Path Ways

Alzheimer's Disease: The Elusive Mystery

Since the German psychiatrist Alois Alzheimer first discussed the clinical features of what is now known as senile dementia of the Alzheimer's type, health care workers have sought to understand the three "Ns" of the neuropathology of SDAT-neuritic plaques, neurofibrillary tangles, and the neurotransmitters involved.

Neuropathologic changes associated with SDAT include loss of cortical neurons and depletion of specific neurotransmitters. Alzheimer pathology is characterized by the presence of two lesions-NPs and NFTs-demonstrable only upon a micro-scopic examination of the brain.

This installment of PathWays reviews the three Ns and their relationship to apolipoprotein E and tau protein.

Neuritic Plaques

NPs (also called senile plaques) are deposits that contain clusters of dead and dying nerve cell endings and the insoluble protein amyloid. Amyloid has been more specifically referred to as beta-amyloid, or A4 protein, in recent articles that search for common protein link in all SDAT patients. Amyloid comprises approximately 40 amino acids and is formed by cleavage of a larger protein called amyloid precursor protein. Amyloid has been linked to a neurotoxic effect and neuronal death in SDAT. Studies have suggested that individuals with SDAT either produce too much APP or an abnormal type of APP.

The amyloid cascade hypothesis proposes that certain neuronal stresses, such as head trauma, may lead to overproduction or up-regulation of APP.

Neurofibrillary Tangles

The distribution of NFTs in the brain are also a classic pathology in SDAT. They are found within neurons, are associated with dying brain cells, and are absent from normal brains. NFTs result from the accumulation of paired helical filaments, composed of two fibers twisted together in rope-like fashion. An integral component of paired helical filaments is a modified form of tau protein. Normal tau protein promotes the formation and stabilization of microtubules, which give the cells their integrity of structure and allow transport of neurotransmitter precursors and protein from the cell body to the synaptic end. In SDAT, this abnormal tau protein does not bind well to microtubules, resulting in their collapse. Each neuron with abnormal tau breaks down, resulting in a loss of a synapse.

The number of both NFTs and NPs correlates with the degree of dementia.

Neurotransmitters

SDAT is a disorder of multiple neurotransmitter deficiencies. Examination of postmortem tissue from SDAT patients reveals a deficiency of the acetylcholine-synthesizing enzyme called choline acetyltransferase. This is the most consistent neurochemical finding in SDAT and suggests a physiologic loss of acetylcholine. There are approximately six major cholinergic pathways in the brain, and studies show degeneration in two of these seem especially important in SDAT-the hippocampus and cerebral cortex. The decrease in choline acetyltransferase activity results from destruction of ACh-containing neurons. Behavioral studies link ACh-related changes to the degree of dementia and to memory function and storage.

Other neurotransmitters affected in SDAT include glutamate, serotonin, and norepinephrine. Deficits in serotonin and norepinephrine may account for changes in mood and behavior, such as depression and aggression. The loss of somatostatin, a peptide that influences memory and learning, has been implicated later in SDAT.

Etiology

The only conclusive information about the etiology of SDAT is that a primary cause has not been identified and the etiology is probably multifactorial. Proposed theories include environmental toxins, infectious agents, acceleration of normal aging, neurotransmitter abnormalities, and heredity.

The genetic association is seen particularly in the familial, early-onset (before age 65) cases of SDAT, which comprise only a small fraction of all cases. Such persons are found to have an SDAT-linked gene on chromosome 21.

Mutations on chromosomes 14 and 21 produce the same cascade of nerve loss, NFTs, and NPs characteristic of SDAT. Patients with Down's syndrome (trisomy 21) exhibit the characteristic lesions of SDAT; both conditions involve possible overexpression of the APP gene. Individuals who inherit an autosomal-dominant mutation have a 50 percent risk of the disease, and the onset usually occurs early in life.

Apolipoprotein

Late-onset disease is associated with specific genes on chromosome 19 that code for cholesterol-bearing protein, or apolipoprotein.

Growing attention has been placed on the implication of a genetic risk factor for the more common, late-onset disease. A gene on chromosome 19 codes for apolipoprotein E4. Homozygous individuals have defective genes from both parents and are at increased risk of developing SDAT at an earlier age. This is true in patients from families prone to late-onset disease and in patients classified as sporadic without apparent family history.

Apolipoprotein E is one of 14 lipoprotein constituents first noticed for its importance in cardiovascular disease; its role as a lipid transporter has been well elucidated. ApoE is a constituent of all types of blood cholesterol carriers except low-density lipoprotein cholesterol. ApoE is now the subject of intense interest for a putative role in SDAT and a possible role in other dementia.

Three different alleles code for ApoE. These are designated E2, E3, and E4, and they differ by one or two amino acids.

The link between ApoE and SDAT may lie in the overproduction of APP, which could cause ApoE synthesis to increase. The E4 allele successfully competes with normal scavenger proteins that sequester and detoxify beta-amyloid. Instead of detoxification, however, ApoE4 binds very tightly to beta-amyloid, pulling it from the blood and depositing it in an insoluble form in the brain. This triggers SDAT, according to the cascade hypothesis. ApoE produced by the E2 and E3 genes do not strongly bind beta-amyloid, and these individuals are much less likely to develop SDAT.

Another role of ApoE is assisting tau protein in binding to microtubules. When tau does not bind properly because of hyperphosphorylation, the result is neuron collapse and cell death. Scientists suggest that ApoE2 or E3 ( but not ApoE4) prevents abnormal phosphorylation and NFT formation by binding to tau. In this respect, the apolipoproteins protect against SDAT. This theory conflicts with the amyloid cascade hypothesis, which maintains that beta-amyloid results from neurodegeneration rather than causing it.

Conclusion

Almost a century after Alzheimer first discussed this type of senile dementia, we seem only a smidgen closer to unraveling its mystery. Perhaps the secrets of the three Ns, ApoE, and tau protein will provide an answer to preventing or treating the disease.

Phyllis M. Parks-Veal, PharmD
103 Cambridge Drive North
Milledgeville, GA 31061