTSTIMULATION

LONGSTIMULATION

This figure shows young and aged rat neurons at rest and with increasingduration of stimulation. When neurons are stimulated, metabolism increases.The stimulated neurons of young rats maintain calcium within normal levels.Older rats are unable to do this. High levels of calcium in old neurons maymake them susceptible to dysfunction and death. The color scale is an indexof cellular calcium with red indicating the highest levels.

Metabolism: TurningChemicals and NutrientsInto Energy to KeepNeurons Working

Metabolism is the process by which cells andmolecules break down chemicals and nutrientsto generate energy and form building blocksthat make new cellular molecules like proteins.

Efficient metabolism needs enough blood cir-culating to supply the cells with oxygen andglucose, a type of sugar. Glucose is the onlysource of energy usually available to the brain.Without oxygen or glucose, neurons will die.

Repair: Keeping Long-lived Neurons in GoodWorking Order

Unlike most cells, which have a fairly shortlifespan, nerve cells, which are generated inthe fetus or a short time after birth, live a longtime. Brain neurons can live for up to 100years or longer. In an adult, when neurons diebecause of disease or injury, they are not usual-

ly replaced. Recent research, however, showsthat in a few brain regions, new neurons canbe born, even in the old brain.

To prevent their own death, living neuronsmust constantly maintain and remodel them-selves. If cell cleanup and repair slows downor stops for any reason, the nerve cell cannotfunction well. Eventually, it dies.

Alzheimer’s Disease: Unraveling the Mystery 19

This figure shows the effects ofexercise on levels of brain-derivedneurotrophic factor (BDNF) in thehippocampus of rats. Growth fac-tors like BDNF help many neuronssurvive. Levels of the messagethat makes BDNF are much higherin exercising rats (A) than insedentary animals (B). Exercisemay promote healthy neurons inrats by causing their neurons tomake more protective BDNF. Redand yellow denote the highest lev-els of BDNF, while green and bluedenote the lowest.

PlaquesandTangles: theHallmarksofAD

Alzheimer’s Disease: Unraveling the Mystery20

Alzheimer’s disease disrupts each of thethree processes that keep neurons

healthy: communication, metabolism, andrepair. This disruption causes certain nervecells in the brain to stop working, lose connec-tions with other nerve cells, and finally, die.The destruction and death of nerve cells caus-es the memory failure, personality changes,problems in carrying out daily activities, andother features of the disease.

The brains of AD patients have an abun-dance of two abnormal structures – beta-amyloid plaques and neurofibrillary tangles.This is especially true in certain regions of thebrain that are important in memory. Plaquesare dense, mostly insoluble (cannot be dis-solved) deposits of protein and cellular materi-al outside and around the neurons. Tanglesare insoluble twisted fibers that build up insidethe nerve cell. Though many older peopledevelop some plaques and tangles, the brainsof AD patients have them to a much greaterextent. Scientists have known about plaquesand tangles for many years, but recent researchhas shown much about what they are made of,how they form, and their possible roles in AD.

Amyloid Plaques

Plaques are made of beta-amyloid, a proteinfragment snipped from a larger protein calledamyloid precursor protein (APP). Thesefragments clump together and are mixed withother molecules, neurons, and non-nerve cells.In AD, plaques develop in the hippocampus, astructure deep in the brain that helps toencode memories, and in other areas of thecerebral cortex that are used in thinking andmaking decisions. We still don’t knowwhether beta-amyloid plaques themselvescause AD or whether they are a by-product ofthe AD process. We do know that changes inAPP structure can cause a rare, inherited formof AD (see p. 33 for more on inherited AD).

An AD Plaque

21Alzheimer’s Disease: Unraveling the Mystery

From APP to Beta-amyloid

APP is a protein that appears to be importantin helping neurons grow and survive. APPmay help damaged neurons repair themselves

and may help parts of neurons grow after braininjury. In AD, something causes APP to besnipped into fragments, one of which is calledbeta-amyloid; the beta-amyloid fragmentseventually clump together into plaques.

APP is associated with the cell membrane, the thin bar-rier that encloses the cell. After it is made, APP sticksthrough the neuron’s membrane, partly inside and partlyoutside the cell.

Enzymes (substances that cause or speed up a chem-ical reaction) act on the APP and cut it into fragmentsof protein, one of which is called beta-amyloid.

The beta-amyloid fragments begin coming together intoclumps outside the cell, then join other molecules andnon-nerve cells to form insoluble plaques.

Beta-AmyloidPlaque

Beta-Amyloid

Enzymes

Cell Membrane APP

Molecule

Cell Interior

PlaquesandTangles:theHallmarksofAD

DisintegratingMicrotubule

Microtubules

StabilizingTau Molecules

Healthy Neuron

Diseased Neuron

DisintegratingMicrotubules

Alzheimer’s Disease: Unraveling the Mystery 23

Neurofibrillary Tangles

Healthy neurons have an internal supportstructure partly made up of structures calledmicrotubules. These microtubules act liketracks, guiding nutrients and molecules fromthe body of the cell down to the ends of theaxon and back. A special kind of protein, tau,makes the microtubules stable. In AD, tau ischanged chemically. It begins to pair withother threads of tau and they become tangledup together. When this happens, the micro-tubules disintegrate, collapsing the neuron’stransport system. This may result first in mal-functions in communication between neuronsand later in the death of the cells.

Microtubule SubunitsFall Apart

Tangled Clumps of Tau Proteins

Alzheimer’s Disease: Unraveling the Mystery24

theChangingBraininAlzheimer’sDisease

PET Scan of Normal Brain PET Scan of Alzheimer’s Disease Brain

No one knows exactly what causes theAlzheimer’s disease process to begin or

why some of the normal changes associatedwith aging become so much more extreme anddestructive in patients with the disease. Wedo know a lot, however, about what happensin the brain once AD takes hold and about the

physical and mental changes that occur overtime. The time from diagnosis to death varies– as little as 3 years if the patient is over 80when diagnosed, as long as 10 or more years ifthe patient is younger. Although the course ofAD is not the same in every patient, symptomsseem to develop over the same general stages.

Alzheimer’s Disease: Unraveling the Mystery 25

Preclinical AD

AD begins in the entorhinal cortex, which isnear the hippocampus and has direct connec-tions to it. It then proceeds to the hippocam-pus, the structure that is essential to the forma-tion of short-term and long-term memories.Affected regions begin to atrophy (shrink).These brain changes probably start 10 to 20

years before any visible signs and symptomsappear. Memory loss, the first visible sign, isthe main feature of mild cognitive impairment(MCI) (see p. 41 for more on MCI). Manyscientists think MCI is often an initial, transi-tional phase between normal brain aging andAD.

CerebralCortex

Hippocampus EntorhinalCortex

theChangingBraininAlzheimer’sDisease

Mild AD

As the disease begins to affect the cerebral cor-tex, memory loss continues and changes inother cognitive abilities emerge. The clinicaldiagnosis of AD is usually made during thisstage. Signs of mild AD can include:

● Memory loss ● Confusion about the location of familiar

places (getting lost begins to occur)● Taking longer to accomplish normal

daily tasks● Trouble handling money and paying bills● Poor judgment leading to bad decisions● Loss of spontaneity and sense of initiative● Mood and personality changes,

increased anxiety

The growing number of plaques and tanglesfirst damage areas of brain that control memo-ry, language, and reasoning. It is not untillater in the disease that physical abilitiesdecline. This leads to a situation in mild ADin which a person seems to be healthy, but isactually having more and more trouble makingsense of the world around him or her. Therealization that something is wrong oftencomes gradually because the early signs can beconfused with changes that can happen nor-mally with aging. Accepting these signs anddeciding to go for diagnostic tests can be a bighurdle for patients and families to cross.

Alzheimer’s Disease: Unraveling the Mystery26

Cortical Shrinkage

Shrinkage ofHippocampus

ModeratelyEnlargedVentricles

Alzheimer’s Disease: Unraveling the Mystery 27

Moderate AD

By this stage, AD damage has spread further tothe areas of the cerebral cortex that controllanguage, reasoning, sensory processing, andconscious thought. Affected regions continueto atrophy and signs and symptoms of the dis-ease become more pronounced and wide-spread. Behavior problems, such as wanderingand agitation, can occur. More intensivesupervision and care become necessary, andthis can be difficult for many spouses and fami-lies. The symptoms of this stage can include:

● Increasing memory loss and confusion● Shortened attention span● Problems recognizing friends and

family members● Difficulty with language; problems with

reading, writing, working with numbers● Difficulty organizing thoughts and

thinking logically● Inability to learn new things or to cope

with new or unexpected situations● Restlessness, agitation, anxiety, tearfulness,

wandering – especially in the late afternoon or at night

● Repetitive statements or movement, occasional muscle twitches

● Hallucinations, delusions, suspiciousness or paranoia, irritability

● Loss of impulse control (shown through sloppy table manners, undressing at inappropriate times or places, or vulgar language)

● Perceptual-motor problems (such as trouble getting out of a chair or setting the table)

Behavior is the result of complex brainprocesses, all of which take place in a fractionof a second in the healthy brain. In AD, manyof these processes are disturbed, and this is thebasis for many distressing or inappropriatebehaviors. For example, a person may angrilyrefuse to take a bath or get dressed because hedoes not understand what his caregiver hasasked him to do. If he does understand, hemay not remember how to do it. The anger isa mask for his confusion and anxiety. Or, aperson with AD may constantly follow herhusband or caregiver and fret when the personis out of sight. To a person who cannotremember the past or anticipate the future, theworld around her can be strange and frighten-ing. Sticking close to a trusted and familiarcaregiver may be the only thing that makessense and provides security. Taking off clothesmay seem reasonable to a person with AD whofeels hot and doesn’t understand or rememberthat undressing in public is not acceptable.

theChangingBraininAlzheimer’sDisease

Severe AD

In the last stage of AD, plaques and tangles arewidespread throughout the brain, and areas ofthe brain have atrophied further. Patientscannot recognize family and loved ones orcommunicate in any way. They are completelydependent on others for care. All sense of selfseems to vanish. Other symptoms can include:

● Weight loss● Seizures, skin infections, difficulty

swallowing● Groaning, moaning, or grunting● Increased sleeping● Lack of bladder and bowel control

At the end, patients may be in bed much orall of the time. Most people with AD die fromother illnesses, frequently aspiration pneumo-nia. This type of pneumonia happens when aperson is not able to swallow properly andbreathes food or liquids into the lungs.

Alzheimer’s Disease: Unraveling the Mystery28

Extreme Shrinkage ofCerebral Cortex Severely

EnlargedVentricles

ExtremeShrinkage ofHippocampus

Alzheimer’s Disease: Unraveling the Mystery 29

Severe AD

Mild to Moderate AD

Preclinical AD

Blue indicates areas affected at various stages of AD.

In the past 25 years, scientists have studiedAlzheimer’s disease from many angles.

They’ve looked at populations to see howmany cases of AD occur and whether theremight be links between the disease andlifestyles or genetic backgrounds. They’veconducted clinical studies with healthy olderpeople and those at various stages of AD.They’ve examined individual nerve cells tosee how beta-amyloid and other moleculesaffect the ability of cells to function normally.

These studies have led to better diagnostictests, new ways to manage behavioral aspectsof AD, and a growing number of possible drugtreatments. Findings from current research arepointing scientists in promising directions forthe future. They are also helping researchersask better questions about the issues that arestill unclear.

Part 2 of Unraveling the Mystery describeswhat we’re learning from our search for:

● The causes of AD● New techniques to help in diagnosis● New treatments● Ways to improve support for families and

other caregivers

Results from this research will bring us clos-er to the day when we will be able to preventor even cure the devastating disease that robsour older relatives and friends of their mostprecious possession – their minds.

Part2 AD Research: Finding NewAnswers and Asking Better Questions

Then and Now: the Fast Pace ofDevelopments in AD Research

What We Didn’t Know Then

15 Years Ago● We didn’t know any of thegenes that could cause AD.

● We had no idea of the bio-logical pathways that wereinvolved in the development ofdamage to the brain in AD.

10 Years Ago● We couldn’t model the dis-ease in animals.

5 Years Ago● NIH did not fund any pre-vention clinical trials.

● We had no way to identifypeople at high risk of develop-ing AD.

1 Year Ago● We didn’t understand any-thing about how plaques andtangles relate to each other.

What We Know Now (2002)

● We know the 3 major genesfor early-onset AD and 1 of themajor risk factor genes forlate-onset AD.● We know a lot about thepathways that lead to thedevelopment of beta-amyloidplaques in the brain – one ofthe main features of AD.

● Scientists have developedspecial kinds of mice that pro-duce beta-amyloid plaques.

● NIH is funding clinical trialsthat are looking at possibleways to prevent AD.

● We can identify individualsat high risk through imaging,neuropsychological tests, andstructured interviews.

● By developing another kindof mice that have both plaquesand tangles, we now knowthat plaques can influence thedevelopment of tangles.

Alzheimer’s Disease: Unraveling the Mystery 30

Alzheimer’s Disease: Unraveling the Mystery31

theSearchforCauses

One of the most important parts of unrav-eling the AD mystery is finding out what

causes the disease. What makes the diseaseprocess begin in the first place? What makes itworse over time? Why does the number ofpeople with the disease increase with age?Why does one person develop it and anotherremain healthy?

Some diseases, like measles or pneumonia,have clear-cut causes. They can be preventedwith vaccines or cured with antibiotics.Others, such as diabetes or arthritis, developwhen genetic, lifestyle, and environmental fac-tors work together to cause a disease process tostart. The importance of each one of these fac-tors may be different for each individual.

AD fits into this second group of diseases.We don’t yet fully understand what causes AD,but we know it develops because of a complexseries of events that take place in the brainover a long period of time. Many studies areexploring the factors involved in the cause anddevelopment of AD.

Genetic Factors at Work in AD

In the last few years, painstaking detectivework by scientists has paid off in discoveries ofgenetic links to the two main types of AD.One type is the more rare, early-onsetAlzheimer’s disease. It usually affects peopleaged 30 to 60. Some cases of early-onset dis-ease are inherited and are called familial AD(FAD). The other is late-onset Alzheimer’sdisease. It is the most common form andoccurs in those 65 and older.

DNA, Chromosomes, and Genes: the Body’s Amazing Control Center

The nucleus of almost every human cell contains a vastchemical information database. This database carries allthe instructions the cell needs to do its job. This databaseis DNA. DNA exists as two long, intertwined, thread-likestrands packaged in units called chromosomes. Each cellhas 46 chromosomes in 23 pairs. Chromosomes aremade up of four chemicals, or bases, arranged in varioussequence patterns. People inherit material in each chro-mosome from each parent.

Each chromosome has many thousands of segments,called genes. The sequence of bases in a gene tells the

cell how to make specific proteins. Proteins determinethe physical characteristics of living organisms. Theyalso direct almost every aspect of the organism’s con-struction, operation, and repair. Even slight alterations ina gene can produce an abnormal protein, which, in turn,can lead to cell malfunction, and eventually, to disease.Any rare change in a gene’s DNA that causes a diseaseis called a mutation. Other more common (or frequent)changes in a gene’s DNA don’t automatically cause dis-ease, but they can increase the chances that a personwill develop a particular disease. When this happens,the changed gene is called a genetic risk factor.

Cell Nucleus Containing23 Pairs of Chromosomes

Genes

Chromosomes

Bases

DNA Strand

Genes and Early-onsetAlzheimer’s Disease

Over the past several decades, researchersworking on AD realized that some cases, par-ticularly of early-onset AD, ran in families.This led them to examine DNA samples fromsuch families to see whether they had somegenetic trait in common. Chromosomes 21,14, and 1 became the focus of attention. Thescientists found that some families have amutation in selected genes on these chromo-somes. On chromosome 21, the mutationcauses an abnormal amyloid precursor protein(APP) to be produced. On chromosome 14,the mutation causes an abnormal proteincalled presenilin 1 to be produced. On chro-mosome 1, the mutation causes yet anotherabnormal protein to be produced. This pro-tein, called presenilin 2, is very similar to pre-senilin 1. Even if only one of these genesinherited from a parent contains a mutation,the person will almost inevitably developearly-onset AD. This means that in these fam-ilies, children have about a 50-50 chance ofdeveloping the disease if one of their parentshas it.

Even though early-onset AD is very rare andmutations in these three genes do not play arole in the more common late-onset AD, thesefindings were crucial because they showed thatgenetics was indeed a factor in AD, and theyhelped to identify some key players in the ADdisease process. Importantly, they showed thatmutations in APP can cause AD, highlightingthe key role of beta-amyloid in the disease.Many scientists believe that mutations in eachof these genes cause an increased amount ofthe damaging beta-amyloid to be made in thebrain.

The findings also laidthe foundation for manyother studies that havepushed back the bound-aries of our knowledgeand created new possibili-ties for future treatment. For example, in thelast several years, a series of highly sophisticat-ed experiments have shown that presenilinmay actually be one of the enzymes (sub-stances that cause or speed up a chemical reac-tion) that clips APP to form beta-amyloid (theprotein fragment that is the main componentof AD plaques). This discovery has helpedclarify how presenilins might be involved inthe early stages of AD. It has also given scien-tists crucial new targets for drug therapy andhas spurred many new studies in the test tube,in animals, and even in people.

A Different Genetic Story inLate-onset Alzheimer’s Disease

While some scientists were focused on the roleof chromosomes 21, 14, and 1 in early-onsetAD, others were looking elsewhere to see ifthey could find genetic clues for the late-onsetform. By 1992, these investigators had nar-rowed their search to a region of chromosome19. At the same time, other colleagues werelooking for proteins that bind to beta-amyloid.They were hoping to clarify some of the stepsin the very early stages of the disease process.They found that one form of a protein calledapolipoprotein E (ApoE) did bind quickly andtightly to beta-amyloid. They also found thatthe gene that produces ApoE was located inthe same region of chromosome 19 pinpointedby the geneticists. This finding led them tosuggest that one form of this gene was a riskfactor for late-onset Alzheimer’s disease.

Alzheimer’s Disease: Unraveling the Mystery 33

Alzheimer’s Disease: Unraveling the Mystery34

Other studies since then have shown thatthe gene that produces ApoE comes in severalforms, or alleles – ε2, ε3, and ε4. The APOEε2 allele is relatively rare and may providesome protection against the disease. If ADdoes occur in a person with this allele, itdevelops later in life. APOE ε3 is the mostcommon allele. Researchers think it plays aneutral role in AD. APOE ε4 occurs in about40 percent of all AD patients who develop thedisease in later life. It is not limited to peoplewhose families have a history of AD, though.AD patients with no known family history ofthe disease are also more likely to have anAPOE ε4 allele than people who do not haveAD. Dozens of studies have confirmed thatthe APOE ε4 allele increases the risk of devel-oping AD. These studies have also helped toexplain some of the variation in the age atwhich AD develops. However, inheriting anAPOE ε4 allele doesn’t mean that a personwill definitely develop AD. Some people withone or two APOE ε4 alleles never get the dis-ease and others who do develop AD do nothave any APOE ε4 alleles.

Although we still don’t exactly know howAPOE ε4 increases AD risk, one theory is thatwhen its protein product binds quickly andtightly to beta-amyloid, the normally solubleamyloid becomes insoluble. This may meanthat it is more likely to be deposited inplaques.

While scientists are working to understandmore fully the APOE gene and its role in AD,they have also identified regions on otherchromosomes that might contain genetic riskfactors. For example, in 2000, three teams ofscientists, using three different strategies, pub-lished studies showing that chromosome 10has a region that may contain several genes

that might increase a person’s risk of AD.Identifying these genes is one important stepin the research process that will lead to newunderstanding about the ways in whichchanges in protein structures cause the diseaseprocess to begin and the sequence of eventsthat occurs as the disease develops. Once theyunderstand these processes, scientists cansearch for new ways to diagnose, treat, or evenprevent AD.

Other Factors at Work in AD

Even if genetics explains some of what mightcause AD, it doesn’t explain everything. So,researchers have looked at other possibilitiesthat may reveal how the Alzheimer’s diseaseprocess starts and develops.

Beta-Amyloid

We still don’t know whether beta-amyloidplaques cause AD or whether they are a by-product of the disease process. We do know,however, that forming beta-amyloid from APPis a key process in AD. That’s why finding outmore about beta-amyloid is an importantavenue of ongoing AD research. Investigatorsare studying:

● The nature of beta-amyloid● Ways in which it is toxic to neurons● Ways in which plaques form and

are deposited● Ways in which beta-amyloid and plaques

might be reduced in the brain

Tau

In the last few years, scientists have been giv-ing an increasing amount of attention to tau,the other hallmark of Alzheimer’s disease.

This protein is commonly found in nerve cellsthroughout the brain. In AD, tau undergoeschanges that cause it to gather together abnor-mally in tangled filaments in neurons (formore on this, see p. 23 in A Walking TourThrough the Brain). In studying tau andwhat can go wrong, investigators have foundthat tau abnormalities are also central to otherrare neurodegenerative diseases. These dis-eases, called tauopathies, include frontotempo-ral dementia, Pick’s disease, supranuclear palsy,and corticobasal degeneration. They share anumber of characteristics, but also each havedistinct features that set them apart from eachother and from AD. Characteristic signs and

symptoms include changes in personality,social behavior, and language ability; difficul-ties in thinking and making decisions; poorcoordination and balance; psychiatric symp-toms; and dementia. Recent advances, includethe discovery of mutations in the tau gene thatcause one tauopathy called frontotemporaldementia with parkinsonism linked to chromo-some 17 (FTDP-17). The development of sev-eral mouse models that produce tau tangleswill allow researchers to address the manyquestions that remain about these diseases.The development of a “double transgenic”mouse that has both tau tangles and beta-amyloid plaques will also lead to furtherinsights about AD.

Cardiovascular Risk Factors

Several recent studies in populations havefound a possible link between factors related tocardiovascular disease and AD. One of thesestudies found that elevated levels of an aminoacid called homocysteine, a risk factor forheart disease, are associated with an increasedrisk of developing AD. The relationshipbetween AD and homocysteine is particularlyinteresting because blood levels of homocys-teine can be reduced by increasing intake offolic acid and vitamins B6 and B12. In fact, inother studies, scientists have shown that folicacid may protect against nerve cell loss inbrain regions affected by AD. Investigatorshave also found that the use of statins, themost common type of cholesterol-loweringdrugs, is associated with a lower risk of devel-oping AD.

Alzheimer’s Disease: Unraveling the Mystery 35

An AD Tangle

Alzheimer’s Disease: Unraveling the Mystery36

Oxidative Damage From Free Radicals

Another promising area of investigation relatesto a longstanding theory of aging. This theorysuggests that over time, damage from a kind ofmolecule called a free radical can build up inneurons, causing a loss in function. Free radi-cals can help cells in certain ways, such asfighting infection. However, too many caninjure cells because they are very active andcan readily change other nearby molecules,such as those in the neuron’s cell membrane orin DNA. The resulting molecules can set off achain reaction, releasing even more free radi-cals that can further damage neurons. Thiskind of damage is called oxidative damage. Itmay contribute to AD by upsetting the deli-cate machinery that controls the flow of sub-stances in and out of the cell. The brain’sunique characteristics, including its high rateof metabolism and its long-lived cells, maymake it especially vulnerable to oxidativedamage over the lifespan. Some epidemiologi-cal and laboratory studies suggest that anti-oxi-dants from dietary supplements or food mayprovide some protection against developingAD. Other studies suggest that low-caloriediets may protect against the development ofAD by slowing down metabolic rates.

Inflammation

Another set of hints about the causes of ADpoints to inflammation in the brain. Thisprocess is part of the immune system and helpsthe body react to injury or disease. Fever,swelling, pain, or redness in other parts of thebody are often signs of inflammation. Becausecells and compounds that are known to beinvolved in inflammation are found in ADplaques, some researchers think it may play arole in AD.

They disagree, though, on whether inflamma-tion is a good or a bad thing. Some think it isharmful – that it sets off a vicious cycle ofevents that ultimately causes neurons to die.Evidence from many studies supports this idea.

Other scientists believe that some aspects ofthe inflammatory process may be helpful – thatthey are part of a healing process in the brain.For example, certain inflammatory processesmay play a role in combating the accumulationof plaques. Many studies are now underway toexamine the different parts of the inflammatoryprocess more fully and their effects on AD.

Brain Infarction

We’ve all heard the sensible advice about waysto live a long and healthy life: eat right, exer-cise, don’t smoke, wear a seat belt. All of thesehabits can help prevent heart attacks, stroke,and injuries. This advice may even have somerelevance for AD as well. Results from onelong-term study of aging and AD show that par-ticipants who had evidence of stroke in certainbrain regions had more symptoms of dementiathan could be explained by the number ofplaques and tangles in their brain tissue. Thesefindings suggest that damage to blood vessels inthe brain may not be enough to cause AD, butthat it could make AD clinical symptoms worse.

Free Radicals

Mitochondrion

Protein

PhospholipidCell Membrane

NewTechniquesHelpinDiagnosingAD

Ahealthy man in his early 60s begins to noticethat his memory isn’t as good as it used to be.

More and more often, a word will be on the tip ofhis tongue but he just can’t remember it. He for-gets appointments, makes mistakes when payinghis bills, and finds that he’s often confused or anx-ious about the normal hustle and bustle of lifearound him. One evening, he suddenly finds him-self walking in a neighborhood a couple of milesfrom his house. He has no idea how he got there.

Not so long ago, this man’s condition wouldhave been swept into a broad catch-all category

called “senile dementia” or “senility.” Today,the picture is very different. We now knowthat Alzheimer’s and other illnesses withdementia are distinct diseases. Armed withthis knowledge, we have rapidly improved ourability to accurately diagnose AD. We are stillsome distance from the ultimate goal – a reli-able, valid, inexpensive, and early diagnosticmarker – but experienced physicians now candiagnose AD with up to 90 percent accuracy.

Early diagnosis has several advantages. Forexample, many conditions cause symptomsthat mimic those of Alzheimer’s disease.Finding out early that the problem isn’t ADbut is something else can spur people into

Alzheimer’s Disease: Unraveling the Mystery 37

The Religious Orders Study and the Nun Study: Livesof Service Continue Even After Death

One way that scientists have tried to unravel the mystery of ADand other complex diseases, like heart disease or cancer, is tocompare the characteristics, lifestyles, and disease rates of dif-ferent groups of people. This approach has often providedclues as to why some people get a disease and others don’t.

Another way is to study one group of people over time. Thenotion here is that data gathered over a period of years willreveal important clues about the origins of the disease underinvestigation. The knowledge gained also may lay the founda-tion for future treatment or prevention strategies. TheFramingham Heart Study is one famous example of this kind ofstudy. It has followed two generations of Massachusetts resi-dents for 50 years, and its findings have revolutionized the waywe think about, treat, and prevent heart disease.

the Human Side of AD Research

(Continued on next page)

Alzheimer’s Disease: Unraveling the Mystery38

The National Institute on Aging is funding twoAlzheimer’s disease studies that are using this approach– but with a unique twist. These studies involve mem-bers of religious communities.

Since 1990, scientists have been working with morethan 650 nuns of the School Sisters of Notre Dame, whoare located in various parts of the U.S. The Nun Study isan expansion of a pilot project begun in1986 with a School Sisters of NotreDame convent in Mankato, Minnesota.

Since 1993, scientists have also beeninvestigating the mental and physicalcapacities of older nuns, priests, andbrothers in the Religious Orders Study.More than 30 religious communities in adozen States are participating in thisstudy.

All of the participants in both studiesagree to have detailed physical and men-tal function exams every year. Volunteersmay spend decades in the study, repeat-ing the tests each year. These examshelp researchers better understand theeffects on the brain of aging, AD, andother disorders. Participants also agreeto donate their brains to the study whenthey die. This allows the investigators tomatch many years’ worth of clinical and psychologicalinformation with the results of examinations of after-death brain tissue. These volunteers consider participat-ing in these studies a wonderful chance to continue theirlives of service to others. As one participant in the NunStudy put it, “[They] can have my brain. What good is itgoing to do me when I’m six feet under?”

The large numbers enrolled in the study ensure thatsome volunteers will still have normal brain function atthe time of death. Others will have developed the clinicalsigns of AD. Still others will have other neurological dis-orders, such as Parkinson’s disease. The yearly examina-

tions enable researchers to detect signs of AD amongparticipants and to track, year by year, the progress andtreatment of the disease among those who develop it.

But why work with religious orders? What’s specialabout them? One reason why members of religiousorders are good study participants is that they often livetogether and have similar lifestyles, educational levels,

daily routines, and activities. This cuts down on the vari-ations among participants that make it difficult for scien-tists to interpret research results. It also makes it easyfor study staff to keep track of volunteers over time andto maintain complete information on them.

Working with these participants has allowed theresearch teams to explore several exciting ideas. Forexample, the Religious Orders Study team recentlyworked with their participants to examine a “use-it-or-lose-it” brainpower hypothesis. At an initialevaluation, the researchers asked more than 700 priestsand nuns about the amount of time they spent in seven

getting treatment for the real condition. Forthe small percentage of dementias that aretreatable or even reversible, early diagnosisincreases the chances of successful treatment.

Even when the cause of the dementia turnsout to be Alzheimer’s disease, it’s good to findout sooner rather than later. One benefit ismedical. The drugs now available to treat ADcan help some people maintain their mentalabilities for months to years, though they donot change the underlying course of the dis-ease (see p. 42 for more on these drugs).

Other benefits are practical. The sooner theperson with AD and family know, the moretime they have to make future living arrange-ments, handle financial matters, establish adurable power of attorney, deal with otherlegal issues, create a support network, or evenmake plans to join a research study. Beingable to participate for as long as possible inmaking decisions about the present and futureis important to many people with AD.

Finally, scientists also see advantages to earlydiagnosis. Developing tests that can revealwhat is happening in the brain in the earlystages of Alzheimer’s disease will help themunderstand more about the cause and develop-ment of the disease. It will also help scientistslearn when and how to start drugs and othertreatments so that they can be most effective.

Scientists are now exploring ways to helpphysicians diagnose AD earlier and more accu-rately. For example, some studies are focusingon changes in personality and mental func-tioning. These changes can be measuredthrough memory and recall tests. Tests thatmeasure a person’s abilities in areas such asabstract thinking, planning, and language canalso help pinpoint changes in function.

Alzheimer’s Disease: Unraveling the Mystery 39

common activities that involve significant infor-mation processing – watching television; lis-tening to the radio; reading newspapers ormagazines; reading books; playing cards,checkers, and puzzle games; and going tomuseums. After tracking the participants for 4 1/2 years, the researchers found that, onaverage, the risk of developing AD was 47 per-cent lower in those who did these activitiesmost frequently than in those who did themleast frequently. The reasons for this findingaren’t entirely clear yet, but it may be thatmentally stimulating activities protect the brainin some way. Or, perhaps some other mecha-nism may be at work that strengthens infor-mation processing skills to compensate forage-related declines in other cognitive areas.

The Nun Study has one particularly richtreasure trove to work with – the autobiogra-phies written by the nuns when they enteredthe order. These personal records providebasic information on the nuns’ early lives andfamilies and are an objective measure of eachwoman’s ability to think, remember, and pres-ent ideas in writing. Study investigators havefound a fascinating link between their earlywriting skills and later cognitive abilities. Theresearchers performed an analysis of the auto-biographies to determine the grammaticalcomplexity and the “density” of ideas in each.They then examined brain tissue from nunswho had died. The investigators found thatmost of the nuns whose brain tissue showedsignificant signs of AD had written autobiogra-phies with low grammatical complexity andidea density. Though the reasons for this linkaren’t fully understood, a higher linguistic abili-ty early in life may provide some protectionagainst the influences that lead to AD.

Alzheimer’s Disease: Unraveling the Mystery40

Researchers are working hard to improve thesestandardized tests so that they can better trackthe changes that might point to early AD orpredict which individuals are at higher risk ofdeveloping AD in the future.

Other studies are examining the relationshipbetween early damage to brain tissue and out-ward clinical signs. Still others are looking forchanges in blood chemistry that might indi-cate the progression of Alzheimer’s disease.

One of the most exciting areas of ongoingresearch in this area is neuroimaging. Overthe last decade, scientists have developed sev-eral highly sophisticated imaging systems thathave been used in many areas of medicine,including Alzheimer’s disease. Positron emis-sion tomography (PET), single photon emis-sion computed tomography (SPECT), andmagnetic resonance imaging (MRI) are allexamples. These “windows” on the livingbrain can help scientists measure the earliestchanges in brain function or structure in orderto identify those people who are at the veryfirst stages of the disease – even before theydevelop signs and symptoms.

These types of scans are still primarilyresearch tools, but one day, neuroimagingmight be used more commonly to help physi-cians diagnose AD early. These tools mayeven be used someday to monitor the progressof the disease and assess patient responses todrug treatment.

Causes of Dementia

Other Causes of Dementia

● Alzheimer’s disease● vascular dementia ● frontotemporal dementia,

including:● frontotemporal dementia

with parkinsonism linked to chromosome 17 (FTDP-17)

● Pick’s disease● supranuclear palsy● corticobasal degeneration

Dementia is the loss of cognitive functioning – thinking,remembering, and reasoning – to such an extent that itinterferes with a person’s daily life and activities. It is not adisease itself, but a group of symptoms that often accom-panies a disease or condition. Some dementias are treat-able or curable; others are less responsive to treatment.

Treatable Causes of Dementia

● medication side effects● depression● vitamin B12 deficiency● chronic alcoholism● certain tumors or

infections of the brain● blood clots pressing

on the brain● metabolic imbalances,

including thyroid, kidney,or liver disorders

A PET Scan in Progress

Alzheimer’s Disease: Unraveling the Mystery 41

Current Tools for Diagnosing AD

A definitive diagnosis of Alzheimer’s disease is still onlypossible after death, during an autopsy, when theplaques and tangles can actually be seen. But with thetools now available, experienced physicians can be prettyconfident about making an accurate diagnosis in a livingperson. Here’s how they do it.

They take a detailed patient history, including:● A description of how and when symptoms developed● A description of the patient’s and his or her

family’s overall medical condition and history● An assessment of the patient’s emotional state

and living environment

They get information from family members or closefriends:● People close to the patient can provide valuableinsights into how behavior and personality havechanged; many times, family and friends know some-thing is wrong even before changes are evident on tests.

They conduct physical and neurological examina-tions and laboratory tests:● Blood and other medical tests help determine neurological functioning and identify possible non-ADcauses of dementia.

They do a computerized tomography (CT) scan or amagnetic resonance imaging (MRI) test:● Brain scans like these can detect strokes or tumors orcan reveal changes in the brain’s structure and functionthat indicate early AD.

They conduct neuropsychological testing:● Q&A tests or other tasks that measure memory,language skills, ability to do arithmetic, and other abilities related to brain functioning help indicate whatkind of cognitive changes are occurring.

Criteria for “Probable” Alzheimer’s Disease

Because no simple and reliable biological test for AD isavailable, the National Institute of Neurological andCommunicative Disorders and Stroke and the Alzheimer’sAssociation together established criteria to help physi-cians diagnose AD. These criteria also help physiciansdistinguish between AD and other forms of dementia.“Probable” Alzheimer’s disease is determined when aperson has:

● Dementia confirmed by clinical and neuropsychological examination

● Problems in at least two areas of mental functioning

● Progressive worsening of memory and other mental functioning

● No disturbances of consciousness (no “blacking out”)

● Symptoms beginning between ages 40 and 90● No other disorders that might account

for the dementia

As they get older, some people develop a memorydeficit greater than that expected for their age. However,other aspects of cognition arenot affected, so these peopledo not meet all the acceptedcriteria for AD. Thus, they aresaid to have “mild cognitiveimpairment” (MCI). About 40percent of these individualswill develop AD within 3years. Others, however, do not seem to progress to AD,at least in the time frame studied thus far (up to approxi-mately 6 years). Understanding more about the charac-teristics and development of MCI is essential in helpingclinicians diagnose early stages of AD.

Alzheimer’s Disease: Unraveling the Mystery42

theSearchforNewTreatments

Research over the last two decades hasrevealed many pieces of the Alzheimer’s

disease puzzle. Using recent advances ingenetics and molecular biology, scientists havebegun to put these pieces into place. In doingso, they’ve vastly increased our understandingof AD and opened many avenues that couldlead to effective treatments.

It has become clear that there probably isn’ta “magic bullet” that will, by itself, prevent orcure AD. However, scientists may be able toidentify a number of interventions that can be used to reduce risk and treat the disease.Today, it is estimated that the NationalInstitute on Aging, other NIH Institutes, andprivate industry are conducting clinical trials(studies involving humans that rigorously testhow well an intervention works) on around30 compounds that may be active against AD.These studies focus on three main areas:

● Helping people with AD maintain their mental functioning

● Slowing the progress of AD, delaying its onset, or preventing it

● Managing symptoms

Helping People with ADMaintain their MentalFunctioning

In the mid-1970s, scientists discovered thatlevels of a neurotransmitter called acetyl-choline fell sharply in people with Alzheimer’sdisease (see p. 16 in A Walking Tour Throughthe Brain for more on neurotransmitters).This discovery was one of the first that linkedAD with biochemical changes in the brain.

Scientists have found that acetylcholine is acritical player in the process of forming memo-ries. It is used by neurons in the hippocampusand cerebral cortex, which are areas of thebrain important to memory function.

By late 2003, the Food and DrugAdministration (FDA) had approved five med-ications to treat AD symptoms. Of these, fourare known as cholinesterase inhibitors and areprescribed to treat mild to moderate AD symp-toms. The first, tacrine (Cognex), has beenreplaced by three newer drugs – donepezil(Aricept), rivastigmine (Exelon), and galanta-mine (Reminyl). They act by stopping or slow-ing the action of acetylcholinesterase, anenzyme that normally breaks down acetyl-choline. These drugs improve some patients’abilities to carry out activities of daily living,may improve certain thinking, memory, orspeaking skills, and can help with certainbehavioral symptoms. However, these medica-tions will not stop or reverse AD and appear tohelp patients only for months to a few years.

The fifth medication is memantine(Namenda), which can be prescribed to treatmoderate to severe AD symptoms. This drugappears to work by regulating excess glutamatein the brain. Glutamate is another chemicalinvolved in memory function. Like thecholinesterase inhibitors, memantine will notstop or reverse AD. Studies have shown thatmemantine may delay loss of daily functions inpatients with moderate to severe AD.

Helping people with AD carry out their dailylives and maintain their mental abilities is oneof the most important goals of AD treatmentresearch. Many investigators are working todevelop new and better drugs that can preservethese critical functions for as long as possible.

Slowing, Delaying, or PreventingAlzheimer’s Disease

Understanding how AD develops—from begin-ning to end—is vital for finding drugs or otherfactors that may slow, delay, or even prevent thedisease.

Investigators are looking at a number of possi-bilities for drug treatments. For example,inflammation of tissue in the brain and overpro-duction of free radicals are two processes thatare thought to be a feature of AD. Clinical tri-als in both of these areas are looking at whetherspecific anti-inflammatory agents and agentsthat protect against oxidative damage can slowor prevent the development of AD.

Scientists are also conducting clinical trials tosee if substances already used to reduce cardio-vascular risk factors also help lower AD risk ordelay progression of the disease. These trials aretesting whether supplementation with folic acidand vitamins B6 and B12 can slow the rate ofcognitive decline in cognitively normal menand women, women at increased risk of devel-oping dementia, and people diagnosed withAD. A study of statins, the most common typeof cholesterol-lowering drug, is also underway tosee whether these drugs can slow the rate of dis-ease progression in AD patients.

Estrogen is a hormone produced by a woman’sovaries during her childbearing years. Over thepast 25 years, laboratory and animal studies, as

Alzheimer’s Disease: Unraveling the Mystery 43

Science on the Cutting Edge

Immunizing Against AD: Just a Neat Idea or a Real Possibility?

Getting vaccinated against measles, tetanus, polio, andother diseases is common practice these days. A personis injected with a weakened form of a disease-causingbacterium or virus. His or her immune system mobilizesto fight against it, and this protects the person againstgetting the disease. One scientist wondered whether thisapproach could work for Alzheimer’s disease as well.

Researchers have developed special kinds of mice(called transgenic mice) that gradually develop AD beta-amyloid plaques in the brain. These mice are invaluabletools to test how plaques can be stopped from forming.Over the course of several studies, scientists tested theeffects of injections of a vaccine composed of beta-amy-loid and a substance known to stimulate the immune sys-tem. They found that long-term immunization resulted inmuch less beta-amyloid being deposited in the brains ofthe mice. Similar transgenic mice that had been immu-

nized also performed far better onmemory tests than did a group ofthese mice that had not beenimmunized.

These exciting developments ledto preliminary studies in humans totest the safety and effectiveness of

the vaccine. Based on positive results, a further studywas designed to measure the immune response in partici-pants with AD who received immunizations with the beta-amyloid vaccine. In this study, which began in the fall of2001, inflammation unexpectedly developed in the brainsof some of the participants. As a result of this complica-tion, the pharmaceutical companies that were conductingthe research stopped the trial and are continuing to close-ly monitor the health of the participants.

Despite their disappointment with this development, thescientists and funders involved in this research emphasizethat a tremendous amount of valuable information hasbeen gained from this work so far. It is not unusual forsuch a revolutionary concept to have setbacks, and theyare moving forward with other possible strategies.

Alzheimer’s Disease: Unraveling the Mystery44

well as observational studies in women, havesuggested that estrogen has some positive effectson brain activity. These findings have createdscientific interest in the relationship amongestrogen, memory, and cognitive function.

Studies of estrogen in postmenopausal womenwith mild to moderate AD did not find estrogenbeneficial. But, even if estrogen does not slowthe progression of the disease in women alreadyaffected with AD, scientists thought perhapsmenopausal hormone therapy might in someway affect age-related cognitive decline or pro-tect a woman from developing AD. Two typesof such therapies have been investigated—theuse of estrogen alone in women who have had ahysterectomy and the use of estrogen plus pro-gestin, which reduces the risk of thickening ofthe lining of the uterus and endometrial cancer,in other women.

In 2002 a large clinical trial showed that com-bined estrogen/progestin therapy taken daily forjust over 5 years increased the risk of heart diseaseand breast cancer in some women. More recently,a substudy of that trial showed that this sametherapy taken daily by women over age 65 actuallyincreased their chance of developing dementia.

Scientists are continuing to evaluate estrogenalone to prevent dementia. This includes anNIA clinical trial of estrogen alone to prevent ordelay development of AD in cognitively normalolder women with a family history of dementia.

Questions remain. Scientists do not knowwhether estrogen or progestin causes theincreased risk of disease. Would giving a differ-ent estrogen or progestational agent change theresult? Would starting therapy around the ageof 50, rather than 65, be more beneficial ormore harmful? More research is needed on thiscomplex matter.

Another area of work involves nerve growthfactor (NGF). NGF is one of several growthfactors in the body that maintain the health ofneurons. NGF also promotes the growth ofaxons and dendrites, the neuron branches thatconnect with other neurons and that are essen-tial in nerve cells’ ability to communicate (seep. 16 in A Walking Tour Through the Brainfor more on the structure and function of neu-rons). Studies have turned up a number ofclues that link NGF to the neurons that useacetylcholine as a neurotransmitter, soresearchers have been eager to see what hap-pens when NGF is added to aging brain tissue.In animal studies, researchers have been able toreverse most of the age-related neuronal shrink-age and loss of ability to make acetylcholine.This success has led to a small-scale, privately-funded gene therapy trial that is testing whetherthis procedure can be done safely in humansand whether it might lessen symptoms of AD.

Finally, a number of clinical trials are focusingon the earliest stages of the disease process.For example, scientists are developing drugsthat prevent enzymes from clipping beta-amy-loid out from APP. Others are working on waysto stop beta-amyloid from clumping togetherinto plaques. Teams of investigators are alsostudying certain enzymes that seem to be ableto break beta-amyloid into pieces after it isreleased from cells but before it has a chance toform into plaques. Still other scientists areexploring the role of neurotransmitter systemsother than acetylcholine, such as glutamate.One especially active area of research involvesthe possibility that a vaccine might be able tostimulate the immune system into getting rid ofplaques once they have formed, stopping beta-amyloid and plaque buildup, or even getting ridof plaques once they have formed.

Alzheimer’s Disease: Unraveling the Mystery 45

Managing Symptoms

“My father is often agitated. He paces up anddown, wringing his hands and crying. I know he’ssad or anxious about something but he can’t tell mewhat’s bothering him. Asking him about it justmakes him more upset.”

“Last week, I visited Gran in the nursing home.We had a great time. Then yesterday, I went to seeher again. When I walked in herroom, she started screaming andcalling for help. I didn’t know what to do.”

“Mom has been getting up in thenight and wandering around thehouse. Last night, I found her alldressed and trying to get out thefront door. None of us is gettingany sleep anymore.”

“My husband used to be such aneasy-going, calm person. Now, hesuddenly lashes out at me and usesawful language. Last week, he gotangry when our daughter and herfamily came over and we sat downto eat. I never know when it’sgoing to happen. He’s changed somuch – it scares me sometimes.”

As Alzheimer’s disease makesinroads into memory and mentalabilities, it also begins to changea person’s emotions and behav-iors. Between 70 to 90 percentof people with Alzheimer’s dis-ease eventually develop one ormore behavioral symptoms.These include sleeplessness,wandering and pacing, aggres-sion, agitation, anger,

depression, and hallucinations and delusions.Some of these symptoms may become worse inthe evening, a phenomenon called “sundown-ing,” or during daily routines, especially bathing.

Unlike a stroke, in which damage to part of the brain occurs all at once, the damage ofAlzheimer’s disease spreads slowly over time and affects many different parts of the brain.

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Alzheimer’s Disease: Unraveling the Mystery46

Participating in a Clinical Trial

Rapid advances in our knowledge about AD have led tothe development of many new drugs and treatmentstrategies. However, before these new strategies can beadopted, they must be shown to work in patients. Thismeans that clinical trials – studies in people to rigorouslytest how well a treatment works – have become anincreasingly important part of AD research. Advances intreatment are only possible through the participation ofpatients and family members in clinical trials.

Clinical trials are the primary way that researchers findout if a promising treatment is safe and effective forpatients. Clinical trials also tell researchers which treat-ments are more effective than others. Trials take place atprivate research facilities, teaching hospitals, specializedAD research centers, and doctors’ offices.

Participating in a clinical trial is a big step for peoplewith AD and their caregivers. That’s why physicians andclinical trials staff spend lots of time talking with partici-pants about what it’s like to be in a trial and the pros andcons of participating. Here are some things that potentialparticipants might want to know about clinical trials.

What kind of trials are there?● Treatment trials with existing drugs assess whetheran already approved drug or compound is useful for otherpurposes. For example, one current trial is testingwhether anti-inflammatory drugs already used to treatarthritis might help to prevent AD.

● Treatment trials with experimental drugs or strate-gies find out whether a brand new drug or treatmentstrategy can help improve cognitive function or lessensymptoms in people with AD, slow the progression to AD,or prevent it. Potential drugs tested in these trials aredeveloped from knowledge about the mechanismsinvolved in the AD disease process. These compoundsare rigorously tested in tissue culture and in animals fortheir action. Safety and effectiveness studies are alsoconducted in animals before the compounds are tested inhumans.

What are the phases of clinical trials?● During Phase I trials, a study team gives the treatmentto a small number of volunteers and examines its actionin the body, its safety, and its effects at various doses.Phase I trials generally last only a few months.

● If results show that the treatment appears safe, it willbe tested in Phase II and Phase III clinical trials. Thesetrials involve larger numbers of people over longer periodsof time. In these trials, the study team wants to knowwhether the treatment is safe and effective and what sideeffects it might have.

After these phases are complete and investigators aresatisfied that the treatment is safe and effective, the studyteam may submit its data to the Food and DrugAdministration (FDA) for approval. The FDA reviews thedata and decides whether to approve the drug or treat-ment for use in patients.

What happens when a person signs up for a clinical trial?

First it is important to learn about the study. Study staffexplain the trial in detail to potential research participantsand describe possible risks and benefits. Staff also talkabout participants’ rights as research volunteers, includingtheir right to leave the study at any time. Participants andtheir family members are entitled to have this

the Human Side of AD Research

Alzheimer’s Disease: Unraveling the Mystery 47

information repeated and explained until they feel theyunderstand the nature of the study and any potential risks.

Once all questions have been answered and if there isstill interest in being a part of the study, a patient partici-pant is asked to sign an informed consent form. Lawsand regulations regarding informed consent differ acrossStates and research institutions, but all are intended toensure that patient participants are protected and wellcared for.

In some cases, a patient participant may no longer beable to provide informed consent because of problemswith memory and confusion. In such cases, it is still pos-sible for an authorized representative (usually a familymember) to give permission for the patient to participate.For example, the patient participant may have previouslyincluded research participation as part of his or herdurable power of attorney. The person (proxy) exercisingthe durable power of attorney can decide to let thepatient participate in a trial if they are convinced that thepatient would have wanted to consent if able to do so.Even so, it is still important that patients assent to be inthe study, even if they can no longer formally consent toit. Different States have different laws about who is alegal representative. These laws are in a state of flux as researchers and the public grapple with the ethicalissues of proxy consent.

Next, patients go through a screening process to see ifthey qualify to participate in the study. If they qualify andcan safely participate, they can proceed with the otherparts of the study.

What happens during a trial?If participants agree to join the study and the screening

process shows they’re a good match, they have a “base-line” visit with the study staff. This visit generallyinvolves a full physical exam and extensive cognitive andphysical tests. This gives the study team informationagainst which to measure future mental and physicalchanges. Participants also receive the test drug or treat-ment. As the study progresses, participating patients andfamily members usually must follow strict medication ortreatment instructions and keep detailed records ofsymptoms. Every so often, participants visit the clinic or

research center to have physical and cognitive exams,give blood and urine samples, and talk with study staff.These visits allow the investigators to assess the effectsof the test drug or treatment, see how the disease is pro-gressing, and see how the participant and the caregiverare doing.

In most clinical trials, participants are randomlyassigned to a study group. One group, the test group,receives the experimental drug. Other groups mayreceive a different drug or a placebo (an inactive sub-stance that looks like the study drug). Having the differ-ent groups is important because only by comparing themcan researchers be confident that changes in the testgroup are the result of the experimental treatment andnot some other factor. In many trials, no one – not eventhe study team – knows who is getting the experimentaldrug and who is getting the placebo or other drug. Thisis called “masking” meaning that the patient/familymember and the staff are “blind” to the treatment beingreceived.

What should people consider before participating in a clinical trial?

Expectations and motivations. Clinical trials general-ly don’t have miraculous results. The test drug or treat-ment may relieve a symptom, change a clinical measure-ment, or reduce the risk of death. With a complex dis-ease like AD, it is unlikely that one drug will cure or pre-vent the disease. Some people choose not to participateor drop out of a study because this reality doesn’t meettheir expectations. Others participate because they real-ize that even if the benefit to them may be slight, theyare making a valuable contribution to knowledge that willhelp future patients.

Uncertainty. Some families have a hard time with theuncertainties of participation – not knowing whether theperson is on the test drug or the placebo, not being ableto choose which study group to be in, not knowing for along time whether the study was successful or not.Ongoing and open communication with study staff canhelp to counter this frustration.

Finding the right clinical trial. Some clinical trialswant participants who are cognitively healthy or have

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Alzheimer’s Disease: Unraveling the Mystery48

Even small tasks require the brain to engage in acomplex process that can involve more than oneregion of the brain. If this process is disrupted,the person may not be able to do the task or mayact in a strange or inappropriate way.

In light of our growing understanding aboutthe effects of AD on the brain, behavior thatmay seem bizarre suddenly makes sense:

For a man who can no longer distinguish betweenpast and present, the anguish caused by the death ofhis parent may be as real today as it was many yearsbefore.

An unknown young man suddenly appearing inher room may be threatening and terrifying to awoman who does not recognize her grandson.

Feelings of responsibility toward a long-ago nightjob resurface and compel a woman to get up in thenight to go to work.

Sitting down to a family meal may produce intenseanxiety when a person has no idea what to do withthe knife and fork in front of him and all the conver-sation and activity feel overwhelming.

Behavioral symptoms are one of the hardestaspects of the disease for families and other care-givers to deal with. They are emotional andupsetting. They are also a visible sign of the ter-rible change that has taken place in the personwith AD. Researchers are slowly learning moreabout why they occur, and they are studying newtreatments – both drug and non-drug – to dealwith them.

A number of ongoing and planned clinical tri-als are looking at ways to treat agitation. Thesetrials include participants who are living in nurs-ing homes or at home. They involve the studyof a variety of drugs, including a beta-blocker, ananti-seizure medication, a cholinesteraseinhibitor, and an antipsychotic.

only mild symptoms because they are testing a drug thatmight delay the decline in cognitive function. Other trialsare interested in working with participants who havemore advanced AD because they are testing a drug thatmight lessen behavioral symptoms, or they are testingnew strategies to help caregivers. Even though a partic-ipant may not be eligible for one trial, another trial maybe just right.

The biggest benefit of all. Many families find thatthe biggest benefit of participating in a clinical trial is theregular contact with the study team. These visits pro-vide an opportunity to get state-of-the-art AD care andalso talk on an ongoing basis with experts in AD whohave lots of practical experience and a broad perspec-tive on the disease. The study team understands andcan provide advice on the emotional and physicalaspects of the person with AD and the caregivers’ expe-rience. They can suggest ways to cope with the presentand give insights into what to expect in the future. Theyalso can share information about support groups andother helpful resources.

For more information about AD clinical trials, visit theNIA’s Alzheimer’s Disease Education and Referral(ADEAR) Center’s Clinical Trials Database website(www.alzheimers.org/trials/index.html). This websiteincludes a list of clinical trials on Alzheimer’s diseaseand dementia currently in progress at centers throughout the U.S. It also provides information on thephases of clinical trials and how to participate, andexplains the drug development process. The site alsoprovides links to other useful websites with related information. For additional information, visit the clinical trials websites of the Alzheimer’s Association www.alz.org/ResourceCenter/ByTopic/Research.htm andthe National Institutes of Health www.clinicaltrials.gov/.

ImprovingSupportforFamiliesandOtherCaregivers

Perhaps one of the greatest costs ofAlzheimer’s disease is the physical and

emotional toll on family, caregivers, andfriends. The changes in a loved one’s personal-ity and mental abilities; the need to provideconstant, loving attention for years on end; andthe demands of bathing, dressing, and othercaregiving duties can be hard to bear. Manycaregivers must assume new and unfamiliarroles in the family and these changes can beboth difficult and sad. Not surprisingly, care-givers of people with dementia spend

Alzheimer’s Disease: Unraveling the Mystery 49

Caregivers vary depending on the culture and eth-nic group involved. Most primary caregivers arefamily members.

● Spouses: This is the largest group of care-givers. Most are older, too, and many have theirown health problems to deal with.

● Daughters: The second largest group of pri-mary caregivers are daughters. Many are marriedand raising chil-dren of their own.Juggling two setsof responsibilitiesis often tough forthese members ofthe “sandwichgeneration.”

● Daughters-in-law: Many women in this group helptake care of an older person with AD. They are the thirdlargest group of family caregivers.

● Sons: Though many are involved in the daily care of aparent with AD, sons often focus on the financial, legal,and business aspects of caregiving.

● Brothers and sisters: Siblings may assume primaryresponsibility for care if they live close by, but many areolder and are coping with their own frailties or healthproblems.

● Grandchildren: Older children may become majorhelpers in caring for a person with AD. Adolescent oryoung grandchildren may need extra help and support iftheir parents’ attention is heavily focused on the ill grand-parent, or if the grandparent with AD lives in the family’shome.

● Other: Friends, neighbors, and fellow faith communitymembers also often help care for a person with AD.

Who are the AD Caregivers?

Alzheimer’s Disease: Unraveling the Mystery50

significantly more time on caregiving tasksthan do caregivers of people with other typesof illnesses.

Although research on caregiver support isstill in its early days, we’ve already learned a lotabout the unique aspects of caregivers’ person-alities and situations. For example, one studyof the psychological and physical responses ofAD caregivers showed that they don’t all havethe same response to caregiving. Certain char-acteristics seem to make some caregivers morevulnerable to the physical and emotional stress-es associated with dementia care. These char-acteristics include being a male spouse, havingfew breaks from caregiving responsibilities, andhaving preexisting illnesses.

Caregiver research is also beginning to teaseout characteristics of support programs thatmight be most useful for particular groups ofcaregivers. For example, peer support programsthat link caregivers with trained volunteerswho also have been dementia caregivers appearto help. These programs are especially good for

caregivers whose social support networks areweak or who are in very stressful situations.Other research has confirmed that the informa-tion and problem-solving needs of caregiversevolve over time as the person with ADchanges. Support programs can respond byoffering services and information geared to different stages of the disease.

One of the most difficult decisions that manyfamilies face is whether and when to place aloved one with Alzheimer’s disease in a nursinghome or other type of care facility. Once thisdecision is made, families must decide whattype of care is best for the person and the fami-ly. Many investigators are working to identifystrategies that can lead to improved quality ofcare in various facilities, including assisted liv-ing facilities, continuing care retirement com-munities, nursing homes, and special care units(a separate area within a nursing home orassisted living facility designed especially forpatients with dementia).

Alzheimer’s Disease: Unraveling the Mystery 51

A reality check for an AD caregiver might look somethinglike this:

● Physical effort and time commitment: Help withbathing, eating, dressing, and other activities of daily livingtakes a lot of time. As the disease progresses, the needfor this kind of help increases. Behavior problems andsafety concerns mean that the caregiver is always “onduty,” even when not actively helping the person.

● Financial costs: The costs of care vary, but can behigh depending on whether the person is cared for athome or in a residential care setting and how much helpthe caregiver has. Many caregivers give up their jobs orcut back on their work hours and this also has financialimplications.

● Psychological loss: Caregivers often experience aprofound sense of loss as the disease slowly takes theirhusband, wife, parent, or friend. The relationship as itonce was gradually ends and plans for the future must beradically changed. Caregivers must come to terms with“the long goodbye.”

Many research studies have shown that caring for aperson with AD can have some negative effects on thecaregiver...

● Employment complications● Emotional distress● Fatigue and poor physical health● Social isolation● Family conflict● Less time for leisure, self, and other family members

...but research has shown that caregiving also hasimportant positive effects:

● A new sense of purpose or meaning in life● Fulfillment of a lifelong commitment to a spouse● An opportunity to give back to a parent some of what

the parent has given to them ● Renewal of religious faith● Closer ties with people through new relationships or

stronger existing relationships

the Realities, the Positives, and theNegatives of Caring for a Person with AD

Alzheimer’s Disease: Unraveling the Mystery52

Studying New Ways to Help Caregivers

It was midnight, the end of a long day of taking care ofher husband. She was exhausted but she couldn’t sleep.A year ago she would have felt totally alone, unable toshare the hardships of caregiving, and desperate for ideasfor how to cope better with his changeable moods andwithdrawal from the world. Tonight was different. Shewent to the living room, switched on her computer, and

plugged into a computer-based support group for familycaregivers. She sent out a message and soon receivedreplies from several fellow caregivers. They knew justwhat she was feeling. Their words of understanding andsupport eased her mind and helped give her the strengthshe needed for the days ahead.

Caring for a person with Alzheimer’s disease has specialstresses and difficulties. As a result, support groups havealways been an important feature of AD caregiver pro-grams. Conventional support groups have been

enormously helpful for many caregivers, but they have afew drawbacks. Attending a group involves finding trans-portation and arranging for care for the person with AD.The group’s meeting time may not coincide with the timethat a caregiver wants advice or needs to express feel-ings. Some caregivers do not feel comfortable discussingtheir experiences publicly in a group. Members of someethnic or cultural groups may be particularly reluctant tojoin a traditional support group.

In 1989, a researcherhad an idea for a radicallydifferent, new kind of sup-port system for familycaregivers. She envi-sioned a computer-basedsystem that would operate24 hours a day, 7 days aweek. It would provideexpert medical advice andinformation about the lat-est developments in ADresearch. It would alsoinclude a “bulletin board”component that wouldallow caregivers to shareideas and give and getsupport by posting mes-

sages on-line. The project would provide a computer ifneeded and would train caregivers in how to use theequipment. From the start, she invited the localAlzheimer’s Association to join her in carrying out the idea. This partnership is still flourishing today.

Although many people doubted that adult and elderlycaregivers with little or no computer experience wouldwant to go online, the project, called the Alzheimer’sDisease Support Center, was a hit from the start. In fact,the bulletin board component, called the Caregiver Forum,

Science on the Cutting Edge

Alzheimer’s Disease: Unraveling the Mystery 53

soon became the most popular element. Users were eagerto communicate, share experiences and feelings, and learnfrom each other. They soon became, as they called it, a“computer family.”

Scientists who have been conducting research with com-puter-based support systems have found they have twoqualities that make them especially useful:

● They reach lots of people simultaneously. Many userscan log on to get information that is posted on the system.In addition to providing lists of useful publications andmaterials, the systems post information on traditional sup-port groups, daycare centers, and other services. They alsoprovide a “Q&A” module where users can get answers totheir specific caregiving questions from a team of physi-cians, nurses, social workers, psychologists, and staff of theAlzheimer’s Association. In addition, users can browse anarchive of previously asked questions and answers organ-ized by topic. Users can also interact with each otherthrough the bulletin board component.

● Computer-based systems address some of the draw-backs of traditional support groups. They put control of thesupport process in the hands of the user. Users can talkwith others and get help whenever they need it, day ornight. Some users log on daily; others log on only whenthey have a specific question or need. Because the com-puter is at home, they don’t need to make special arrange-ments to get to a support group meeting. Users canexpress themselves publicly if they want to or they can beanonymous if that is better for them. For every user whoposts messages on the system, researchers have docu-mented that several just read what others have posted.These users seem to benefit from the sense of kinship withothers facing similar situations and may in time begin toparticipate more actively.

One of the most fascinating findings from this project washow quickly users overcame the potential barriers posed byan electronic communication system. Here are just a few ofthe techniques users have adopted to “humanize” the sys-tem, especially the Caregiver Forum:

● Using punctuation keys, users have incorporated anarray of icons into their messages to represent faces andgestures. They also intentionally misspell words andmanipulate the placement of letters. All of these deviceshelp users convey their feelings.

:-) :)ing :-o :-| ( )s [hugs]

“I am soooooooo tired.”

“It was reeeeeeeeeally scary.”

“...this is one way I have to think not to go wayD

OW

N”

● Users talk about all sorts of things, not just caregivingissues. Sharing details of everyday life – weddings, chil-dren’s activities, hobbies, even the weather – seems to helpusers reduce their feelings of isolation and brings a senseof normality and balance to their relationships with others.

● Friendships begun over the computer have blossomedinto regular meetings for meals and get-togethers.

In 2000, the NIA funded a follow-up study to the originalproject. Called Computer Mediated Support for FamilyCaregivers, or CO-MES, the study is exploring how best touse computers to provide information and support to familycaregivers. The study team is trying to learn more aboutwho uses this type of support and whether computer-basedgroups help to lessen the negative effects of caregiving.Two types of computer-based groups are being studied – agroup led by a family caregiver and a group led by a nurse.Many of the system’s features are the same as before,though users now access the system through the Internet.The system also now has a chat room, which allows usersto have “real-time” conversations. At the same time, theoriginal computer-based support group continues to operate.

Alzheimer’s Disease: Unraveling the Mystery54

Acetylcholine – a neurotransmitter that playsan important role in learning and memory.

Amyloid precursor protein (APP) – the larg-er protein from which beta-amyloid is formed.

Amyloid plaques – largely insoluble depositsfound in the spaces between nerve cells in thebrain that are made of beta-amyloid, othermolecules, and different kinds of nerve andnon-nerve cells.

Apolipoprotein E – a protein that carries cho-lesterol in blood and that appears to play somerole in brain function. The gene that producesApoE comes in several forms, or alleles – ε2,ε3, and ε4. The APOE ε2 allele is relativelyrare and may provide some protection againstAD. APOE ε3 is the most common allele andit appears to play a neutral role in AD. APOEε4 occurs in about 40 percent of all ADpatients who develop the disease in later life;it increases the risk of developing AD.

Axon – the long, tube-like part of a neuronthat transmits outgoing signals to other cells.

Beta-amyloid – a part of the APP proteinfound in the insoluble deposits outside neuronsand that forms the core of plaques.

Brain stem – the part of the brain that con-nects the brain to the spinal cord and thatcontrols automatic body functions, such asbreathing, heart rate, and blood pressure.

Cerebellum – the part of the brain that isresponsible for maintaining the body’s balanceand coordination.

Cerebral cortex – the outer layer of nerve cellssurrounding the cerebral hemispheres.

Cerebral hemispheres – the largest portion ofthe brain, composed of billions of nerve cellsin two structures connected by the corpus cal-losum; the cerebral hemispheres control con-scious thought, language, decisionmaking,emotions, movement, and sensory functions.

Chromosome – a threadlike structure in thenucleus of a cell that contains DNA,sequences of which make up genes; mosthuman cells contain 23 pairs of chromosomes.

Clinical trial – a research study involvinghumans that rigorously tests how well an inter-vention works.

Cognitive functions – all aspects of consciousthought and mental activity, including learn-ing, perceiving, making decisions, and remem-bering.

Corpus callosum – the thick bundle of nervesthat connects the two hemispheres of the cere-bral hemispheres.

Dementia – a broad term referring to thesymptoms associated with a decline in cogni-tive function to the extent that it interfereswith daily life and activities.

Glossary

Alzheimer’s Disease: Unraveling the Mystery 55

Dendrite – the branchlike extension of neu-rons that receive messages from other neurons.

DNA (deoxyribonucleic acid) – a long doublestranded molecule within the nucleus of thecell that forms the chromosomes and containsthe genes.

Early-onset Alzheimer’s disease – a rare formof AD that usually begins to affect peoplebetween ages 30 and 60; it is called familialAD (FAD) if it runs in the family.

Entorhinal cortex – an area deep within thebrain where damage from AD first begins.

Enzyme – a substance that causes or speeds upa chemical reaction.

Free radical – a highly reactive oxygen mole-cule that combines easily with other mole-cules, sometimes causing damage to cells.

Gene – the biologic unit of heredity passedfrom parent to child; genes are segments ofDNA and they contain instructions that tell acell how to make specific proteins.

Genetic risk factor – a change in a cell’s DNAthat does not cause a disease but may increasethe chance that a person will develop a dis-ease.

Glial cell – a specialized cell that supports,protects, or nourishes nerve cells.

Hippocampus – a structure in the brain thatplays a major role in learning and memory andis involved in converting short-term to long-term memory.

Hypothalamus – a structure in the brain underthe thalamus that monitors activities such asbody temperature and food intake.

Late-onset Alzheimer’s disease – the mostcommon form of AD; it occurs in people aged65 and older.

Limbic system – a brain region that links thebrain stem with the higher reasoning elementsof the cerebral cortex; it controls emotions,instinctive behavior, and the sense of smell.

Magnetic resonance imaging – a diagnosticand research technique that uses magneticfields to generate a computer image of internalstructures in the body; MRIs are very clear andare particularly good for imaging the brain andsoft tissues.

Metabolism – all the chemical processes thattake place inside the body. In some metabolicreactions, complex molecules are broken downto release energy; in others, the cells use ener-gy to make complex compounds out of simplerones (like making proteins from amino acids).

Microtubules – the internal support structurefor neurons that guides nutrients and mole-cules from the body of the cell to the end ofthe axon and back.

Alzheimer’s Disease: Unraveling the Mystery56

Mutation – a rare change in a cell’s DNA thatcan cause a disease.

Nerve growth factor (NGF) – a substancethat maintains the health of nerve cells. NGFalso promotes the growth of axons and den-drites, the parts of the nerve cell that areessential to its ability to communicate withother nerve cells.

Neurofibrillary tangles – collections of twisted tau found in the cell bodies of neuronsin AD.

Neuron – a nerve cell in the brain.

Neurotransmitter – a chemical messengerbetween neurons; a substance that is releasedby the axon on one neuron and excites orinhibits activity in a neighboring neuron.

Nucleus – the organ within a cell that contains the chromosomes and controls manyof its activities.

Positron emission tomography (PET) – animaging technique that allows researchers toobserve and measure activity in different partsof the brain by monitoring blood flow andconcentrations of substances such as oxygenand glucose in brain tissues.

Single photon emission computerized tomog-raphy (SPECT) – an imaging technique thatallows researchers to monitor blood flow to dif-ferent parts of the brain.

Synapse – the tiny gap between nerve cellsacross which neurotransmitters pass.

Tau – a protein that is a principal componentof the paired helical filaments in neurofibril-lary tangles; tau helps to maintain the struc-ture of microtubules in normal nerve cells.

Thalamus – a small organ in the front of thecerebral hemispheres that sends sensory infor-mation to the cerebral cortex and sends otherinformation back to the body.

Transgenic mice – mice that have had ahuman gene (like APP) inserted into theirchromosomes. Mice carrying the mutatedhuman APP gene often develop plaques intheir brains as they age.

Ventricle – cavity within the brain that con-tains cerebrospinal fluid. During AD, braintissue shrinks and the ventricles enlarge.

Organizations

Alzheimer’s Association. The Alzheimer’sAssociation is a national, nonprofit organizationwith a network of local chapters that provideeducation and support for people diagnosed withAD, their families, and caregivers. Chapters offerreferrals to local resources and services, andsponsor support groups and educational pro-grams. Online and print publications are alsoavailable.

Alzheimer’s Association919 North Michigan Avenue, Suite 1100Chicago, IL 60611-16761-800-272-3900Website: www.alz.org

Alzheimer’s Disease Cooperative Study. TheAlzheimer’s Disease Cooperative Study (ADCS)is a cooperative agreement between the NationalInstitute on Aging (NIA) and the University ofCalifornia, San Diego, to advance research inthe development of drugs to treat AD. TheADCS is a consortium of medical research cen-ters and clinics working to develop clinical trialsof medicines to treat behavioral symptoms ofAD, improve cognition, slow the rate of declineof AD, delay the onset of AD, or prevent the dis-ease altogether. The ADCS also develops newand more reliable ways to evaluate patientsenrolled in clinical trials.

Alzheimer’s Disease Cooperative StudyUniversity of California, San Diego9500 Gilman Drive - 0949La Jolla, CA 92093-0949858-622-5880Website: http://antimony.ucsd.edu/

Alzheimer’s Disease Education and Referral(ADEAR) Center. The ADEAR Center, part ofthe NIA, provides publications and informationon AD, including booklets on caregiving, factsheets and reports on research findings, a data-base of clinical trials, recommended reading lists,and the Progress Report on Alzheimer’s Disease.Information specialists provide referrals to localAD resources.

Alzheimer’s Disease Education and Referral(ADEAR) Center PO Box 8250Silver Spring, MD 209071-800-438-4380Website: www.alzheimers.org

Children of Aging Parents. Children of AgingParents is a nonprofit organization that providesinformation and referrals for nursing homes,retirement communities, elderlaw attorneys,adult day-care centers, medical insuranceproviders, respite care, assisted living centers,and State and county agencies. Also offered arefact sheets on various topics, a bimonthlynewsletter, conferences and workshops, supportgroup referrals, and a speaker’s bureau.

Children of Aging Parents1609 Woodbourne Road, Suite 302ALevittown, PA 19057-15111-800-227-7294Website: www.caps4caregivers.org

Alzheimer’s Disease: Unraveling the Mystery 57

For More Information

Organizations

Alzheimer’s Association. The Alzheimer’sAssociation is a national, nonprofit organizationwith a network of local chapters that provideeducation and support for people diagnosed withAD, their families, and caregivers. Chapters offerreferrals to local resources and services, andsponsor support groups and educational pro-grams. Online and print publications are alsoavailable.

Alzheimer’s Association225 N. Michigan Avenue, Suite 1700Chicago, IL 606011-800-272-3900Website: www.alz.org

Alzheimer’s Disease Cooperative Study. TheAlzheimer’s Disease Cooperative Study (ADCS)is a cooperative agreement between the NationalInstitute on Aging (NIA) and the University ofCalifornia, San Diego, to advance research inthe development of drugs to treat AD. TheADCS is a consortium of medical research cen-ters and clinics working to develop clinical trialsof medicines to treat behavioral symptoms ofAD, improve cognition, slow the rate of declineof AD, delay the onset of AD, or prevent the dis-ease altogether. The ADCS also develops newand more reliable ways to evaluate patientsenrolled in clinical trials.

Alzheimer’s Disease Cooperative StudyUniversity of California, San Diego9500 Gilman Drive - 0949La Jolla, CA 92093-0949858-622-5880Website: http://adcs.ucsd.edu

Alzheimer’s Disease Education and Referral(ADEAR) Center. The ADEAR Center, part ofthe NIA, provides publications and informationon AD, including booklets on caregiving, factsheets and reports on research findings, a data-base of clinical trials, recommended reading lists,and the Progress Report on Alzheimer’s Disease.Information specialists provide referrals to localAD resources.

Alzheimer’s Disease Education and Referral(ADEAR) Center PO Box 8250Silver Spring, MD 209071-800-438-4380Website: www.alzheimers.org

Children of Aging Parents. Children of AgingParents is a nonprofit organization that providesinformation and referrals for nursing homes,retirement communities, elderlaw attorneys,adult day-care centers, medical insuranceproviders, respite care, assisted living centers,and State and county agencies. Also offered arefact sheets on various topics, a bimonthlynewsletter, conferences and workshops, supportgroup referrals, and a speaker’s bureau.

Children of Aging Parents1609 Woodbourne Road, Suite 302ALevittown, PA 19057-15111-800-227-7294Website: www.caps4caregivers.org

For More Information

Alzheimer’s Disease: Unraveling the Mystery 57

Alzheimer’s Disease: Unraveling the Mystery58

Eldercare Locator. The Eldercare Locator is anationwide, directory assistance service helpingolder people and their caregivers locate localsupport and resources. It is funded by the U.S.Administration on Aging, whose website atwww.aoa.gov also features AD information forfamilies, caregivers, and health professionals.

Eldercare Locator1-800-677-1116Website: www.eldercare.gov

Family Caregiving Alliance. The FamilyCaregiver Alliance (FCA) is a nonprofit organi-zation that offers support services for those caringfor adults with AD, stroke, traumatic braininjuries, and other cognitive disorders. FCA pro-grams and services include an InformationClearinghouse for FCA’s publications.

Family Caregiving Alliance690 Market Street, Suite 600San Francisco, CA 94104415-434-3388Website: www.caregiver.org

National Institute on Aging (NIA). Part of theNational Institutes of Health (NIH), the NIA isthe Federal government’s lead agency forresearch on AD. NIA also offers informationabout health and aging, including the Age Pageseries and the NIA Exercise Kit, which containsan 80-page exercise guide and 48-minute closed-captioned video. Caregivers can find many AgePages on the website.

National Institute on Aging Information CenterPO Box 8057Gaithersburg, MD 20898-80571-800-222-22251-800-222-4225 (TTY)Website: www.nia.nih.gov

National Library of Medicine. Part of NIH, theNational Library of Medicine is the world’slargest medical library with 6 million items,including books, journals, technical reports,manuscripts, microfilms, photographs and

images. A large searchable health informationdatabase of biomedical journals, called MED-LINE/PubMed is accessible via the Internet. Aservice called MEDLINEplus links the public togeneral information about AD and caregiving,plus many other sources of consumer healthinformation, including a searchable clinical trialsdatabase located at http://clinicaltrials.gov.

National Library of Medicine8600 Rockville PikeBethesda, MD 208941-888-346-3656Website: www.nlm.nih.gov

Partnership for Caring. Partnership For Caring(PFC) is a nonprofit organization that works toimprove how people die in our society. PFCoperates an information hotline dealing withend-of-life issues and provides State-specific liv-ing wills, medical powers of attorney, and otherinformation materials. PFC also provides educa-tion and consultation services to doctors, nurses,social workers, attorneys, and clergy concerningend-of-life decisions.

Partnership for Caring1620 Eye Street NW, Suite 202Washington, DC 200061-800-989-9455Website: www.partnershipforcaring.org

Well Spouse Foundation. Well SpouseFoundation is a nonprofit organization that givessupport to spouses and partners of the chronical-ly ill and/or disabled. Well Spouse maintains sup-port groups, publishes a bimonthly newsletter,and helps organize letter writing programs tohelp members deal with the effects of isolation.

Well Spouse Foundation63 West Main Street, Suite HFreehold, NJ 077281-800-838-0879Website: www.wellspouse.org

Alzheimer’s Disease: Unraveling the Mystery 59

Recommended Reading

Check with your local library, bookseller or withmajor Internet book distributors for the following:

Ballard, E.L., Poer, C.M. Lessons Learned:Shared Experiences in Coping. Durham, NC:The Duke Family Support Program. 1999.Available from the Alzheimer’s DiseaseEducation and Referral (ADEAR) Center, POBox 8250, Silver Spring, MD 20907-8250. 1-800-438-4380.

This book documents the experiences ofpeople caring for loved ones with AD. Filledwith short stories and advice, it is intendedfor caregivers who wish to take comfort andlearn from the experiences of others.Caregivers discuss the caregiving process,such as getting a diagnosis, finding supportservices, making decisions about treatmentand living arrangements, and coping withstress and caregiver burden.

Davies, H.D., Jensen, M.P. Alzheimer’s: TheAnswers You Need. Forest Knolls, CA: ElderBooks. 1998.

This book is designed for people in the earlystages of AD. It provides information aboutthe nature and causes of AD, the symptomsand how to deal with them, the assessmentprocess, taking part in a drug research pro-gram, continuing to work, handling finances,driving, and the effects of AD on a spouseand other family members.

Mace, N.L., Rabins, P.V. The 36 Hour Day: A Family Guide To Caring for Persons WithAlzheimer’s Disease, Related DementingIllnesses, and Memory Loss in Later Life. 3rded. Baltimore, MD: Johns Hopkins UniversityPress. 1999.

This practical and detailed reference bookprovides a wealth of information to familieson caring for persons with AD or related dis-orders. The book presents background infor-mation on dementia, brain disorders, and the

causes of dementia, and gives practical sug-gestions and advice on how families andcaretakers can deal with problems.

McKhann, G., Albert, M. Keeping Your BrainYoung: The Complete Guide to Physical andEmotional Health and Longevity. Hoboken, NJ:John Wiley and Sons. 2002.

This book examines scientific research andcase histories to summarize the most effec-tive ways to reduce the impact of physicalchanges to the brain as we age. The authorsoffer techniques to improve memory and recommend mental and physical exerciseprograms. Their strategies to stay healthyalso include a well-balanced diet, propersleep, and getting treatment for depression,vision and hearing loss, and other healthproblems. The book also discusses brain disorders.

Petersen, R., ed. Mayo Clinic on Alzheimer’sDisease. Rochester, MN: Mayo Clinic HealthInformation. 2002.

This book discusses current knowledge ofAD and its relationship to other forms ofdementia. It also provides an overview oftreatment and caregiving, using the experi-ence of physicians, psychiatrists, neurolo-gists, and allied healthcare professionals atthe Mayo Clinic. Topics include how thebrain works and what can go wrong; how ADaffects a person; diagnosis treatments;research; and caregiving.

Restak, R. The Secret Life of the Brain.Washington, DC: Joseph Henry Press. 2001.

This companion to the PBS documentarytakes the reader on a fascinating journeythrough the developing brain, from infancyand childhood, through adulthood, to oldage. The author examines brain disordersand mechanisms of brain repair and healing.

Alzheimer’s Disease: Unraveling the Mystery60

Shenk, D. The Forgetting. Alzheimer’s: Portraitof an Epidemic. New York, NY: Random House,Inc. 2001.

An eloquent and moving description ofAlzheimer’s disease, The Forgetting is anexploration of, and meditation on, the natureof memory and perceptions of self. It is areadable, accessible description of the historyof AD, research, and the human impact ofthe disease. The author, calling AD a “deathby a thousand subtractions,” describes the sci-ence of AD in terms that are easy for thosewho know nothing about AD to understand.

Snowdon, D. Aging With Grace: What the NunStudy Teaches Us About Leading Longer,Healthier, and More Meaningful Lives. NewYork, NY: Random House, Inc. 2001.

This book describes the participants and find-ings from the Nun Study, a long-term projectexamining aging and AD in a unique popula-tion of 678 Catholic sisters. The nunsallowed Dr. Snowdon access to their medicaland personal records, and agreed to donatetheir brains upon death. The book discussesthe relationship of early linguistic ability torisk of AD, the association of stroke anddepression to AD, and the role of heredityand lifestyle in healthy aging.

Tanzi, R.E., Parson, A.B. Decoding Darkness:The Search for the Genetic Causes ofAlzheimer’s Disease. Cambridge, MA: PerseusPublishing. 2000.

This book presents a history of the medicaljourney to find the genetic causes of AD. Itdescribes the experiences of Dr. Rudy Tanzi, apioneer in the search to identify AD genes.The book is easy to read and examines thecomplex research involved in moleculargenetics. The authors speculate that AD mayultimately be effectively treated and even pre-vented.

CreditsWriterAnne Brown Rodgers

Medical IllustratorChristy Krames, MA, CMI

EditorsPatricia D. Lynch and Karen M. Pocinki National Institute on Aging

DesignRodney C. Williams and Brian TaylorRCW Communication Design Inc.

Project CoordinatorDavid BurtonJohnson, Bassin & Shaw Inc.

PhotographyFront Cover (top), Back Cover (top), Page 45 – Corbis

Front Cover (bottom), 9 – Brand X Pictures

Back Cover (bottom), 5, 6, 49 – Getty

Page 2, 40, 42 – Photoresearchers

Page 6, 7, 8, 41, 46, 48, 50, 51 – Rick Brady

Page 31, 33, 48, 52 – Max Hirshfeld

Page 14 – Courtesy of Dr. Susan Bookheimer,Brain Mapping Center, UCLA School of Medicine

Page 15, 24 – Courtesy of Dr. Gary Small,University of California at Los Angeles

Page 18 – Courtesy of Dr. Philip Landfield,University of Kentucky and with permission of the Journal of Neuroscience, 2001. Dec 15, 21(24), 9744-56

Page 19 – Courtesy of Dr. Carl Cotman,University of California at Irvine and with permission of Trends in Neuroscience, 2002. Jun, 25(6), 295-301

Page 20 – Courtesy of Dr. William Markesbery,University of Kentucky

Page 35 – Courtesy of Dr. Bradley Hyman,Harvard Medical School/Massachusetts General Hospital

Page 37 – Courtesy of Dr. David Bennett,Rush Presbyterian-St. Luke’s Medical Center, the BenedictineMonks, Collegeville, MN, and the Benedictine Sisters,St. Cloud, MN

Animation Design and ProductionStacy Jannis and Rebekah FredenburgVicky Cahan, National Institute on Aging

Special thanks to:The staff of the Neuroscience and Neuropsychology of AgingProgram, National Institute on Aging

For additional copies of this report or furtherinformation about Alzheimer’s disease,please contact:

Alzheimer’s Disease Education andReferral (ADEAR) CenterPO Box 8250Silver Spring, MD 20907-8250

Phone: 1-800-438-4380E-mail: [email protected] address: http://www.alzheimers.org

U.S. Department of Health and Human ServicesNational Institutes of HealthNIH Publication Number: 02-3782December 2003


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