What Causes Dementia?

Basic Introduction to Causes
Changes that Occur During Alzheimer's Disease
Genetic Issues
Cellular and Molecular Mechanisms

Basic Introduction to Causes

The exact cause of Alzheimer's Disease, a form of dementia, is still unknown. However, scientists have been able to indentify several contributing factors. Alzheimer's Disease is known to have a genetic componant as well as an environmental one. While Alzheimer's is a form of dementia, dementia is not necessarily Alzheimer's. There are many forms of demetia, some which are entirely curable. It is imporatant to understand the distinction between Alzheimer's disease and dementia.

The most common causes of dementia are listed below:

Degenerative Disorders

• Alzheimer's disease
• Diffuse Lewy Body dementia and Lewy Body Variant
• Frontal and Frontal-temporal lobe dementias
• Down syndrome

Stroke

• Vascular or Multi-infarct dementia
• Heart disease producing emboli or reduced perfusion

Trauma

• Head trauma

Toxic or Metabolic Diseases

• Depressive pseudodementia
• Alcohol
• B12 deficiency
• Folate deficiency

Immunologic Diseases

• Multiple Sclerosis
• Chronic Fatigue Syndrome

Infections

• Acquired Immunodeficiency Syndrome (AIDS)

Rarer Causes of Dementia

Degenerative Disorders

• Amyotrophic lateral sclerosis (ALS) and Other Frontal Lobe Dementias
• Pick's disease and other frontal temporal lobe dementias
• Creutzfeld-Jakob Disease
• Primary Progressive Aphasia
• Parkinson's disease
• Parkinson's Plus diseases
• Huntington's Chorea
• White matter diseases (Leukodystrophies)

Ventricular Disorders

• Normal Pressure Hydrocephalus
• Obstructive or Non-communicating Hydrocephalus
• Non-obstructive or Communicating Hydrocephalus

Vascular Diseases

• Binswanger's Disease
• Subarachnoid Hemorrhage
• Chronic Subdural Hematoma
• Vasculitis or Small Vessel Disease

Immunologic Diseases

• Immunoglobulin Deficiencies

Systemic or Metabolic Diseases

• Alcoholism
• Liver Disease
• Kidney Disease
• Lung Disease
• Diabetes
• Wilson's Disease

Convulsive Disorders

• Epilepsy
• Transient Global Amnesia

Cancer

• Brain and Metastatic Tumors

Infections

• Acquired Immunodeficiency Syndrome (AIDS)
• Chronic Encephalitis
• Neurosyphyllis

Changes that Occur During Alzheimer's Disease

Alzheimer's Disease is essentially caused by massive degeneration in specific areas of the brain, mainly those that serve learning, memory, and other higher levels of cognitive function (eg: the hippocampus and cerebral cortex). Throughout the progression of Alzheimer's Disease neurons rapidly deteriorate and brain tissue begins to show signs of accumulating senile plaques and tangles.

The figures below show how a healthy brain appears, and how one appears in the later stages of degeneration. Note the extensive spaces in the infoldings (fissures and sulci) of the brain. This reflects the loss of brain tissue caused by dementia.

Normally Aged Brain	Brain with AD

In the course of aging, the brain is affected by a variety of insults often leading to dementia. One of the major goals of research in the future is the development of rational strategies for promoting successful aging and preventing decline due to dementia. At a cellular level several changes occur in the course of AD

• neurons degenerate and others lose many of their processes and
• aberrent structures form within the brain called senile plaques and neurofibrillary tangles.

Thus, in order to stop the loss of function and slow the progression of dementia, it is important to discover how to prevent degeneration and the accumulation of plaques and tangles. It is also necessary to stimulate healthy neurons to regenerate their lost processes (a thin branch like structure that comes out of the cell body in order to communicate with other neurons) and restore their synaptic connections. The two neurons shown below illustrate the differences between a healthy neuron (left panel) and one in an AD brain that has lost many of its processes and connections (right panel).

Healthy Neuron	AD Neuron

Genetic Issues

Apolipoprotein E (Apo E) genotyping in differential diagnosis, not prediction of Alzheimer's disease.

Recently, a gene involved in the transport of cholesterol (apolipoprotein E) has been identified to be associated with AD in the population at large.

The Apo E locus on chromosome 19 is a gene that contributes to the susceptibility of a person for Alzheimer's disease. Apo E exists in people in three different forms or alleles (Apo E 2,3,4) which differ from each other by one to two base pairs. Each person has two copies of the Apo E gene. Thus an individual could have any of the following combinations:

Apo E 2/2 3/3 4/4
2/3 3/4
2/4

The exact combination of Apo E alleles affects the susceptibility for Alzheimer's disease.

APO E genetype is related to the age of onset distribution of Alzheimer's disease

Figure 1 illustrates an analysis of the proportion of individuals remaining normal at increasing ages for two, one, or zero copies of Apo E. Several conclusions can be drawn from this data. First of all, it can be seen that Alzheimer's disease can occur with all genotypes, but the inheritance of either one or two Apo E4 alleles is associated with earlier age onset of the disease. Secondly, this figure also shows the relative risk for Alzheimer's disease for a genotype at any given age. This is important because each indivdual who presents symptoms of dementia, does so at a unique age. For example, a 75 year old individual with the Apo E 4/4 genotype has approximately a 20% chance of remaining normal; Apo E 3/4, 40%; Apo E 3/3 or Apo E 2/4, 55%; Apo E 2/3, 80%. It should be emphasized that the accuracy of these estimates depends on future epidemiological studies, since these data will vary according to race and ethnicity. The effect of Apo E 4 on the distribution of age onset is the same for men and women, except that women live longer than men.

What is the difference between a diagnostic and a predictive test?

It is very important to emphasize that the content of Apo E is not to be interpereted in any way as a diagnosis of Alzheimer's disease. Apo E is a susceptibility characteristic. People and physicians are familiar with susceptibility data in other contexts. For example, it is well-known that certain risk factors, such as high cholesterol levels, are associated with an increased risk of heart disease. Being aware of these risks allows the individual to take therapeutic steps to prevent / delay the onset of the disease. In the case of Alzheimer's disease however, the discovery of susceptibility / risk factors has been quite recent, and there are presently no relevant therapies. On the other hand, susceptibility gene data can be applied as an aid in differential diagnosis.

Dementia is associated with many different diseases including vascular disease, depression, Pick's disease, and Alzheimer's disease, among others. Knowing an individual's Apo E geneotype can be useful in differential diagnosis. This means that a person presenting signs of dementia is more likely to be correctly diagnosed with Alzheimer's disease if they are at high risk for Alzheimer's disease, such as by having Apo E in their geneotype. A high risk does not mean a person will get Alzheimer's disease. Thus, the test is not a means of diagnosis per se. Some individuals, even those with E4/4 remain normal. There are many other factors that contribute to the final outcome.

Thus, the Apo E geneotype provides a predictive measure of susceptibility. Although currently no definitive conclusions can be drawn from Apo E genetyping, this data will play a pivital role in the future as new safe and effective treatments for Alzheimer's disease arise.

Several genes have been identified that appear to effect the probability that an individual will be affected by AD. These genes run in families and are usually associated with an early onset (prior to 60 years of age) and an unusually high incidence rates of Alzheimer's Disease in the family.

Cellular and Molecular Mechanisms

Beta-Amyloid initiates cell death

Only a few yearas ago Beta-Amyloid, the first 42 amino acids of the amyloid precursor protein (APP), was thought to be an inert deposit devoid of biological activity. Recent research by investigators here and elsewhere has shown that Beta- Amyloid organizes molecular cascades and initiates the degeneration of neurons.

Throughout life, there is a normal process of cleaving APP, which is a long protein of about 700 amino acids that sticks out from the cell into the extracellular space. Secretases cleave the APP between the 16th and 17th amino acid to fragment beta-amyloid in two; endosomes and lysosomes digest APP leaving the 42 amino acid beta-amyloid peptide intact; other pathways secrete the first 40 amino acids of the beta-amyloid peptide extracellularly.

Normally, the APP cleavage products are soluble; however, the intact beta-amyloid has a strong tendency to self-aggregate into an insoluble, beta-pleated sheet form, which is neurotoxic. In AD there is an ongoing process of neuronal death, which recent research has defined to be due to two mechanisms, necrosis and apoptosis.

• Necrosis:
  The soluble, unaggregated form of beta-amyloid can be neurotoxic when it occurs in conjunction with other potentially injurious conditions to the neuron, such as hypoglycemia, hypoxia, the presence of free radicals, or the presence of glial cell-derived cytokines that can initiate complement-mediated cell lysis. It does so by disturbing calcium ion gradients across the cell and initiating death due to necrosis. Necrosis is characterized by dilation of the endoplasmic reticulum and mitochondria, and ultimately membrane disintegration with subsequent loss of cytoplasmic contents, leading to inflammation and further damage to surrounding healthy tissues. The cells swell and explode.
• Apoptosis:
  Apoptosis (also referred to as programmed cell death) is a natural form of cell death that occurs during development or tissue regression. Apoptosis is characterized by cell surface protuberances (blebs), chromatin condensation and nuclear shrinkage (pyknosis), followed by nuclear fragmentation (karonexis) into multiple nuclear bodies. Cytoplasmic changes include polyribosome dispersal and cell shrinkage resulting from the blebbing process. Limited amounts of endoplasmic reticulum remain and mitochondria appear normal and unswollen. Importantly, plasma membrane integrity is maintained . In apoptosis, the membrane bound bodies are removed directly by macrophages. An additional mechanism in the apoptotic pathway, is the activation of endogenous nucleases and subsequent DNA fragmentation into oligonucleosome-length fragments.