Treatment Strategies

In addition to plaques, tangles and inflammation, Alzheimer‘s Disease is characterized by a loss of acetylcholine receptors in the hippocampus and cortex, leading to an impairment of nicotinic cholinergic neurotransmission and deficits in other neurotransmitter systems.

Because of the direct involvement of the cholinergic system in the medical symptoms of AD, several treatment strategies aim to enhance the activity of the remaining acetylcholine receptors in the brain of AD patients. The classical approach is inhibition of the enzyme acetylcholinesterase (AChE) which breaks down acetylcholine, leading to quick inactivation of the neurotransmitter

However, there are at least two drawbacks associated with this therapeutic approach. If the AChE inhibition is too strong or too long lasting, as can be the case in continuous treatment of dementia, the therapeutic effect wears off because

• nicotinic acetylcholine receptors (nAChRs) become inactivated, rather than activated,
  by excessive levels of  acetylcholine (a process called desensitization), and
• expression of the enzyme AChE is up-regulated.

Both effects lead to even lower levels of cholinergic neurotransmission.

Therefore, all presently available cholinesterase inhibitors are relatively weak inhibitors of AChE, so that adaptive effects are avoided or delayed. The pros and cons of available drugs influencing acetylcholine levels in the brain can be summarized as follows:

AChE inhibitors: These drugs inhibit the acetylcholinesterase enzyme, so that it cannot break down acetylcholine. Low affinity reversible AChE inhibitors, such as donepezil and tacrine which are marketed for AD, represent an acceptable balance between therapeutic efficacy on the one hand and risks of receptor desensitization and AChE up-regulation on the other hand. AChE inhibitors, which are significantly more potent than already approved AD drugs, are likely to trigger unfavorable side effects and toxicity. Therefore, clinical developments of stronger AChE inhibitors have been discontinued.

Nicotinic agonists: These drugs aim to enhance the action of nicotinic acetylcholine receptors. Because they are not rapidly eliminated, their levels in the brain carry an intrinsic risk of nAChR desensitization. Therefore, they will in our view  probably be unsuitable for AD treatment.