The effect of the currently used cholinergic precursors and agonists and acetylcholinesterase inhibitors, such as donepezil, is modest. With regard to the latter group of drugs, several large trials have demonstrated a slight prolongation of the patient’s ability to sustain an independent life, but such evidence generally requires that the medications be taken for 6 to 12 months. For example, a meta-analysis of the drugs collectively demonstrated a mean improvement of 2 to 3 points on the 70-point Alzheimer Disease Assessment Scale and a slight delay in progression. Despite some trials that have failed to demonstrate benefit (c.f., AD 2000 Collaborative Group), the balance of evidence probably favors the use of these medications in practice, but only in mildly or moderately affected patients.
Side effects of the aforementioned class of drugs may include nausea and less often, vomiting. The families of our patients report from time to time that the medication caused insomnia or increased confusion. It is worth mentioning that when the acetylcholine receptor antagonist succinylcholine is used prior to general anesthesia, its effects may be prolonged in patients taking the above drugs. The use of trazodone, haloperidol, thioridazine, risperidone, and related drugs may suppress some of the aberrant behavior and hallucinations when these are problems, making life more comfortable for both patient and family, but several trials suggest that their general application causes more problems than it solves and they must often be discontinued in response to adverse effects. The randomized trial conducted by Schneider and coworkers found that olanzapine, quetiapine, and risperidone for the treatment of psychosis, aggression, or agitation with Alzheimer disease were approximately as good as placebo in relieving these symptoms, but largely because the drugs were not tolerated. Olanzapine was slightly preferable in those who continued taking the medication. The clinician is left with little recourse but to use this class of medications or haloperidol to control unmanageable behavior. Small doses of diazepines, such as lorazepam, are useful when sleep is severely disturbed, but they often increase confusion as well.
The N-methyl-d-aspartate (NMDA) glutaminergic antagonists, specifically memantine (20 mg daily), have also been tried. In a study of memantine by Reisberg and colleagues of 252 patients (187 of whom completed the trial), there were better results on a few scales that reflected functional behavior compared to the use of placebo, but there was no change in 3 main measures of cognitive performance. Because the side effects were ostensibly minor, this drug has been approved for use in late-stage Alzheimer disease and in conjunction with cholinergic drugs. Nevertheless, hallucinations or agitation may occur and require discontinuation. The combination of memantine and donepezil in moderately to severely affected patients offered no benefit over either drug alone (Howard et al). The effects of these drugs in later stages of the disease are, in any case, minimal.
A series of trials using a small molecule inhibitors of the enzyme γ-secretase (Doody et al, 2013), or of an inhibitor of β-site amyloid precursor protein–cleaving enzyme 1 (BACE-1, see Egan et al), or of a monoclonal antibody directed at soluble forms of amyloid (solanezumab; see Doody et al, 2014) have failed to demonstrate clear benefit in even early stages of Alzheimer disease. The presumption is being explored that amyloid is deposited well before the onset of clinical symptoms and such agents might be useful if started in the presymptomatic stages of disease but there have also been several failed trials at this stage of disease. This is one goal of studies in dominantly inherited forms of the disease, in which presymptomatic patients can be treated.