Table of Contents

Therapy of Alzheimer's Disease



Symptoms associated with Alzheimer's disease contribute to diminished quality of life for patients and caregivers and increase the cost of care in nursing homes. Early recognition of behavioural symptoms and appropriate treatment are important for successful management. Non-pharmacologic strategies remain the cornerstone of the management of Alzheimer's disease-related behavioural symptoms. However, non-pharmacologic strategies may not be effective for problem behaviours, and pharmacologic intervention may be necessary.

Pharmacological Strategies include:

Compensation of neurotransmitter deficits:

Enhancement of acetylcholine:

Early attempts to raise level of Acetylcholine with either lecithin or choline had no effect. Probably, this is because choline is in excess over Acetylcholine and it is not limiting for synthesis of Acetylcholine.

Prolongation of Acetylcholine Action

Probably the most promising therapeutic approach and the first drugs for treating Alzheimer Disease belong to this group. Physostigmine was the first Acetylcholine Esterase inhibitor to show a beneficial effect. Probably cholinergic neurones in Alzheimer Disease were making less Acetylcholine or releasing less when stimulated. However, physostigmine is short-lived and has poor access to the brain.

Longer-lived and better-penetrating analogues of physostigmine, eg. heptyl-physostigmine, have been developed.

Tetrahydroaminoacridine (THA)

THA is also an Acetylcholine Esterase inhibitor and it was reported to show dramatic improvement. THA has now been demonstrated to have limited but positive beneficial effects. THA was approved for treatment under the name of Tacrine for use in treating “mild to moderate” Alzheimer's disease.

The dosage of tetrahydroaminoacridine varies widely, between 20 mg and 114 mg a day, as does the duration of treatment.

Other THA-like compounds were developed by other pharmaceutical companies. Other Acetylcholine Esterase inhibitors include Rivastigmin, Galantamine, and Donepezil, which is marketed under the trade name Aricept by its developer Eisai and partner Pfizer, and has a centrally acting reversible acetylcholinesterase inhibitor effect.


These compounds may work by enhancing the effects of limited release of Acetylcholine at synapses. Muscarinic agonists are being developed but they have adverse cardiac side effects that might limit their usefulness. Nicotine may be useful because there is some evidence that it has an effect and there is some epidemiological evidence that smoking may be protective.

Enhanced release of Acetylcholine:

Again this might enhance the poor release of degenerating neurons. Aminopyridines is one of the agents which may enhance Acetylcholine release.

Attempts to preserve neuronal survival:

Growth factors:

It has been shown that Nerve Growth Factor (NGF) will protect against nerve cell death, including cholinergic neurones in the brain, after various lesions. NGF also reduces age-related cholinergic loss. Brain-derived neurotrophic factor (BDNF) and Basic fibroblast growth factor (bFGF) like NGF have protective effects on cholinergic neurones. There are trials of infusion of NGF into Alzheimer Disease patients. It will be impracticable to treat routinely by infusion. There are programmes to produce small molecular weight mimetics of growth factors.


It has often been suggested that neuro-degeneration is the result of free radical damage. Superoxide dismutase (SOD) are a class of enzymes that catalyse the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defence in nearly all cells exposed to oxygen. They are located on Chromosome 21 and SOD levels are elevated in Down's and so SOD has been implicated in the Down's changes and by extrapolation to AD because of similar brain pathologies. Discovery of SOD mutations in ALS has leant considerable weight to this hypothesis. Thus, free radical scavengers, eg. vitamin E, might he therapeutically useful.


There is evidence that there is an inflammatory response in the brain in AD, e.g. reactive glia are present and up-regulation of the major histocompatibility complex (MHC) antigens. This has led to the suggestion that anti-inflammatory agents would be beneficial.


It is not clear if excitotoxic mechanisms operate in Alzheimer Disease. If they do, then compounds that are being developed for treating stroke may be useful.


Obviously if Aluminium turns out to he an aetiological factor, then avoiding Aluminium or chelating it would be beneficial.

It has been claimed that treatment of Alzheimer Disease patients with desferrioxamine which chelates Aluminium, has a beneficial effect.

Amyloid toxicity:

If b-amyloid (AB) is neurotoxic in vivo then finding compounds that protect, e.g. reduce AB-induced calcium influx, would be protective by prevention or limitation of neurodegeneration

The Amyloid Precursor Protein (APP) proteases:

There is a vast effort directed at identifying the proteases involved in processing APP since inhibiting AB production would potentially be beneficial. However, if AB is a normal physiologically important species with a function, reducing its production without side effects may be difficult. Compensation of neurotransmitter deficits:

kinase inhibitors:

Probably premature to start looking for inhibitors of the kinases that phosphorylate tau but knowledge of the signal transduction in Alzheimer Diseases regulating tau phosphorylation may result in target being identified.