Cognition enhancing or neuroprotective compounds for

the treatment of cognitive disorders: why? when? which?

Lockhart BP, Lestage PJ.

January 2003

Prevalence of Alzheimer's and other dementias in the U.S.A.

• Alzheimer's 65-70% of dementias (1.1 – 4.5 million affected individuals)

• Parkinson's 8-10%

• Lewy-Body 13-15%

• Other cerebrovascular dementias 5-10%

• Symptomatic treatment of AD is currently based to a large degree on the cholinergic hypothesis, suggesting that many of the cognitive, functional and behavioral symptoms of AD derive in part from reductions in acetylcholine (ACh) synthesis via choline acetyltransferase and reduced choline uptake.

• Much effort aimed at reversing cholinergic deficit based in increasing ACh neurotransmitter levels by stimulating release or blocking degredation

• Basis of approved AD drugs:– Donepezil (Aricept)– Rivastigmine (Exelon)– Galanthamine (Reminyl)– Tacrine (Cognex)

• These drugs give similar, moderate improvement in randomized, controlled trials within the first 6 months of treatment.

• Slower decline of cognitive function observed in longer trials.

• No data has shown that these drugs reduce the underlying cause(s) of AD.

• Most of the studies recruited patients < 75 years with mild symptoms.

• Note: Recent studies question efficacy.

Glutamatergic systems as targets for drugs

• Modest efficacy of ACh drugs in AD patients suggests that hypofunction of the cholinergic system may not necessarily be the primordial or key event in the cognitive deficits in AD and other dementias.

• Possible principal factor behind these findings may be that fast excitatory synaptic transmission in hippocampal and cortical structures is mediated by the excitatory amino acid glutamate.

• The glutamate receptors include the NMDA family and AMPA family. Drug strategy has focused on NMDA and AMPA.

• The NMDA antagonist memantine completed phase III trials in AD and showed a significant improvement in the cognitive function of AD patients with reduced adverse effects compared to ACh drugs.

• Modulators of the AMPA receptor have been evaluated in clinical trials for cognitive function, with promising results. Clinical trials are ongoing.

The amyloid beta hypothesis

• amyloid beta protein forms “senile plaques” in the brain that are diagnostic of AD

• Considerable evidence, both genetic and biochemical, that amyloid beta causes or contributes to development and progression of AD.

• amyloid beta is a generator of free radicals, and induces oxidative stress damage to neurons in vitro.

• Potential target for drugs to treat AD• Evidence that free radicals play a role in

neurodegeneration