Department of Neurology
Kuopio University Hospital
Alzheimer’s disease (AD) is the most common cause of dementia. Presynaptic cholinergic deficit correlates with the degree of cognitive impairment in AD.(1)
Acetylcholinesterase (ChE) inhibitors act by inhibiting acetylcholinesterase at cholinergic synapses, thereby increasing the availability of acetylcholine within the brain. They are the first class of drugs that have shown modest, dose-related improvement in cognition, global functions and daily functioning in AD patients. Three drugs that are widely used are donepezil (Aricept(™); Eisai-Pfizer), rivastigmine (Exelon(™); Novartis) and galantamine (Reminyl(™); Janssen-Cilag). The most common side-effects are gastrointestinal symptoms, which are dose-dependent and cholinergic in nature. Otherwise these drugs are well tolerated.
The efficacy of ChE inhibitors has been verified in controlled, multicentre clinical trials.(2–11) These drugs have improved cognition and global functioning and result in significantly slower decline in daily functioning (Table 1). Neuropsychiatric symptoms are an important dimension of AD because they produce distress in caregivers and are a common cause of patient institutionalisation. Open-label studies and two trials suggest that ChE inhibitors have a beneficial effect on these symptoms.(9,12,13) Data suggest that treatment should be started as early as possible. Patients in which initiation of therapy was delayed by 6 months never attained the same level of benefit as those who received active treatment from the beginning.(10,14,15) The long-term efficacy of these drugs is unknown. Studies have shown that cognition is preserved above the baseline levels until 38–52 weeks. (10,14,15) These also suggest that cognitive decline and deterioration of daily functions in treated patients is slower than that expected in untreated patients (historical controls) up to 2 years.
Evidence-based practice parameters in many countries recommend that patients with mild or moderate AD should have the opportunity of a treatment trial with these drugs. However, translation of the beneficial effects observed in trials into everyday practice is a difficult task. There are no comparisons between the long-term efficacy of ChE inhibitors – the main differences between these agents are in their side-effect profiles and dosing.
Figure 1 summarises the key elements in the treatment of AD patients with ChE inhibitors. The assessment of therapeutic response requires a careful interview of the patient and caregiver covering the changes in the patient’s behaviour, daily functioning and general functioning, as well as some measure of cognitive functions. Therapeutic response is stabilisation of the disease, lack of functional decline and delay in the emergence of neuropsychiatric symptoms, as would be expected given the progressive nature of the disease. Once started, treatment should last for at least 6 months to reliably appraise stabilisation.
In most countries patients with mild to moderate AD are reimbursed for treatment with ChE inhibitors. However, recent studies imply that patients with more advanced disease may also benefit from these drugs. ChE inhibitors are currently studied in patients with mild cognitive impairment (MCI) who are at high risk of developing AD. It is possible that these drugs will prove to be effective at all stages of AD.
Extensive data have shown evidence of oxidative stress in AD brains. In one trial, antioxidant vitamin E as well as selegiline delayed times to institutionalisation, loss of ability to perform basic activities of daily living, severe dementia or occurrence of death in patients with moderate AD.(16) Extract of Ginkgo biloba also has putative antioxidant properties. One trial showed a modest beneficial effect of Ginkgo biloba on cognition but no significant effect on global functioning in patients with AD or vascular dementia.(17) Although the effects of vitamin E and Ginkgo biloba have been modest, and clinical relevance of the results is uncertain, these agents are widely used in some countries. More studies are needed.
What the future holds
The understanding of the molecular basis and pathological processes of AD has provided novel therapeutic opportunities for treatment. Amyloid plaque formation is a characteristic feature in the AD brain, and neurotoxicity of aggregated amyloid-beta peptide (Abeta) is well established. Therapeutic approaches that decrease amyloid burden, such as beta- and gamma-secretase inhibitors, as well as Abeta immunisation, are currently entering clinical trials in humans.
Epidemiological data have implied new opportunities for treatment and prevention of AD. HRT in women with menopause is associated with a reduced risk or delayed onset of AD.(18) Although controlled studies failed to show efficacy of oestrogen in AD,(19,20) a large controlled clinical trial is underway. Recent studies showed that high cholesterol and high systolic blood pressure in midlife are associated with an increased risk of AD,(21) and cholesterol-lowering may reduce the risk of AD.(22)
Any treatment that can improve the symptoms and daily functioning in AD may improve quality of life of patients and caregivers, alter need for institutional care, increase the possibility of care in the home and reduce caregiving costs. Although ChE inhibitors have a small role in overall management of AD patients, they have begun a new era in the treatment of dementing diseases. Their introduction has increased the general awareness of dementia and improved overall management of dementia patients. Pharmacoeconomic studies have suggested that ChE inhibitors do not increase treatments costs of AD patients, and may lead to cost savings.(23–26)
Improvements in diagnosis, reorganisation of provision of services and advances in treatment are much needed to minimise the economic impact of AD.
- Francis PT, et al. The cholinergic hypothesis of Alzheimer’s disease:a review of progress. J Neurol Neurosurg Psychiatry 1999;66:137-47.
- Rogers SL, Friedhoff LT and the Donepezil Study Group. The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. Dementia 1996;7:293-303.
- Rogers SL, Doody RS, Mohs RC, Friedhoff LT, and the Donepezil Study Group. Donepezil improves cognition and global function in Alzheimer disease. A 15-week, double-blind, placebo-controlled study. Arch Intern Med 1998;158:1021-31.
- Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT, and the Donepezil Study Group. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Neurology 1998;50:136-45.
- Burns A, Rossor M, Hecker J, et al. The effects of donepezil in Alzheimer’s disease – results from a multinational trial. Dement Geriatr Cogn Disord 1999;10:237-44.
- Homma A, et al. Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer’s disease. A 24-week, multicenter, double-blind, placebo-controlled study in Japan. Dement Geriatr Cogn Disord 2000;11:299-313.
- Corey-Bloom J, Anand R, Veach J for the ENA 713 B352 Study Group. A randomised trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer’s disease. Int J Geriatr Psychopharmacol 1998;1:55-65.
- Rösler M, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ 1999;318:633-40.
- Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Dins C and the Galantamine USA-10 Study group. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology 2000;54:2269-76.
- Raskind MA, Peskind ER, Wessel T, Yuan W and the Galantamine USA-1 Study Group. Galantamine in AD. A 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology 2000;54:2261-8.
- Wilcock GK, Lillienfeld S, Gaens E, on behalf of the Galantamine International-1 Study Group. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. BMJ 2000;321:1-7.
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- Farlow M, et al. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol 2000;44:236-41.
- Sano M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med 1997;336:1216-22.
- Le Bars PL, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA 1997;278:1327-32.
- Henderson VW. The epidemiology of estrogen replacement therapy and Alzheimer’s disease. Neurology 1997;48 Suppl 7:S27-S35.
- Mulnard R, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer’s disease: a randomized, controlled trial. JAMA 2000;283:1007-15.
- Henderson VW, et al. Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology 2000;54:295-301.
- Kivipelto M, et al. Midlife vascular risk factors and late-life Alzheimer’s disease: a longitudinal, population-based study. BMJ 2001;322:1447-51.
- Wolozin B, et al. Decreased prevalence of Alzheimer’s disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000;57:1439-43.
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Alzheimer’s Disease International (ADI)
American Academy of Neurology: Clinical Practice Guidelines
American Psychiatric Association
Canadian Medical Association
Scottish Intercollegiate Guidelines Network
New Zealand Guidelines Group
Doody RS, et al. Practice parameter: management of dementia (an evidence-based review). Report of the quality standards sub-committee of the AAN. Neurology 2001;56:1154-66
Feldman H, et al. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology 2001; (in press)
New Zealand Guidelines Group. Guidelines for the use of acetylcholinesterase inhibitor drugs in the treatment of people with Alzheimer’s disease. (www.nzgg.org.nz)