The Brain and Alzheimer's Disease-Part XXI


Alzheimer's disease (AD) is not a normal process of aging. It is an irreversible, progressive disease that eventually affects our ability to do the simplest tasks of everyday living. The incidence of Alzheimer's disease increases with age, with the first symptoms appearing mainly in people over 60 years of age. Techniques (PET scans) allow scientists to "see" the effects AD has on the brain, an organ that absent disease can function well into the tenth decade of life. We believe the information presented below, about the brain itself, might provide our readers with a better idea of the nature of Alzheimer's disease.

Composition of the Brain
The brain manages many of the body functions including, among others, speaking, moving, breathing, blood circulation and digestion. We make decisions; feel emotions because of complicated mix of chemical and electrical processes that take place in the brain.

The average adult brain weighs about three pounds and is the size of a medium cauliflower. It contains about 100 billion neurons and a trillion synapses, which put cells in touch with their neighbors. Each cell has an axon and many dendrites. The axon, which is much narrower than the width of a human hair, extends out from the cell body and transmits messages to other neurons. Dendrites also branch out from the cell body, receiving messages from the axons of other nerve cells. The neurons are surrounded by glial cells, which support, protect and nourish them.

The cerebral hemispheres account for 85% of the brain's weight. The two hemispheres are connected by a thick bundle of nerves called the corpus callosum. The two hemispheres are believed to differ in how they process information. The left hemisphere appears to focus on the details (such as recognizing a particular face in a crowd). The right hemisphere focuses on the broad background (such as understanding the relative position of objects in space). The outer layer of the cerebral hemispheres is called the cerebral cortex. This is where the brain processes sensory information received from the outside world, controls voluntary movement, and regulates conscious thought and mental activity.

Another part of the brain, the cerebellum takes up a little more than 10% of the brain. It also has two hemispheres and its function relates to balance and coordination. It thus receives information from the eyes, the ears, and muscles and joints about the bodies' movements and position. After it processes the information, it sends messages through the rest of the brain and spinal cord.

Another main player in the brain is called the brain stem. It sits at the base of the brain and connects the spinal cord with the rest of the brain. Its function is crucial to our survival by controlling automatic actions of the body such as heart rate, blood pressure and breathing. The brain stem is involved in sleep and dreaming. Acting as a rely station, it mediates information between the brain and the spinal cord.

Within the cerebral hemispheres are other essential parts of the brain:

(1).the limbic system which links the brain stem with the highest reasoning elements of the cerebral cortex, controlling emotions and instinctive behavior as well as smell; the hippocampus, important for learning and short-term memory and the site where short-term memories are converted into long-term memories for storage in other brain areas.

(2).the thalamus receives sensory and limbic information, processes it, and then sends it to the cerebral cortex;

(3).the hypothalamus, s structure under the thalamus, monitors activities like body temperature and food intake, issues instructions to correct any imbalances and controls the body's internal clock.

As we age, so does the brain, resulting in certain changes in parts of the brain. Some neurons shrink, especially large ones in areas important to learning, memory, planning and other complex mental activities. Tangles and plaques develop in neurons and surrounding areas, though in smaller amounts than in Alzheimer's disease. Damage by free radicals increases.

Plaques are largely molecule deposits found in the spaces between nerve cells in the brain that are made of beta-amyloid, other molecules, and different kinds of nerve and non-nerve cells. Tangles are a collection of twisted tau found in cell bodies. Tau is a protein that is a principle component of the paired helical filaments in neurofibrillary tangles. Tau helps to maintain the structure of microtubules in normal nerve cells.

This process of normal change has an impact on the brain. In a healthy older person, there is a decline in their ability to learn new things and retrieve information, such as remembering names. Complex tasks of attention, learning and memory become highly vulnerable. However, if given enough time to perform the task, healthy people in the 70s and 80s can perform just as competently as younger adults. Processing and retrieving the information is where they are most vulnerable. Even here, some of the slowness may be accounted for by lack of mental exercise. The adage, "use it or lose it may apply".

Action of the Brain
As a neuron receives messages from surrounding cells, an electrical charge, or nerve impulse, builds up. This charge travels down the axon until it reaches the end. Here, it triggers the release of chemical messengers called neurotransmitters, which move from the axon across a tiny gap to the dendrites or cell bodies of other neurons. The typical neuron has up to 15,000 of these gaps, or synapses. After they move across the synapse, neurotransmitters bind to specific receptor sites on the receiving end of dendrites of the nearby neuron. They can also bind directly to cell bodies.

Once the receptors are activated, they open channels through the cell membrane into the receiving nerve cell's interior or start processes that determine what the receiving cell will do. Some neurotransmitters inhibit cell function, making it less likely that the nerve cell will send an electrical signal down its axon, while other neurotransmitters stimulate nerve cells, priming the receiving cell to become active or send an electrical signal down the axon to more neurons in the pathway. If neurons are disconnected, they become sick and may die. In order for neurons to survive several processes have to work smoothly together. This includes communication, metabolism and repair. The longer one lives, the more stresses experienced by cells, the more susceptible this coordinated process becomes subject to chance errors, resulting in potential pathological outcomes.

Metabolism is the process by which cells and molecules break down chemicals and nutrients to generate energy and form building blocks that make new cellular molecules like proteins. Efficient metabolism needs enough blood circulating to supply the cells with oxygen and glucose, a type of sugar. Glucose is the only source of energy usually available to the brain. Without oxygen and glucose, neurons will die.

In general, brain neurons live up to 100 years or longer; with recent research pointing out that a few brain regions can generate new neurons, even in old brains. To prevent their own death, living neurons must constantly maintain and remodel themselves. If cell cleanup and repair slows down or stops for any reason, the nerve cell cannot function well and eventually dies.

Alzheimer's disease (excess plaques and tangles, and possibly some genetic drift due to stress over time) disrupts each of the three processes that keep neurons healthy: communication, metabolism and repair. This disruption causes certain nerve cells in the brain to stop working, lose connections with other nerve cells, and finally die. The destruction and death cells cause the memory failure, personality changes, problems in carrying out daily activities, and other features of the disease. There is still more to be learned about the brain before a debilitating disease such as AD is effectively challenged. Today, all we have are some medications that can bring some symptom relief or slow down the process of decline.

Scientists have discovered a brain-derived neurotrophic factor (BDNF), which they consider a growth factor that helps neurons survive and is increased in exercising, thus promoting healthy neurons. This discovery opens up all sorts of possibilities to try to prevent, treat or reverse the process where plaques and tangles interfere with vital functions. It reinforces the old adage of "healthy body healthy mind"

We present the latest Cochrane Review (a highly respected medical research reviewer service) conclusions of pharmaceutical treatment of AD for our readers to peruse.
1. Hydergine: "research uncertainty remains regarding hydergine's efficacy in dementia".
2. Hormone Replacement Therapy/ Estrogen Replacement Therapy: "Currently, HRT or ERT for cognitive improvement or maintenance is not indicated for women with AD."
3. D-cycloserine: "The lack of a positive effect of D-cycloserine on cognitive outcomes in controlled clinical trials with statistical power high enough to detect a clinically meaningful effect means that D-cycloserine has no place in the treatment of patients with Alzheimer's disease."
4. Galantamine: "There is therefore evidence for efficacy of galantamine on global ratings, cognitive tests, assessments of ADLs and behaviour. This magnitude for the cognitive effect is similar to that associated with other cholinesterase inhibitors including donepezil, rivastigmine, and tacrine."
5. Thiamine: "It is not possible to draw any conclusions from this review. The number of people included in the studies if less than 50 and the reported results are inadequate."
6. Donepezil: "In selected patients with mild or moderate Alzheimer's disease treated for periods of 12, 24 or 52 weeks, donepezil produced modest improvements in cognitive function and study clinicians rated global clinical state more positively in treated patients. No improvements were present on patient self-assessed quality of life and data on many important outcomes are not available. The practical importance of these changes to patients and carers is unclear."
7. Rivastigmine: "Rivastigmine appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, improvements were seen in cognitive function, activities of daily living, and severity of dementia with daily doses of 6 to 12 mg. Adverse events were consistent with the cholinergic actions of the drug. Further research is desirable on dosage (frequency and quantity) in a search for ways to minimize adverse effects. This review has not examined economic data."
8. Selegiline: "Despite its initial promise, ie the potential neuroprotective properties, and its role in the treatment of Parkinson's disease sufferers, selegiline for Alzheimer's disease has proved disappointing. Although there is no evidence of a significant adverse event profile, there is also no evidence of a clinically meaningful benefit for Alzheimer's disease sufferers."
9. Indomethacin: "On the basis of this one trial and subsequent analysis of data as reported by the authors, indomethacin cannot be recommended for the treatment of mild to moderate severity Alzheimer's disease. At doses of 100-150 mg daily, serious side effects will limit its use."
10. Piracetam: "At this stage the evidence available from the published literature does not support the use of piracetam in the treatment of people with dementia or cognitive impairment. Although effects were found on global impression of change, no benefit was shown by any of the more specific measures."
11. Nimodipine: "Dementia is a chronic disorder and the short-term benefits of nimodipine demonstrated in the trials reviewed do not justify its use as a long-term anti-dementia drug. New research must focus on longer term outcomes"
12. Statins: "There is no good evidence to recommend statins for reducing the risk of Alzheimer's disease. There is, however, a growing body of biological, epidemiological, and limited but non-randomized clinical evidence that lowering serum cholesterol may retard the pathogenesis of Alzheimer's disease. Mounting the clinical studies to determine the potential benefit of statin therapy should be a high priority for future research agendas."
13. Physostigimine: "The evidence of effectiveness of physostigmine for the symptomatic treatment of Alzheimer's disease is limited. Even in a controlled release formulation designed to overcome the short half-life, physostigmine showed no convincing benefit and adverse effects remained common leading to a high rate of withdrawal."
14. Vitamin E: "There is insufficient evidence of efficacy of vitamin E in the treatment of people with Alzheimer's disease. The one published trial of acceptable methodology (~~Sano 1997~~) was restricted to patients with moderate disease, and the published results are difficult to interpret. There is sufficient evidence of possible benefit to justify further studies. There was an excess of falls in the vitamin E group compared with placebo, which requires further evaluation."

Alzheimer's disease consortium primary research sites
For those of our readers who would want to get in touch with Alzheimer's disease research centers, we provide the following resource material.

There is a Alzheimer's Disease Education and Referral Center (ADEAR) that provides information on clinical trials and other research to the public. You can call them at 1-800-438-4380 weekdays during business hours. For your information, we list below, by States, 31 ADEAR sites that may be recruiting patients for clinical trials

California-Stanford UniversityStanford, CA(650) 852-3287; University of California, Davis Martinez, CA(925) 372-2485; University of California, Irvine
Irvine, CA (949) 824-8726; University of California, Los Angeles Los Angeles, CA (310) 825-8908; University of California, San Diego La Jolla, CA
(858) 622-5820; University of Southern California Los Angeles, CA (323) 442-3715

Connecticut-Yale University School of Medicine New Haven, CT (203) 764-8100

Florida- Mayo Clinic, Jacksonville Jacksonville, FL (904) 953-7103; University of South Florida, Tampa Tampa, FL
(813) 974-4355

Georgia-Emory University Atlanta, GA (404) 728-6453

Illinois- Northwestern University Chicago, IL (312) 695-2343; Rush-Presbyterian-St. Lukes Medical Center Chicago, IL
(312) 942-8264

Indiana- Indiana University Indianapolis, IN (317) 278-3934

Kentucky-University of Kentucky, Lexington, Lexington, KY (859) 257-6508

Massachusetts- Memorial Veterans Hospital, Boston University Bedford, MA (781) 687-2845

Michigan- University of Michigan, Ann Arbor Ann Arbor, MI (734) 936-8764

Minnesota-Mayo Clinic, Rochester, Rochester, MN (507) 266-8485

Missouri- Washington University, St. Louis, MO (314) 286-2364

New York- Columbia University, New York, NY (212) 305-2371; Mt. Sinai School of Medicine, New York, NY
(212) 241-0438; University of Rochester Medical Center, Rochester, NY, (716) 760-6561

Ohio- University Hospitals of Cleveland, Cleveland, OH (216) 844-6419

Oregon- Oregon Health Sciences University, Portland, OR, (503) 494-7615

Pennsylvania- University of Pennsylvania, Philadelphia, PA (215) 349-5903; University of Pittsburgh, Pittsburgh, PA,
(412) 692-2705

Rhode Island- Brown University, Memorial Hospital of Rhode Island Pawtucket, RI, (401) 729-3752

South Carolina- Medical University of South Carolina, North Charleston, SC, (843) 740-1592 x17

Texas- Baylor College of Medicine, Houston, Houston, TX (713) 798-5325; University of Texas, Southwestern Medical Center
Dallas, TX, (214) 648-7466

Washington-University of Washington. Seattle, WA. (206) 277-1493

Washington, DC- Georgetown University, Washington DC (202) 784-6671


See: Alzheimer's Disease Part I-Medications for Alzheimer's.
See: Alzheimer’s Disease Part II- Selegiline and AD.
See: Alzheimer's Disease Part III- Use of Gingko Biloba in memory problems of Alzheimer patients
See: Part IV-Alternative Treatments for AD
See: Part V-Possible New Drugs for Alzheimer's Disease
See: Part VI-Early Diagnosis
See: Part VII-Metrifonate
See:Alzheimer's Disease PartVIII - Implications of Longer Life Expectancies
See: Alzheimer's Part IX-Ethical Care Principles
See: Alzheimer's Disease-Part X-Estrogen and Alzheimer's Disease
See: Alzheimer's Disease Part XI-Pocket Smell Test (PST)
See: Alzheimer's Disease Part XII-MAO-B
See: Alzheimer's Disease Part XIII -Critical Flicker Fusion Threshold Test
See: Alzheimer's Disease Part XIV-Donepezil
See: Alzheimer's Disease Part XV-Cerebrolysin
See: Alzheimer's Disease Part XVI-MCI
See: Alzheimer's Disease Part XVII-Summary
See: Alzheimer's Disease Part XVIII-NO Releasing NSAIDs
See: Alzheimer's Disease Part XIX-Vitamin E
See: Alzheimer's Disease-Part XX-Clinical Trials
See Dementia with Lewy Bodies- Part XXII-by Gourete Broderick
See: Alzheimer's Disease-Part XXIII-HMG
See: Alzheimer's Disease-Part XXIV-A Prequel
See: Alzheimer's Disease-Part XXV-Psychosis
See: Alzheimer's Disease-Part XXVI-Amyloid-beta Hypothesis Controversy
See: Alzheimer's Disease-Part XXVII- AD and Diabetes
See: Alzhemeir's Disease-Part XXVIII - Insulin and AD


Harold Rubin, MS, ABD, CRC, Guest Lecturer
posted May 4, 2003

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