Alzheimer's Disease

What is Alzheimer's Disease? In 1986, President Ronald Reagan's"I don't remember," "I don't recall" responses seemed to many to be lameanswers to questions about political dealings. However, it turns outthat they may have been the truth. In 1994, former President Reagan announced thathe had Alzheimer's disease (AD).

RonaldReagan

Alzheimer's disease attacks the brain; it is not a normal part ofaging. People with AD have a gradual memory loss and difficulties withlanguage and emotions. The progressive loss of intellectual abilities istermed dementia. As the disease advances, theperson may need help in all aspects of life: bathing, eating, and usingthe restroom. Becauseof this round-the-clock care, families and friends of people with AD aregreatly affected. The disease is irreversible andthere is currently no cure.

Estimated Number of Cases
of AD in the U.S.(millions)

Who Gets AD? About 5-6% of the US population has AD or a related dementia. This meansthat approximately four million Americans have AD. As the population ages,the burden to caregivers and cost to society will grow. It is estimatedthat by 2050, 14 million people in the US will suffer from AD. Alzheimer's disease ranks fourth in the cause of death among adults. About100,000 people die per year as a result of AD. Five to 10 percent of thepopulation over age 65 have AD. At the age of 85 and older, about 50%have AD. Although age is a factor, research has shown that genetics alsoplay a role. Because women tend to live longer than men, more womenare affected by AD than men. Furthermore, 80% of caregivers are women, sothey are also secondarily affected by the disease.

Symptoms Memory loss, especially of recent events and newly acquired information,is perhaps the most noticeable trait of AD. The first symptoms have agradual, subtle onset, and can be a sign of many dementias, not just AD.For example, a person may become lost in familiar surroundings, forgetwhether a task was done, repeat the same story, or is unable to learn newthings. As the disease worsens, the person may be unable to find the rightword or to make responsible decisions.

One of the most painful aspects of the disease is that the personsometimes will not recognize friends or family members. Personalitychanges can occur, such as unusual agitation, paranoia, depression, andsocial withdrawal. Later, people with AD may wander, or be unable to findtheir way home. New research, however, has shown that a part of the brainthat processes visual and spatial information may be damaged in peoplewith AD. This may account for the problems AD patients have withorienting themselves.) Patients may also become inattentive, thus unableto care for their day-to-day bodily needs. Other parts of the brainincluding the basal forebrain and hippocampus, areas important for memory,are also affected by AD. Many AD sufferers die from other causes such aspneumonia. From the time of diagnosis, AD patients generally live 6-8years, although many live for as long as 20 year after the diagnosis. The symptoms of AD vary tremendously from person to person, but intime, eachperson who has AD will experience worsening symptoms. Many ofthe behavioral changes associated with AD - depression, paranoia, anddelusions - can be helped with medication. However, there is no cure forAD, although some treatments hold promise.

Areas of the brain affected by AD A = Cerebral Cortex B =Basal Forebrain C = Hippocampus Image courtesy of the NIA Illustrator: Lydia Kibiuk

A Closer Look at an AD Brain The microscopic changes that occur in the brain of a person with ADwere first noted by German neurologist AloisAlzheimer in 1906. He performed an autopsy on a woman whohad become more and more confused in the years preceding her death. Hecalled the changes he observed in her brain plaquesand tangles. These features can only be seen uponautopsy. Tangles and plaques interfere with neuronal functions, such ascommunicating with each other and sending messages to other parts of thebody. Research suggests that the formation of tangles in thebrain may be a part of the normal aging process. Dr. John Morris ofWashington University School of Medicine in St. Louis, Missouri, publisheda report titled "Tangles and plaques in nondemented aging and preclinicalAlzheimer's disease" in the March 1999 issue of Annals ofNeurology, Volume 45 Number 3, pages 358-368. This study showed thatof the 39 nondemented people (people with no behavioral evidence ofAlzheimer's disease), all had tangles in their brains. So perhapsdeveloping tangles is an inevitable part of growing old. "This is furtherevidence that there is such a thing as truly healthy aging and thatAlzheimer's disease is not inevitable," states Morris. Moreresearch isneeded to figure out what role tangles and plaques play in AD. Are onlyplaques responsible, or do tangles and plaques interact? Other observed changes in the brain affected by AD include: neuronal degeneration in a part of the brain called the nucleus basalis of Meynert. decreased brain levels of the neurotransmitter acetylcholine.

Image courtesy of the NIA Illustrator: Lydia Kibiuk

Neurofibrillary Tangles It is unclear how neurofibrillary tangles (NFT) form. NFTs are foundinside of the neuron: the neurons themselves become deformed and clumptogether. NFTs have been described as looking like a rope tied in knots. Aprotein named tau has been shown to be involved informing NFTs, but more research is needed to solve the mystery of how andwhy NFTs form, and how exactly they affect the brain. Plaques Unlike tangles, plaques occur outside the neuron. Plaques are mainlycomposed of a protein called beta amyloid, althoughother proteins contribute to plaque formation. Research has shown that aprotein in our bodies called amyloid plays asignificant role in AD. Proteins are vital molecules that control allsorts of processes in our body. The amyloid protein occurs naturally inour brains, but as we age, too much of it (in a form called beta amyloid)accumulates in the brain, forming plaques. Betaamyloid is formed when an enzyme clips the amyloid precursor protein; betaamyloid, a fragment from this process then aggregates in deposits. It isunknown whether these deposits are due to excess production or whether theenzymes that usually break it down are not functioning properly. Thissituation is similar that of cholesterol in our bodies. Some cholesterolis needed to keep our cells healthy, but too much cholesterol can blockarteries and lead to heart attacks and other problems.

Image courtesy of the NIA Illustrator: Lydia Kibiuk

Drug Therapies Only two drugs for treating AD have been approved by the US Food and DrugAdministration (FDA): Cognex and Aricept. These drugs arecholinesteraseinhibitors (generic names tacrine anddonepezil, respectively). These drugs inhibit the breakdownof acetylcholine by blocking the action of cholinesterase, the key enzymein the breakdown of acetylcholine. Both drugs increase the level of theacetylcholine in the brain. Both drugs also slow memory loss and help theperson perform daily tasks. It is important tonote that these drugs are not a cure, they only lessen the symptoms ofAD. Tacrine has side effects on liver enzymes, so a new experimental drug,rivastigmine, may soon be approved for AD. It is "brain selective" anddoes not affect liver enzymes. At least 17 other drugs for treating AD are awaiting approval from the USFDA. Other Therapies Vitamin E (an antioxidant) and aspirin (ananti-inflammatory) arebeing considered as treatments. How each works to lessen the symptoms ofAD is not clear. It has been suggested that Vitamin E protects thenerve cell membranes from damage by a harmful chemical process calledoxidation. Studies have shown that some architectural designshelp AD patients. For example, buildings with circular floor plansallow AD patients towander until they find their room. Signs reminding AD patients to docertain tasks can help focus attention. Having the same schedule each daycan also aid the AD patient's memory. Some studies have shown modest effects of the plant GingkoBiloba on the symptoms associated with AD. A controversial surgicaltreatment for AD has been reported by Dr. Harry S. Goldsmith at theUniversity of Nevada School of Medicine. He places part of the omentum, a fatty membrane in the abdomen which holdsorgans in, on the brain. This has been shown to improve short-term memoryin AD patients, perhaps because of a chemical in the omentum. Furtherresearch is warranted to explain how (and if) this surgery works. For a more in-depth look at therapies being considered for treating AD,see Alzheimers.com.

Expanding Diagnostic Tools Since a definitive diagnosis of AD canonly be made by examining the brain after a person dies, AD diagnosis inthe living mustbe made by exclusion. This means that other diseases must be ruled out asa cause of the dementia. There is no single test to show that a personhas AD, but several tests can suggest the presence of AD. When analyzingcerebrospinal fluid, an elevated level of certain proteins, includingamyloid beta protein, may indicate that a person is likely to have AD. Asimaging technology becomes more sophisticated and accessible, healthprofessionals can use CAT scans to visualize brain shrinkage. A brainwithwidened sulci (the indentations on the surface of the brain), and enlargedcerebral ventricles (the spaces in the brain which are filled withCSF) - all characteristics of AD (and other neurological disorders). Brainimaging methods can also be used to gain information about blood flow andmetabolic activity in various parts of the brain. PET Scans

Risk Factors First and foremost, the chance of developing ADincreases with age. With each additional year of life, there is increasedlikelihood that one will display symptoms of AD. Alzheimer's diseaseaffects men and women about equally, and strikes all ethnic groups. There are actually two types of AD: familial (early onset) and sporadic(late onset). Familial AD is a rare form of AD thataffects a small subset of people at a younger age, usually before theirfifties. It has a strong genetic component: mutations on genes 21, 14, and1 cause a predisposition to AD.(Reported in Neurology, July1998.) Sporadic AD is the type most people are familiar with. Itaffects people most often after they reach 65 years of age. A gene calledAPOE on chromosome 19 has been pinpointed as being a risk factor for AD(JAMA, August 19, 1998, Vol. 280, #7.), as it has a gene called APOE onchromosome 12.

What Can You Do to Protect Your Brain As You Age? As you age,some connections in your brain may fail due to tangles or plaques, so itmakes sense that the more neural connections you have overall, the moreyou will be able to compensate for the damaged connections. It's like asports team. If one player gets injured and there is aqualified player on the bench who can substitute, the team will stillfunction well. The more players available to play for injured teammembers, the better the team will fare. How do you get and maintain neural connections? It is thought that stayingactive, both mentally and physically, will help. Challenge your mind.Remember people's names. Work crossword puzzles. Do math. Read. Learn newwords.

Future Research Understanding Alzheimer's disease is one of the most active areas inneuroscience research. In 1998, scientists took a big step forward bybreeding mice that develop the symptoms of AD. These mice will helpresearchers unravel the mysteries of AD. Research into future treatmentscan be divided into several categories. Chemical Theories Biochemical Changes inthe Brain Braincells need certain nutrients to grow. One of these nutrients is calledNGF, fornerve growth factor. A decrease in NGF could contribute to AD. Experimentson rats have shown that NGF promoted growth of new synaptic connections ina part of the brain called the hippocampus. This new growth, in theory,could help restore memory loss. The flip side to chemicals which helpneurons grow are the chemicals which kill neurons. These chemicals areneurotoxic. Perhaps an increased level of neurotoxins contributes to thedisease. If levels of these neurotoxic substances could be regulated,fewer neurons would die, thus lessening the symptoms of AD. Neurotransmitter Deficiencies in the Brain Neuronsuse neurotransmitters to communicate. As mentioned previously,acetylcholine levels are lower in AD brains compared to non-AD brains. Ithas been shown that drugs with the side effect of lowering acetylcholinecan cause temporary memory loss. Thus, drugs which promote increasedlevels of acetylcholine in the brain may slow the dementia. Toxic Chemical Excesses in the Brain In thepast, aluminum, mercury and other metals found in the brain tissue of ADpatients caused speculation that these compounds contributed to thedisease. Most scientists agree that aluminum and other metals probably donot cause AD, although they result from the disease process. Furtherresearch is needed to clarify these metals' role in AD. The Genetic Theory The genetics of AD are confusing at best. Somefamilies may have many members affected, but because family members may beexposed to the same environment, it is impossible to say how much heredityis to blame. Several genes have been identified on chromosomes 21 and 14in the familial type of AD. In the more common sporadic type, people witha gene for a protein called apolipoprotein E on chromosome 19 tend to havea higher incidence of AD than the general population. Much more work needsto be done to fully understand how genetics influences the incidence ofAD. The Autoimmune Theory Your immune system fights off infectionfrom bacteria, viruses, and other threats to your well-being. If thissystem goes awry, your immune system can attack its own tissue. Scientistshypothesize that if your immune system attacks your brain as you age,AD symptoms could result. However, it is unclear whether this leads to AD,since signs of this type of attack have been seen in non-AD brains. The Slow Virus Theory Some brain disorders which cause symptomssimilar to AD are caused by slow viruses. However, no one has identifieda virus specific for AD.

References and further information Alzheimer's: FewClues on the Mysteries of Memory Alzheimer'sDisease - Administration on Aging Fact Sheet Alzheimer'sDisease - Unraveling the Mystery Alzheimer'sDisease Fact Sheet Alzheimer's Disease - NINDS Alzheimer's Disease Educationand Referral (ADEAR) Center Alzheimer'sDisease Resource Center The Alzheimer's Associationinformation onissues relating to AD Dr. Koop'swebsite Mediconsult NIA public serviceannouncements - RealMedia Videos

This article prepared by Ellen Kuwana
Neuroscience for Kids Staff Writer