(spinal cord and brain stem)

No drugs are available yet that can prevent the degeneration of neurons in the brain and spinal cord in people with these neurodegenerative disorders (Table I).


Alzheimer's disease is the most common cause of dementia occurring in middle and late life. About 70% of all cases of dementia are due to AD. It affects 7-10% of individuals >65 years of age and up to 40% of people > 80 years of age. The prevalence of AD is increasing proportionally to increased life expectancy. AD thus will continue to be a major health concern because estimates predict that ~25% of the population will be > 65 years of age in the year 2050. AD now affects >4 million people in the United States. Most cases of AD have unknown etiology and are called sporadic; however, some cases of AD, particularly those with early onset, are familial and are inherited as an autosomal dominant disorder linked to mutations in the gene that encodes amyloid precursor protein or in the genes that encode for presenilin proteins (Table II). For late-onset sporadic cases, a variety of risk factors have been identified in addition to age. The apolipoprotein E (apoE) allele is a susceptibility locus with the apoE4 type showing dose-dependent contributions. Cardiovascular disease and head trauma are additional risk factors for AD.

The mechanisms that cause the profound brain atrophy (Fig. 1), neuronal degeneration and progressive impairments in memory and intellect that occur with AD are not understood. Atrophy of the cerebral cortex (i.e., loss of cerebral cortex volume) correlates strongly with cognitive decline. Normal cognition and memory, as well as neuronal survival, depend on synapses (Fig. 2A). Regulated release of neurotrans-mitter-containing vesicles is necessary for normal synaptic function. Some proteins that control synaptic operation are abnormal in AD (Fig. 2B). These proteins function in the presynaptic terminal by controlling the regulated exocytosis of neurotransmitter packets. Particular proteins are reduced in the hippocampus of individuals with AD who have moderate to severe abnormalities in memory (Figs. 2 and 3). Another important discovery is that the synaptic proteins that control neurotransmitter vesicle translocation and priming at the release site of the presynaptic nerve terminal are more vulnerable than proteins involved in vesicle exocytosis at the cell membrane. It appears that these proteins begin to be lost in individuals in the early stages of AD who do not yet have detectable cognitive impairments, but as the synaptic defects progressively become more severe, individuals manifest more severe memory impairment. Abnormalities in the presynaptic proteins that regulate neurotransmitter release may be an early pathological process in the development of AD (Fig. 2).

A variety of brain lesions occur in people with AD. The major lesions are called neurofibrillary tangles and senile plaques (Fig. 4). These brain lesions are formed abundantly in individuals with AD and patients with Down's syndrome and less frequently in people aging

Table II

Gene Mutations Associated with Some Neurodegenerative Diseases

Table II

Gene Mutations Associated with Some Neurodegenerative Diseases

Neurodegenerative disease

Gene mutation-deletion


Familial amyotrophic lateral sclerosis0

Copper-zinc superoxide dismutase

10% of all FALS cases

Familial Alzheimer's disease6

Amyloid precursor protein

<10% of all familial AD cases

Familial Alzheimer's disease


<10% of all familial AD cases

Familial Alzheimer's disease


< 10% of all familial AD cases

Huntington's disease


100% of cases

Parkinson's disease


Very rare

Spinal muscular atrophy

Survival motor neuron,

Majority of cases

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