Although there have been tremendous developments in the understanding of the molecular biology of Alzheimer’s disease (AD), this has not yet been translated into substantially improved therapies. There are still only two classes of licensed symptomatic treatments; however, the management of neuropsychiatric symptoms remains a huge clinical problem, and despite increasing efforts to identify novel treatment targets there are still only a handful of new potentially disease-modifying compounds that have been developed as far as phase II and III clinical trials. The main drugs discussed are summarised in Table 1.

Licensed Symptomatic Treatments for Alzheimer’s Disease

Cholinesterase Inhibitors

There is evidence from more than 30 randomised clinical trials of cholinesterase inhibitors in various stages of AD with a variety of outcome measures. In systematic meta-analyses,^1–3 each of the three widely prescribed cholinesterase inhibitors (donepezil, rivastigmine, galanthamine) conferred significant benefit compared with placebo for the treatment of mild to moderate AD in the treatment of cognitive deficits. The Alzheimer's Disease Assessment Scale for Cognition (ADAS-Cog) advantages compared with placebo were measured at 1.3–4.4 points. Due to the the large number of different methods and scales utilised, it is more difficult to quantify the improvements in activities of daily living (ADL) and global outcome across trials, but they are highly significant for all three drugs. Of note, the mean level of cognitive performance remained above baseline for six to 12 months in most studies.

Only a handful of studies have maintained a placebo-controlled design for more than six months. The initial evidence is encouraging, with placebo-controlled trials showing continued benefit over 124 and 24 months.⁵ The majority of trials have focused on people with mild to moderate AD, although work examining the value of cholinesterase therapy in people with more severe AD indicated significant cognitive and functional benefits associated with treatment.^4,6,7 However, the trials conducted so far do not indicate in general that cholinesterase inhibitors significantly delay the onset of AD in people with mild cognitive impairment (MCI). Further work is needed to determine whether there is benefit in MCI patients carrying the apoliprotein ε4⁸ or the butrylcholinesterase K⁹ genotypes.

There has been considerable debate about whether the magnitude of the symptomatic improvements is substantial enough to meaningfully influence quality of life. The absence of formal quality of life measures in the majority of clinical trials is disappointing and makes it difficult to address this concern. A survey completed by the Alzheimer’s Society in the UK, which included more than 2,000 carers of people with AD taking antidementia drugs, highlighted that the majority of people feel that the treatments did give them meaningful improvements.¹⁰ More systematic evidence comes from goal attainment scaling, which enables people to choose the outcome measures most important to them as the primary evaluation for clinical trials. Using this approach in a placebocontrolled trial of the cholinesterase inhibitor galantamine, Rockwood et al. demonstrated that important goals were significantly more likely to be achieved among people taking galantamine compared with the placebo-treated individuals.¹¹