Alzheimer’s disease (AD) is a progressive degenerative brain disorder that impairs cognition and the ability to carry out normal activities and is associated with behavioural disorders and psychiatric symptoms.(1) It is the commonest form of dementia in Caucasian populations, accounting for 54% of prevalent cases (ranging from 38% to 78% depending on the country)(2) and 50–70% of incident cases in Europe.(3) The prevalence increases with age, and AD is more common in women than men (see Figure 1).(2)
Although substantial differences have been reported in various studies,(2) the overall prevalence of AD in different Caucasian populations is similar when disease severity is taken into account.(4) There do appear to be differences between developed and developing countries, urban and rural populations, and Western and Asian societies,(5) but ethnic origin may not be a significant factor within a population (in the United States, at least).(6) Although it has been suggested that the disease is less common among very elderly people, a study in Finland has found that neuropathologically confirmed AD is twice as common as clinical diagnoses suggest: in a population of 532 aged over 85, the prevalence by clinical diagnosis was 16%, compared with 33% identified by postmortem.(7)
AD is associated with reduced life expectancy. In a pooled analysis of eight cohort studies from seven European countries, the relative risk of death among patients with dementia (AD subgroup not defined separately) compared with age- and sex-matched controls was 2.38 over four years of follow-up.(8) In a smaller UK study, survival among patients with AD or vascular dementia was similar and significantly lower than in age- and sex-matched controls (see Figure 2), with a median survival of approximately six years after diagnosis.(9)
The management of AD in Europe falls into three categories: social care and support, the treatment of associated behavioural and psychiatric disorders, and drug treatment of the cognitive deficit. Guidance on the diagnosis and management of AD and other dementias, and in particular on the role of neurologists, has been published by the European Federation of Neurological Societies.(10)
Models of care and support vary in different countries and depend on the resources available, but carers provide a large proportion of care (8.5 times more than the state in one Swedish study),(11) and their need for support is recognised by state provision of respite care, day centres, home social services and sheltered accommodation.(12) Informal care is acknowledged as a valuable means of avoiding hospital admission,(13) and its importance is likely to increase as drug treatment delaying cognitive decline becomes more widely used.
Behavioural disorders associated with dementia, which include aggression, depression, delusions, anxiety, agitation and sleep problems, present a challenge to carers and may result in early admission to residential care. These symptoms may be aetiologically related to the neuropathological changes associated with AD or to psychosocial and other factors specific to individual patients.(14) Drug treatments are not specific for patients with dementia and include antidepressants, atypical antipsychotic agents and antiepileptic agents.(15) Treatment with a cholinesterase inhibitor may also reduce agitation and aggression. Patients with AD may be frail and therefore at increased risk of adverse effects, and administering medication may be difficult. Nonpharmacological treatments, such as behavioural management,(16) are therefore important.
Drug treatments specifically to improve cognitive function include the cholinesterase inhibitors galantamine, donepezil and rivastigmine; the N-demethyl-D-aspartate (NMDA) receptor antagonist memantine; other drugs traditionally used as nootropic agents such as nicergoline and nimodipine; and the herbal preparation Ginkgo biloba. Comprehensive data are lacking but patterns of prescribing appear to vary within Europe. For example, memantine has been available for several years in Germany and France but was only recently licensed in the UK, and uptake of the cholinesterase inhibitors is variable.(17,18) Systematic reviews have concluded that there is a lack of good evidence to support the use of many treatments.(19)
There is strong evidence that the cholinesterase inhibitors significantly improve cognitive function in patients with mild to moderate AD, although the gain is modest.(15,20,21) On the most widely used scale, the 70-point Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog), treatment improves the score by an average of two to three points over six months compared with a decline of five to six points per year without treatment; there is a corresponding increase of one to two points on the mini-mental state examination (MMSE) score over six months compared with a decrease of four to five with placebo.(20) These figures suggest that successful treatment is equivalent to delaying cognitive decline by about six months. Carers report improvement in functional performance, motivation, concentration, control and independence, and in behavioural symptoms. Treatment does not affect disease progression.
Not all patients benefit from treatment with these agents. For donepezil 10mg/day, the number needed to treat (NNT) for a clinically meaningful (four-point) improvement in ADAS-cog score is four, and seven for a six-point improvement; for galantamine, the NNT for a four-point change is seven at a dose of 24mg/day and six at 32mg/day.(15) Adverse effects include nausea, vomiting and diarrhoea, agitation and insomnia.
Memantine is a noncompetitive NMDA antagonist which, by contrast with the cholinesterase inhibitors, is licensed in the UK for the treatment of moderate to severe AD. Excessive glutamate activity is believed to contribute to the symptoms and may underlie the progression of AD; memantine reduces glutamate-mediated neurotransmission. The major clinical trials demonstrating its efficacy in AD have yet to be published, but one 12-week trial found that memantine improved clinical and functional status in patients with severe dementia of different types;(22) a second study lacks intent-to-treat analysis, but, among the 72% of patients with moderate to severe AD (median baseline MMSE 7.9) who completed six months’ treatment, the decline in cognitive and functional impairment was significantly reduced compared with placebo.(23) Memantine appears to be well tolerated, and further trials are needed to clarify its role.
Ginkgo biloba (the maidenhair tree) is a traditional herbal remedy widely prescribed in France and Germany for disorders of concentration and memory. A systematic review of published trials of Ginkgo biloba in AD has concluded that treatment appears to be well tolerated and improves cognition, daily functioning, mood and emotional functioning.(24) However, the published studies had important methodological shortcomings (including small size, imperfect blinding and high withdrawal rates),(15) and a larger study using current methodology is required to determine its clinical role.(24)
Potentially preventive therapies
There is growing observational evidence that certain drug therapies are associated with a reduced risk of developing AD. Important examples include hormone replacement therapy,(25) the statins(26) and nonsteroidal anti-inflammatory drugs (see Hospital Pharmacy Europe 2002;4:21–3).(27) While these reports are encouraging, they are not currently supported by evidence from randomised trials, and it is likely to be several years before their effectiveness is determined.
- Burns A, Byrne EJ, Maurer K. Alzheimer’s disease. Lancet 2002;360:163-5.
- Lobo A, Launer LJ, Fratiglioni L, et al, for the Neurologic Diseases in the Elderly Research Group. Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurology 2000;54 Suppl 5:S4-9.
- Fratiglioni L, Launer LJ, Andersen K, et al, for the Neurologic Diseases in the Elderly Research Group. Incidence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurology 2000;54 Suppl 5:S10-5.
- Hy Le H, Keller DM. Prevalence of AD among whites. A summary by levels of severity. Neurology 2000;55:198-204.
- Alzheimer’s Disease International. Factsheet 3. The prevalence of dementia. London: ADI; 1999. Available from URL:http://www.alz.co.uk
- Gurland BJ, Wilder DE, Lantigua R, et al. Rates of dementia in three ethnoracial groups. Int J Geriatr Psychiatry 1999;14:481-93.
- Polvikoski T, Sulkava R, Myllykangas L, et al. Prevalence of Alzheimer’s disease in very elderly people. Neurology 2001;56:1690-6.
- Jagger C, Andersen K, Breteler MM, et al, for the Neurologic Diseases in the Elderly Research Group. Prognosis with dementia in Europe: a collaborative study of population-based cohorts Neurology 2000;54 Suppl 5:S16-20.
- Kay DW, Forster DP, Newens AJ. Long-term survival, place of death, and death certification in clinically diagnosed pre-senile dementia in Northern England. Br J Psychiatry 2000;177:156-62.
- Waldemar G, Dubois B, Emre M, et al. Diagnosis and management of Alzheimer’s disease and other disorders associated with dementia. The role of neurologists in Europe. Eur J Neurol 2000;7:133-44.
- Wimo A, von Strauss E, Nordberg G, et al. Time spent on informal and formal care for persons with dementia in Sweden. Health Policy 2002;61:255-68.
- Colvez A, Joël M-E, Ponton-Sanchez A, Royer A-C. Health status and work burden of Alzheimer patients’ informal caregivers. Comparisons of five different care programs in the European Union. Health Policy 2002;60:219-33.
- Andrieu S, Reynish E, Nourhashemi F, et al. Predictive factors of acute hospitalization in 134 patients with Alzheimer’s disease: a one-year prospective study. Int J Geriatr Psychiatry 2002;17:422-6.
- Michel J-P, Gold G. Behavioural symptoms in Alzheimer’s disease: validity of targets and present treatments. Age Ageing 2001;30:105-6.
- Warner J, Butler R. Dementia. Clin Evid 2002;7:846-66.
- Teri L, Logsdon RG, McMurray SM. Nonpharmacologic treatment of behavioural disturbance in dementia. Med Clin North Am 2002;86:641-56.
- Frisoni GB. Reimbursement of acetylcholinesterase inhibitors for Alzheimer’s disease in Europe. Int J Geriatr Psychiatry 2001;16:233-4.
- Ruof J, Mittendorf T, Pirk O, et al. Diffusion of innovations: treatment of Alzheimer’s disease in Germany. Health Policy 2002;60:59-66.
- Cochrane Dementia and Cognitive Improvement Group. The Cochrane Collaboration. Available from URL: http://www.cochrane.org/cochrane/revabstr/g170index.htm
- National Institute for Clinical Excellence. Guidance on the use of donepezil, rivastigmine and galantamine for the treatment of Alzheimer’s disease. Technology Appraisal No. 19. London: NICE; 2001. Available from URL: http://www.nice.org.uk
- NICE. Clinical and cost effectiveness of donepezil, rivastigmine and galantamine for Alzheimer’s disease. Health Technology Appraisal. London: NICE; 2000.
- Winblad B, Poritus N. Memantine in severe dementia: results of the 9M-BEST study (Benefit and Efficacy in Severely demented patients during Treatment with memantine). Int J Geriatr Psychiatry 1999;14:135-46.
- Reisberg B, Ferris S, Sahin K, et al. Results of a placebo-controlled 6-month trial with memantine in moderately severe to severe Alzheimer’s disease. ECNP, Munich; September 2000.
- Birks J, Grimley Evans J, Van Dongen M. Ginkgo biloba for cognitive impairment and dementia (Cochrane review). The Cochrane Library, Issue 4. Oxford: Update Software; 2002. Available from URL:http://www. cochrane.org
- Fillit HM. The role of hormone replacement therapy in the prevention of Alzheimer disease. Arch Int Med 2002;162:1934-42.
- Scott HD, Laake K. Statins for the prevention of Alzheimer’s disease (Cochrane Review). The Cochrane Library, Issue 4. Oxford: Update Software; 2002.
- in t’Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidalanti-inflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 2001;345:1515-21.