An Alzheimer's Primer:

Navigating through the Web

of

Plaques and Tangles

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Alzheimer's disease (AD) is the leading cause of dementia in the elderly and the fourth leading cause of death late in life, yet little is known about its cause. Five percent of individuals over 65 suffer from severe dementia, and it is believed that over half of these cases are the result of Alzheimer's. Because AD cannot be definitively diagnosed until an autopsy or cortical biopsy is performed, this figure is only an estimation. Currently, there are approximately 4.1 million cases in the U.S. As people live longer and longer, dementia will become an even greater health problem in the future than it is today (Kimble, 1992). Refer to the Alzheimer's Association or the Alzheimer's Society of Ottawa-Carleton for more information. There is also an Alzheimer Web Home Page from University of Melbourne, Australia that provides a comprehensive list of links to research sites and recent articles, as well as a summary current theories.

Two Types of AD

Early onset or presenile familial AD can occur as early in life as the late forties or early fifties. These individuals make up a very small percentage of AD cases. This form of the disease is known to be due to an autosomal dominant mutation in the gene that codes for amyloid precusor protein which lies near the centromere on chromosome 21q.

Late onset AD can be divided into familial and nonfamilial forms. Among the two familial forms, early and late onset, late onset represents a larger proportion of cases and is associated with a locus on chromosome 14. No gene has been located yet. For research and case studies of familial Alzheimer's, refer to the Online Mendelian Inheritance in Man Database. A recently published book, Hannah's Heirs: The Quest for the Genetic Orgins of Alzheimer's Disease by Daniel A. Pollen, M.D., may also be of interest.

The majority of AD cases are late onset in which genetic involvement is unclear. However, possesing one or two copies of the E4 allele of the alipoprotein E gene on chromosome 19 is now considered a risk factor.

Three Stages of Decline

Stage 1: lasts 2-4 years;confusion about names and places, decreased recall of information, difficulty handling money, loss of initiative, poor decision making, and anxiety about symptoms.

Stage 2: lasts 2-10 years; increasing memory loss and confusion, difficulty recognizing friends and family, perceptual and motor problems, loss of language facility and logical thinking.

Stage 3: lasts 1-3 years; inability to recognize self or family, weight loss, little or no capacity to care for self, incontinence, aphasia, difficulty swallowing, and seizures.

For a more complete list of warning signs see this list..

Changes in the Brain

There are five hallmarks of AD that occur in all forms:

Neuronal Loss

Loss in neuronal numbers is a normal part of the aging process-- up to a 30% loss of neocortical neurons by age 65 occurs in healthy individuals. AD patients lose 50% or more of their neocortical neurons, primarily in the frontal and temporal lobes.

Dendritic Degeneration

The degree of degeneration of the basal dendrites of the neocortex, rather than the age of the patient, is more predictive of the extent of dementia. In presenile dementia, "lawless" dendritic growth is commonly seen. These chaotic tangles of dendrites impair normal brain functioning.

Neurofibrillary Tangles

These are abnormally shaped neurofibrils and neurotubles that twist together in a spiraling pattern. The result is reduced flow of material in these neurons, impeding normal functioning. In fact, the density of the tangles, rather than the number of amyloid plaques (discussed below), is closely correlated with the degree of dementia. This intracellular phenomenon is present to a small degree in normal aging brains. These tangles occur in larger numbers in individuals over forty with Down Syndrome, leading researchers to look at chromosome 21 for a genetic link.

Amyloid Plaques

These consist of decaying nerve endings and astrocytes with a core of an amyloid beta protein fragment. This fragment comes from a glycoprotein precusor that occurs in most cells as an integral membrane protein. The amyloid protein may also be secreted from normal cells. The gene for the amyloid protein precursor is located on chromosome 21. A mutation of this gene has been implicated in early onset familial AD. To download the protein motif fingerprint of the amyloid precursors in humans, mice, and rats from the National Institutes of Health, click here. Amyloid plaques are also present in the brains of individuals with Down Syndrome. The plaques occur mainly in the cerebral cortex and hippocampus, regions which control memory, thinking, reasoning, and sensory perception --all areas of impairment in AD patients.

The question is, what causes these proteins to clump together into a plaque? Alipoprotein E is suspected of being involved in this process. One scientist's self-proclaimed "ramblings" on alipoprotein E's possible role in AD can be found here. For research on amyloid beta protein and its relationship to AD and other diseases refer to The Laboratory of Molecular Biophyisics at Oxford.

Abnormal Neurotransmitter Levels

Decreased levels of acetylcholine, norepinephrine, and serotonin are found in the brains of AD patients. Attention has focused on acetylcholine since the number of cholinergic neurons is markedly lower in AD patients. Levels of acetylcholine can be measured by the concentration of choline acetyltransferase (ChAT), the enzyme that catalyzes the synthesis of acetylcholine. ChAT levels are 60-90% lower in AD patients than in age-matched nondemented individuals. One experimental treatment is to administer drugs, such as tacrine, that will inhibit acetylcholinesterase, the enzyme that hydrolizes acetylcholine. The anticipated result is to increase levels of acetycholine since the enzyme required for its degradation is disabled. Thus far, results have not been promising. It remains to be discovered whether the decreased number of cholinergic neurons are a cause or a consequence of AD.

Diagnosis and Imaging Techniques

Diagnosing AD consists of ruling out other causes of dementia because evidence of amyloid plaques and neurofibrillary tangles can only be found by directly examing the brain (i.e.cortical biopsy or autopsy). Refer to the Physician's Guide to Diagnosis for guidelines.

Although definitive diagnosis requires autopsy or biopsy, current imaging techiniques have improved the diagnostic ability to 90% accuracy.This is possible because the brains of AD patients show areas decreased blood flow and shrinkage. These changes can be seen in single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) scans, respectively. Areas of decreased blood flow indicate areas of decreased functioning. In SPECT images, decreased blood flow is seen as blue to black, whereas regions of high blood flow are orange to white.

The following movie is an overlay of SPECT images and MRI scans.

The Whole Brain Atlas offers tours through an Alzheimer's brain using

MRI images or SPECT images. Go directly to the Whole Brain Atlas to view hundreds of MRI's of a normal brain. To learn more about imaging of the Alzheimer's brain.

Organizations and Communications

Bibliography
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