Past/Current Research into Pharmaceutical Interventions of AD

At present, all treatments for AD offer only modest symptomatic relief for periods between six to eighteen months. Cholinergic therapies are the mainstay of AD management today. Unfortunately, there are no drugs that can halt or reverse AD progression. This section provides some information on some of the areas of ongoing research for AD. The past 5 years has seen a growth in the number of drugs being developed for AD. Future compounds under research are aimed at delaying, preventing progression of the illness and drugs that may alleviate the underlying pathology.^{8, 9}

Drugs for Disease Modification

Secretase inhibitors. One of the features of AD pathophysiology is the accumulation of senile plaques at the end of degenerating brain neurons. b amyloid, a major constituent of  these plaques, is toxic to neurons in vitro and  is considered to be responsible for the neuronal cell loss in AD. b and g secretases are the two enzymes critically responsible for forming b amyloid. This discovery has prompted new therapies directed at blocking these enzymes, thus preventing or slowing the progression of the disease. At present most of the research is limited to animal testing.[i]

Metal chelation. As mentioned above, brain damage in Alzheimer disease is caused by b amyloid, but metal ions, such as zinc and copper, both of which accumulate in the brain with old age, are also neurotoxic.  Research has shown that these metals cause b amyloid aggregation, and the mixture of the two (i.e. b amyloid and metal ions) results in the production of hydrogen peroxide, which in turn causes oxidative damage. Clioquinol, an antibiotic, which acts as a chelating agent, facilitates the removal of metal ions, and has the potential to slow progression of AD. Phase II trial results have been promising and large treatment trials are expected.30

Vaccine.  Efforts to develop a vaccine so that an immune mediated response targets the disease are still being investigated. The phase II trial of an active vaccination approach in AD was stopped in 2001 since it resulted in meningoencephalitis (inflammation of the brain and surrounding areas). Despite this set back, research still continues in the area of safe vaccine development, which may be able to combat AD.30 The use of passive immunization is less likely to cause the inflammation seen with the active vaccination approach.

Statins.  High cholesterol, an increased risk factor for AD, has also been implicated in the pathology of AD and is thought to promote b amyloid production. New focus on 8^th international conference on AD reports that an autopsy study in the US found that a 10% increase in blood cholesterol level doubles the risk of b amyloid deposits in the brain. Clinical trials in the US to compare the progression of AD in those taking statins versus placebo are to be launched.30

Neurotransmitter targets. Cholinesterase inhibitors, are currently the only widely approved class for the treatment of AD. This therapeutic class inhibits the enzyme acetylcholinesterase, which breaks down acetylcholine in the synaptic cleft and therefore they increase acetylcholine levels in the brain. These drugs, do not attack the underlying disease pathology, instead they compensate for the loss of neurons that communicate via this enzyme. Cholinesterase inhibitors appear to slow down cognitive decline, however the improvements are very modest.  Memantine, which works to inhibit the action of neurotransmitter glutamate, has been launched in the US and some European countries. It has been approved for moderate to severe patients Experts within the field suggest that the two classes may be used in combination or combined with other therapies under development.

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[i] Helmuth L. New Alzheimer’s Treatments That May ease the Mind. From the 8^th International Conference on Alzheimer’s diseases and Related Disorders, Stockholm 20-25^th July 2002. Science August 2002; 297: 1260-1262.