The deteriorations in cognition and function that occur in AD have been linked to the degeneration of numerous neuronal systems. Evi-dence is especially strong, however, for an association between these symptoms and the loss of cholinergic neurons. Therefore, increasing available levels of brain acetylcholine may be expected to attenuate decline in AD. Three approaches to increasing cholinergic trans-mission have been subject to research: increasing availability of the chemical precursors of acetylcholine (e.g. lecithin), enhancing cholinergic transmission by direct receptor stimulation, and inhibit-ing the breakdown of acetylcholine at its receptor site^1,2. Early studies involving the use of acetylcholine precursors were not encouraging. Lecithin, phosphatidylcholine and acetyl-L-carnitine were ineffec-tive, with the former also causing significant body odour^1,2. While modest cognitive and behavioural benefits were demonstrated in tri-als of two cholinomimetic agents, milameline and xanomeline, the frequent occurrence of sweating, gastrointestinal symptoms and syn-cope limited their usefulness². While the first two strategies have to date been unsuccessful, both efficacy and safety have been estab-lished for cholinesterase inhibitors, which increase the availability of acetylcholine for neurotransmission by inhibiting the enzyme acetyl-cholinesterase. Four cholinesterase inhibitors are currently approved by the FDA for the treatment of AD. Three of these are discussed in detail below. The fourth, tacrine, is now rarely used due to both its complex titration schedule and risks of hepatotoxicity.

Cognitive Benefits

A reversible acetylcholinesterase inhibitor, donepezil has been FDA-approved since 1997 for the treatment of mild to moderate Alzheimer’s disease. In one double-blind, placebo-controlled study of 468 participants with mild to moderately severe Alzheimer’s disease³, those in the donepezil group improved significantly com-pared to placebo on a 70-point cognitive battery. The improvement, however, was modest: 2.5 points in the 5 mg/d group and 3.1 in the 10 mg/d group. On the 30-point Mini-Mental State Examination (MMSE), this improvement was 1.0 and 1.3 points respectively. On a scale of global impression of function, 32% and 38% respectively in the donepezil group improved, compared to only 18% with placebo. Correlation was found between clinical improvement and the degree of red blood cell acetylcholinesterase inhibition. Comparable benefits were found in additional trials up to 24 weeks⁴. In an open-label extension trial of two 15–30 week studies⁵, benefits were observed to possibly persist for up to 2.8 years. Donepezil’s benefits have been demonstrated in the nursing home setting⁶,and in one study⁷, treatment delayed nursing home placement by 18 months. A one-year, double-blind study⁸ found donepezil to be both cost effective and to reduce the time caregivers spent providing care by 400 hours annually. The sustained benefits of long-term treatment remain controversial, however. One study suggested no significant benefits compared to placebo persisting after three years⁹, while another study¹⁰ did demonstrate sustained benefits over three years, particularly in participants who began treatment immediately, as opposed to receiving placebo for the first year.

Donepezil’s benefits have been found to extend to the severe stages of AD as well. In one six-month, placebo-controlled, double-blind study of participants with MMSE scores less than or equal to 10¹¹, those receiving donepezil performed better on measures of cognitive function and activities of daily living. In 2006, donepezil received FDA approval for the treatment of severe AD and is currently the only acetylcholinesterase inhibitor approved for treatment during all disease stages.

Side Effects

Cognitive Benefits

Galantamine was FDA approved in 2001 for the treatment of mild to moderately severe AD. A reversible, competitive inhibitor of acetylcholinesterase derived from the snowdrop variety of daffodils, galantamine is also an allosteric modulator of nicotinic acetylcholine receptors. Although nicotinic receptors may increase cholinergic transmission, any additional cognitive benefits specifically conferred by this mechanism remain theoretical. In one six-month, double-blind, placebo-controlled study¹² of 636 participants with mild to moderate AD, those treated with galantamine at doses of 24 mg/d and 32 mg/d scored 3.9 and 3.8 points higher on the 70-point ADAS-Cog scale than those in the placebo group. At the end of a 6-month, open-label extension with all participants receiving 24 mg/d, ADAS-Cog scores for those treated for the entire 12 months with 24 mg/d remained stable, with less benefit seen in those who started on 32 mg/d and then decreased to 24 mg/d, possibly due to a rebound effect. Although the six-month, double-blind phase showed no benefit on the Disability Assessment for Dementia (DAD) measurement of activities of daily living (ADLs), at the end of the open-label extension, ADL scores for participants receiving galantamine remained at pre-treatment baseline. A later double-blind, placebo-controlled study of 653 participants demonstrated the benefit of galantamine on DAD scores¹³. In a 36-month, open-label trial of galantamine¹⁴, the 194 participants with mild to moderate AD were assessed as experiencing 50% less cognitive decline than would be expected without treatment. An extended-release form of galantamine was FDA approved in late 2004, and has been shown to have similar bioavailability to the immediate-release galantamine. The benefits of galantamine in severe AD are less certain than is the case for donepezil. In a recent placebo-controlled, double-blind study of 407 participants with severe AD, those treated with galantamine demonstrated improvement in cognitive function, but not in activities of daily living. Galantamine remains approved for treatment of mild to moderate AD only. Galantamine is also currently the only acetylcholinesterase inhibitor available in generic form.

Rivastigmine was approved in 2000 and, unlike donepezil and galantamine, is a reversible inhibitor of both acetylcholinesterase and butyrylcholinesterase. Although research suggests that butyryl-cholinesterase plays a role in acetylcholine breakdown in AD, as is the case for the allosteric nicotinic properties of galantamine, the clinical significance of this additional mechanism of action remains unclear. Like galantamine, rivastigmine is currently approved for the treatment of mild to moderate AD. In a placebo-controlled, double-blind study of 725 participants with mild to moderate AD¹⁵, the treatment group was randomized to either 1–4mg/d or 6–12mg/d, and more participants in the 6–12mg/d group improved by ?4 points on the ADAS-Cog; improvement compared to the other groups was also seen in a scale of progressive deterioration. Nearly a quarter of participants discontinued the higher dose treatment due to side effects, however, mostly gastrointestinal. In a study demonstrating similar clinical outcomes¹⁶, only 55% tolerated the 12 mg/d dose. In a 26-week, open-label extension of a 26-week, double-blind study of rivastigmine at 6–12mg/d¹⁷, participants treated with rivastigmine for the entire 52-week study duration had improved cognition compared to those initially receiving placebo. Open-label data suggest benefit for rivastigmine over even longer durations. Using a baseline-dependent mathematical model, Small etal.¹⁸ demonstrated that patients treated with rivastigmine for up to five years experienced less decline on the MMSE than would be expected in a modelled untreated group.

Since 2007, a rivastigmine 24-hour transdermal patch has also been approved by the FDA for the treatment of mild to moderate AD. The efficacy of the transdermal patch appears to be similar to that of 12 mg/d oral rivastigmine, with three-fold fewergastrointestinal side effects¹⁹.

Side Effects

While oral rivastigmine has been associated with a high occurrence of gastrointestinal side effects, with the 24-hour transdermal patch, these side effects now appear comparable to those of donepezil and galantamine. Side effects otherwise are similar to donepezil (see above) and galantamine. Rare cases of oesophageal rupture have been reported, and restarting rivastigmine at higher than the mini-mum dose after several weeks or more off from the medication may place patients at increased risk for this. Oral rivastigmine should be taken with food.

Dosing

Oral rivastigmine is usually begun at 1.5 mg twice daily. At minimum two-week intervals, the dose is gradually increased in 1.5 mg twice-daily increments up to a maximum dose of 6 mg twice daily. Increas-ing the dose titration intervals from two weeks to four weeks may decrease side effects, and rivastigmine should be taken with food². The rivastigmine 24-hour transdermal patch is started at 4.6 mg/24 hours, and after one month can be increased to 9.5 mg/24 hours. Switching from oral rivastigmine to transdermal patch typically does not require delay, and most patients taking 9–12mg of oral rivastig-mine daily can immediately switch to the 9.5 mg/24 hours patch².

Several studies have compared the efficacy and tolerability of cholinesterase inhibitors in the treatment of AD. In one 12-week, open-label study of donepezil and oral rivastigmine in the treatment of mild to moderate AD²⁰