SEMINAR
Seminar
The dementias
Karen Ritchie, Simon Lovestone Dementia affects about 5% of the elderly population over age 65 years and has an unexplained predominance in women and a low rate in some cultures. Different forms of dementia are now distinguished—Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, and dementia secondary to disease, such as AIDS dementia. However, such nosological boundaries are being re-evaluated because different dementias are believed to have common underlying neuropathology. Neurochemical and neurobiological research has led to advances in understanding causes of dementia, and functional imaging has allowed identification of possible biomarkers; from these, a range of potential treatment approaches have arisen that focus on enhancement of neurotransmitter function, intervention at the level of amyloid production and deposition, and reduction of secondary risk factors such as hypertension, depression, and hypolipidaemia. Molecular diagnostic testing and genetic counselling for families with autosomal dominant early-onset dementia are new developments; however, this approach is not useful for late-onset dementia, in which the identified candidate susceptibility genes have a relatively small effect on risk. While fundamental research works towards new biological treatment strategies, much remains to be done in the area of disease management and the development of appropriate models of long-term care. Dementia is a generic term that describes chronic or progressive dysfunction of cortical and subcortical function that results in complex cognitive decline. These cognitive changes are commonly accompanied by disturbances of mood, behaviour, and personality. A distinction is often made between primary degenerative dementias such as Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, and dementia secondary to another disease process, such as AIDS dementia. Since The Lancet International Conference on Dementias in 1996,1 such simplistic distinctions are being re-assessed as the complex interactive effects of genetic predisposition, neurochemical changes, and disease co-morbidity in the genesis of dementia syndromes are elucidated. Different forms of dementia are now known to have common underlying neuropathologies and histopathological studies have shown that mixed states (people presenting with features of more than one type of dementia) are probably more usual than pure dementia syndromes. These observations lead us towards a re-examination of nosological boundaries.
Epidemiology The development of internationally recognised diagnostic algorithms for case identification in the 1980s prompted a proliferation of epidemiological studies, most of which are descriptive. Meta-analyses of studies done in developed countries have established dementia prevalence at around 1·5% at age 65 years, which doubles every 4 years to reach about 30% at 80 years.2–4 Overall incidence increases with age and is about 1% per year and is low in men and in people of African or Asian origin.5–7 In Europe and north
America, Alzheimer’s disease is estimated to be more common than vascular dementia. On the other hand, vascular dementia has been reported to be more prevalent than Alzheimer’s disease in China, Japan, and the Russian Federation; although a study in Shanghai7 noted that Alzheimer’s disease accounted for 65% of all dementias. In developing countries, dementia of any type seems to be rare. Results from community surveys and autopsy reports5 suggest that Alzheimer’s disease does not occur in Nigerians. Differences in rates of dementia between developing and developed countries are difficult to explain, but might be attributable partly to difficulties in dementia diagnosis in areas with high rates of illiteracy, and survival bias due to high death rates at all ages. Dementia patients have a substantially shortened life expectancy; the average survival is 8 years from diagnosis.8 A longer survival time is reported for patients with Alzheimer’s disease than for those with vascular dementia9,10 and women have longer survival than men for both Alzheimer’s disease and vascular dementia, independent of sex differences in life expectancy.8,11 Extensive exploration of possible risk factors, which has largely focused on Alzheimer’s disease, has been disappointing. Age, dementia in a close family member, and the E4 allele of the APOE gene are the only confirmed risk factors for the disease.2–4,12–14 Although early clinical studies in selected families showed that the APOE*E4 allele was specific for up to 90% of cases of dementia,15 subsequent population studies noted lower rates with decreased gene effects at higher ages.16 Female sex, herpes infection, low lipid concentrations, a history of head injury, and the protective effect of hormonal replacement therapy, are all factors that interact with APOE genotype to modify relative
Lancet 2002; 360: 1759–66
Search strategy and selection criteria Institut National de la Santé et de la Recherche Médicale (INSERM), EMI 99–30, Hôpital La Colombière, Montpellier, France (K Ritchie PhD) and Section of Old Age Psychiatry, Institute of Psychiatry, London, UK (S Lovestone PhD) Correspondence to: Karen Ritchie (e-mail: ritchie@montp.inserm.fr)
THE LANCET • Vol 360 • November 30, 2002 • www.thelancet.com
This seminar is not an exhaustive review of all research in the area of dementia, but rather it presents an overview of some of the principal advances that have occurred based on the extensive and regularly updated literature databases that have been developed in the authors’ research institutes.
1759
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
risk.17–21 High education has been associated with low rates of Sex Genetic predisposition Alzheimer’s disease, which could be at least partly attributable to compensatory strategies that delay detection of the disease.22 Several other possible risk Mid-life Lipid factors for Alzheimer’s disease such as hypertension metabolism exposure to anaesthetic agents, diabetes, and the protective effects of nonsteroidal anti-inflammatory drugs and alcohol are being re-evaluated with Ageing-related Vascular Environment improved methodology. brain changes pathology Herpes simplex virus Studies of risk factors for vascular Head injury dementia, the second most frequent form of dementia, are fewer in number than those for Alzheimer’s disease, Cognitive impairment principally because of difficulties with the definition of research criteria for Possible protective agents this group of disorders. Significant Alcohol differences are seen in the number of Anti-inflammatory agents vascular dementia cases identified Oestrogen replacement according to whether or not cerebral Modification of lipid imaging is used in the research concentrations criteria—studies using imaging tend to give low specificity, and those without have low sensitivity. Estimates of Dementia onset vascular dementia prevalence thus vary widely from 10–50% of all cases of dementia.23 Main risk factors identified Figure 1: Hypothetical causation pathways for Alzheimer’s disease for the disease are age, male sex, hypertension, myocardial infarction, coronary heart factors (figure 1). The challenge now is to calculate the disease, diabetes, generalised atherosclerosis, smoking, relative importance of individual risk factors and their high lipid concentrations, and a history of stroke.24,25 interactive effects, and to obtain maximum likelihood estimates for alternative models to assess their relative Although results from some studies suggest an association robustness in predicting of transition to Alzheimer’s between vascular dementia and APOE*E426,27 this relation disease. is not consistently noted, and might be attributable to difficulties in the differential diagnosis of Alzheimer’s disease and vascular dementia. Vascular pathology, Biology notably atherosclerosis, white matter lesions, and mid-life Increases in the understanding of the basic biology of arterial hypertension, have also been associated with Alzheimer’s disease and related dementias during the past Alzheimer’s disease and could enhance cognitive loss.28 20–30 years have been substantial, and have led to potential treatment strategies that are just beginning to Thus, most cases of dementia have a common vascular undergo clinical evaluation. Such advances have been pathology, which suggests that early diagnosis and made using three overlapping approaches: neuropathtreatment of vascular disorders could modulate the onset ology, neurochemistry, and molecular biology. of dementia. Results from descriptive studies have raised two Neuropathological advances important issues. First, dementia is no longer regarded as Alzheimer and his colleagues and contemporaries made a single nosological entity and, even within its principal an almost complete description of the core form, clinical subgroups of Alzheimer’s disease with their neuropathological lesions that occur in the dementias of own risk factors and causes are likely to exist Thus, young and middle-aged people. The first real advance in epidemiological studies that group together all forms of their work came with the realisation that the so called dementia are likely to hide individual patterns of risk, senility that occurs in some, but not all, elderly people was clinical manifestation, and treatment success. Consensus accompanied by the exact same changes seen in criteria now exist to differentiate early-onset and latedementias. This work had the important effect of onset Alzheimer’s disease and Vascular dementia,29 and reclassifying senile neurodegeneration as a set of disease diagnostic guidelines have also been suggested for entities that are suitable subjects for development of dementia with Lewy bodies, frontotemporal dementia and treatments. progressive non-fluent aphasia.30–32 Second, although early Neuropathological studies have begun to redefine our studies calculated odds ratios for individual risk factors, it nosological understanding of these conditions. For has become clear that the co-occurrence of multiple risk example, immunohistological techniques were used to factors increases risk beyond the additive effect of each identify Lewy bodies in the cortex. A co-worker of factor, and that some risk factors might only be activated Alzheimer first described these intraneuronal inclusion in the presence of other factors. For example, signs of bodies in the substantia nigra of patients with Parkinson’s vascular disease detected in neuroimages and an disease, and they are now known to accompany a distinct APOE*E4 genotype combine to increase risk of dementia syndrome—dementia with Lewy bodies— Alzheimer’s disease in very elderly people.33 Analytical characterised by parkinsonism, visual hallucinations, and epidemiology has become increasingly important and fluctuating confusion. Lewy bodies are composed of allows testing of the predictive validity of complex models aggregated synuclein and, in very rare instances, of disease causes that incorporate many interacting risk
1760
THE LANCET • Vol 360 • November 30, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
mutations in the SNCA gene can cause autosomal dominant familial Parkinson’s disease.34 The same pattern of rare variants of disease being associated with mutations in a gene that codes for a protein that is abnormally aggregated in both rare and common forms of the disease is found repeatedly. Thus, mutations in the MAPT (tau) gene can be a cause of frontal lobe dementia and aggregations of tau protein in neurons and glia are seen in both frontal lobe dementia and Alzheimer’s disease.35 All this work has begun to lead to a redefinition of the dementias—ie, one grouped by pathogenesis and pathological changes rather than by clinical symptoms. Thus, the synucleinopathies include Parkinson’s disease, dementia with Lewy bodies, and multisystem atrophy. Tauopathies include frontal lobe dementia and progressive supranulcear palsy. Alzheimer’s disease is both an amyloidopathy (as are the transmissible encephalopathies to some extent) and a tauopathy. This regrouping of disease entities is not entirely academic because an intervention to prevent synucleinopathy might be effective against all synucleinopathies but not tauopathies, and vice versa, leading to the somewhat unexpected conclusions that therapies for frontal lobe dementias might also be useful in progressive supranulcear palsy. Likewise, if therapies for Alzheimer’s disease target amyloid, they might have some relevance for other amyloidopathies, but not for frontotemporal degeneration even though these two disorders have many of the same clinical characteristics.
tissue from patients with Alzheimer’s disease shows a loss of cholinergic markers and pronounced attrition of neurons in the locus coeruleus, the region where cholinergic fibres originate. Evidence from work in animals suggests that lesions of cholinergic tracts induce severe cognitive deficits. Such combined evidence prompted investigators to develop strategies to rectify cholinergic loss,36 which resulted in development of cholinesterase inhibitors. Subsequent work has shown other neuronal markers are also lost, and some evidence suggests that the diversity of clinical symptoms results from relative loss of serotonergic or noradrenergic function in addition to cholinergic function.37 The loss of these other neurotransmitter systems probably also sets the limits of potential benefits of the cholinergic, symptomatic approach. Advances in molecular biology Although research into the neurochemistry and neuropathology of dementia has produced practical outcomes, the real hope of advances in treatment comes from studies in molecular biology, which could advance our knowledge of the pathogenesis of neurodegeneration. Studies in molecular biology and genetics have led to an almost complete understanding of the process of formation of the two key pathological lesions of Alzheimer’s disease—ie, the plaque and tangle. Animal models of both processes have been developed and compounds that affect both, at least in the laboratory setting, have been discovered. We do not yet understand how these lesions relate to each other, why some neurons are more vulnerable than others, and which factors determine individual susceptibility to neuronal lesions. The plaque is an extracellular lesion composed of a core of an amyloid peptide of 40–42 aminoacids designated A .38 This peptide is in turn derived from amyloid precursor protein (APP), the gene for which is on
Neurochemical advances Studies of the neurochemistry of Alzheimer’s disease have resulted in tangible benefits in treatment of symptoms. The finding that markers of cholinergic function are lost first and most in Alzheimer’s disease led to the cholinergic hypothesis that postulates that this disease is mainly a cholinergic disorder. Post-mortem examination of brain
Swedish 670/671
London 717
Amyloid precursor protein
BACE
-secretase
-secretase
Amyloidogenic metabolism
Non-amyloidogenic metabolism BACE
-secretase
-secretase
A
Plaques Figure 2: Postulated pathway for plaque formation
THE LANCET • Vol 360 • November 30, 2002 • www.thelancet.com
1761
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
chromosome 21. Mutations in the gene occasionally cause familial Alzheimer’s disease, and these mutations cluster around the three sites where APP is known to be cleaved in vivo (figure 2). Cleavage at two of these sites—at the -amyloid cleaving enzyme (BACE) and the -secretase sites—liberates the A peptide, whereas cleavage at -secretase is non-amyloidogenic. BACE has been cloned and characterised, and potentially therapeutic inhibitors have been developed.39 In fact, -secretase has been shown to be very closely associated with (and perhaps even is) the product of genes that are also mutated in some families with the rare autosomal dominant form of Alzheimer’s disease. These genes are known as the presenilins—PS-1 on chromosome 14 and PS-2 on chromosome 1.40 Inhibition of -secretase activity might also be effective in the treatment of Alzheimer’s disease. However, loss of the -secretase function in transgenic mice is lethal, whereas loss of the BACE gene in mice causes no apparent deficits. A very unexpected advance in treatment came about when researchers showed that immunological treatment could reduce plaque formation in transgenic mice.41 Subsequently this result was repeated with both active and passive immunisation, and workers showed that such treatment had positive effects on the cognition of the transgenic animals.42,43 Phase 2 trials of vaccination with amyloid (AN-1792) began in 2001, on 375 patients with mild to moderate disease. These trials were the first product of research into the molecular biology of Alzheimer’s disease to reach the stage of clinical assessment, but were halted in March, 2002, because of signs of nervous system inflammation and worsening of Alzheimer’s disease symptoms in 5% of patients. The exact cause of these deleterious side-effects remains uncertain, although it has been speculated that activated T cells might have entered the brain, or that specific tissue types could have overstimulated the immune system. Research on mice with two Alzheimer’s-disease-linked transgenes has shown that immunisation upregulates a membrane protein in immune-system cells in the hippocampus, which causes microglial activation, which in turn is a sign of inflammation.44 However, this study was
Tau bound to microtubules Mutations resulting in loss of function
Phosphorylation by GSK-3
Mutations resulting in altered gene expression
Mutations resulting in increased self-aggregation
Aggregated tau
Neurofibrillary tangles
Figure 3: Postulated pathway for tangle formation
1762
done on young mice and, furthermore, was unable to establish a direct link between microglial activation and autotoxic inflammation. The other lesion of Alzheimer’s disease is the neurofibrillary tangle—an intraneuronal lesion of highly phosphorylated and aggregated tau (figure 3). Tau protein is a normal and essential component of neurons where it stabilises the microtubule cytoskeleton that is essential for axonal transport.45 In Alzheimer’s disease this cytoskeleton is lost and the aggregation of tau is an early event in pathogenesis that correlates well with cognitive loss.46 We do not know why tau aggregates, but it might be due to the loss of normal tau function that accompanies some tau mutations in frontotemporal dementia, the altered isoform expression caused by other tau mutations, or the increase of phosphorylation that occurs in Alzheimer’s disease.47 Tau phosphorylation is regulated in neurons, in part, by an enzyme, glycogen synthase kinase-3 (GSK-3), and inhibition of this enzyme is another potential treatment strategy, especially since the neurotoxic effects of A are reduced by GSK-3 inhibition.48,49 This reduction might be the answer to one of the most enduring and frustrating puzzles in our understanding of Alzheimer’s disease—ie, the link between plaques and tangles. Such a link must exist, but proof that amyloid production leads to tau aggregation has remained elusive.50 Apart from the mutations associated with early-onset familial Alzheimer’s disease, polymorphic variation in genes affect personal susceptibility to late-onset disease. Only one gene is known thus far to affect risk—APOE. The E4 allele increases risk, or reduces age of disease onset (three to four-fold for the heterozygous form of disease, and up to ten-fold for the rare homozygous condition), but the E2 allele decreases risk.51 Other genes are almost certainly associated with Alzheimer’s disease, and linkage suggests that there are regions of interest on chromosome 10, 12, and 9.52–54 Practical consequences of advances in biology Acetylcholinesterase inhibitors55–57 are modestly efficacious in treating the symptoms of cognitive deficts, and there is some evidence for an effect on behaviour and function. Results from early trial data suggest that for every three to seven patients treated with acetylcholinesterase inhibitors, only one will have improvement in symptoms, or a delay in clinical deterioration.58 Trials that led to the licensing of these compounds were done almost exclusively in people with mild to moderate Alzheimer’s disease, but some evidence shows that the cholinergic loss in early stages of this disorder is mild,59 suggesting that effectiveness might not be lost entirely in those with severe disease. Evidence about long-term use of acetylcholinesterase inhibitors, their use in severe dementia, use in vascular dementia, and head-to-head comparisons between different compounds is being gathered and should help to inform evidencebased practice. Early signs are that the cholinesterase inhibitors might be especially useful in dementia with Lewy bodies.60 Other approaches in development of treatment for dementia seek to modulate different neurotransmitter systems to those affected by acetlycholinesterase inhibitors, suggesting the possibility of combination therapies. Genetic advances have led to molecular diagnostic testing, and predictive testing is now a reality for those few families with clear-cut autosomal dominant early-onset dementia. Such people should be referred to clinical geneticists for counselling. The molecular biology of lateonset Alzheimer’s disease is more complicated than earlyonset disease, since the APOE susceptibility gene alters
THE LANCET • Vol 360 • November 30, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
Neuropsychiatric disorders in dementia Mood
Behaviour
Psychotic features
Alzheimer’s disease
Apathy Depression Anxiety
Agitation Disinhibition Eating disorder
Hallucinations Delusions Euphoria
Dementia with Lewy bodies
Depression
Vascular dementia
Depression
Frontotemporal Euphoria dementia Anxiety Suicidal ideation Apathy
Parkinson’s disease
Depression Anxiety
Hallucinations Delusions Thoughtlessness Crying
Hallucinations Delusions
Inappropriate behaviour Disinhibition Agitation Hyperorality Eating disorder Perseveration Hypersexuality Hallucinations Delusions
risk only slightly. There are no discernible clinical uses of genetic testing for late-onset Alzheimer’s disease—APOE testing should not be used for prediction of disease likelihood, and few feel it has any use in diagnosis at present. The most promising practical advances in research for treatment, are identification of hundreds of compounds that show promise in reducing amyloid formation or reducing tau phosphorylation. Such compounds include; inhibitors of -secretase or -secretase, either of which should reduce production of amyloid; agents to reduce fibrillinogenesis of the amyloid peptide, which might reduce its toxicity; and inhibitors of glycogen synthase kinase-3 (GSK-3), which might reduce tau aggregation and tangle formation. Other approaches based on epidemiological findings include NSAIDs, vitamin E or vitamin B12 supplementation, and hormone replacement therapies. All methods hold some promise, but none have been adequately tested. Structural and functional neuroimaging Neuroimaging is becoming increasingly important as a means to identify potential biomarkers in dementia. CT and MRI are now often used in research, and to a lesser extent in clinical settings, to identify rare forms of dementia and to add specificity to the differential diagnosis of Alzheimer’s disease, dementia with Lewy bodies, and vascular dementia. These imaging techniques have also been used to show the extensive overlap in the underlying pathologies of dementias; Alzheimer’s disease, for example, is often associated with white-matter lesions on MRI and vascular dementia with temporal lobe atrophy on both CT and MRI.61–63 Functional MRI with dynamic susceptibility contrast provides information on blood flow, and is an indirect indicator of brain metabolism with the advantage of not requiring radioactive isotopes, yet it provides superior spatial resolution and better rates of dementia identification than MRI alone (90%).64,65 Functional imaging without the injection of paramagnetic contrast agents is also now possible, but requires considerable cooperation from the
THE LANCET • Vol 360 • November 30, 2002 • www.thelancet.com
patient. Neuropsychological research has consistently shown that tests of delayed free recall, verbal fluency, and spatial organisation are sensitive to early neuropathological degeneration. In combination with neuroimaging, these tests can be used to chart the precise locations of functions within the brain, monitor compensatory processes, and observe treatment effects. Presently however, functional imaging is largely confined to research studies and has not been integrated into standard clinical practice. Another procedure that could advance diagnosis of dementias is serial registration (the mathematical comparison of images taken at different points in time), which might detect progressive preclinical hippocampal atrophy even before cognitive decline is detected by clinical examination. Presently, the principal use of this method is for the estimation of power calculations to detect drug effects in clinical trials.66,67 Biochemical changes in the brain that are associated with dementia can now be detected by magnetic resonance spectroscopy. By contrast with post-mortem studies, this imaging technique offers a non-invasive method to follow disease progression. Detection of biochemical changes that occur before cognitive and behavioural changes, could eventually provide a method of screening for dementia before the onset of clinical signs.68
Neuropsychiatric disorders in dementia In terms of patients’ management, one of the most important developments in recent years has been the recognition of the role of psychiatric and behavioural disorders in dementia syndromes. Such disorders include affective disorder (depression, anxiety, euphoria), personality change, behavioural difficulties (agitation, apathy, irritability, disinhibition, aberrant motor behaviour), hallucinations, delusions, and eating disorders. Neuropsychiatric disorders, which occur in up to 90% of dementia patients,69,70 are one of the main causes of care-giver stress and patients’ admission to institutions. However, they provide important clues to the underlying pathophysiological processes of dementia, and are key determinants of differential diagnosis and prognosis.71–73 Depression is perhaps the most widely studied of these disorders, because of the difficulties of differential diagnosis between early dementia and depressive syndromes. It is now recognised that depression and dementia are not mutually exclusive; on the contrary, depression occurs in about 40–50% of cases.74,75 Some evidence suggests that depressive symptoms change in the course of the disease from a reactive syndrome, to loss of competence, and increasing psychomotor and vegetative signs attributable to deterioration of limbic-system structures.75 Apart from the distress caused by depressive symptoms, the cooccurrence of depression in dementia accelerates loss of autonomy, and treatment with antidepressants is now widely advocated.76 Preference is given to therapy by selective serotonin reuptake inhibitors (SSRIs) and related drugs that do not have a significant anticholinergic effect, which could accelerate cognitive loss. Similarly, in the treatment of psychotic symptoms in dementia some of the older antipsychotic medications have a substantial anticholinergic effect and should be avoided. For both depression and psychosis, however, non-pharmacological strategies, such as elimination of physical causes including pain and infection, environmental and behavioural management, and professional and non-professional carer training should be attempted first—if only because the risk
1763
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
of harm to patients is lower than that associated with medication. The management of what has become known as the behavioural and psychological symptoms of dementia is receiving much-needed attention, and randomised controlled trials of pharmacological and nonpharmacological treatments are being done. Patterns of neuropsychiatric disorder vary with the type of dementia syndrome (panel) Several scales developed for use in clinical research and drug trials, might also be useful in clinical practice. Most often used are the BEHAVE-AD,77 the NeuroPsychiatric Inventory,78 MOUSEPAD,79 and the CERAD behaviour rating scale for dementia.80 A detailed review of these scales has been published elsewhere.81
Care and caregivers Care strategies have developed in parallel with research into causes and management of Alzheimer’s disease. Perhaps the most important advance in this area is the recognition that caregiving can cause pathology; professional and lay carers of dementia patients have high rates of physical and mental disorder.82,83 Caregivers who live with the person they care for are more reluctant to admit the person into an institution, and more likely to be depressed than carers who live apart from their patient.84 Results from community studies have also shown high rates of abuse both of and by the dementia patient.85–88 These observations have not only led to the development of preventive health-care strategies for carers89 and availability of respite care, but also to a questioning of the long-held assumption that all elderly people with dementia are better off in the community. On the other hand, institutionalisation is not always the perfect solution to care-giver stress, often creating other difficulties such as guilt, exclusion from decision making and care, a financial burden, and difficulties in maintaining relationships.90 An alternative approach has been to develop models of care that bring the institution closer to the community, involve family care-givers within the professional care setting,91,92 and to adapt the architecture of institutions to the needs of dementia patients—eg, the elimination of corridors.93 The move from community to institutional care is still, in most cases, poorly planned and often a response to a crisis rather than an organised transition. Behavioural disorder and functional loss, notably aggression and incontinence, are the main determinants of institutionalisation rather than cognitive deterioration. The transition to institutional care is also more likely to occur in holiday periods than at other times of the year, and if the carer is a husband rather than a wife, and a child rather than a spouse.94,95 Lay and professional care givers should work as a team, allocate responsibilities for medical care and psychosocial intervention, and plan institutionalisation as a response to a predicted stage of the disorder rather than a reaction to a family crisis or care-giver burn-out.
Conclusions Overall rates of dementia are much the same in developed countries, and incidence rises exponentially until the eighth decade of life. Advances in medical technology have prolonged survival at high ages, but have had little effect on disease incidence. Because dementia prevalence increases with age, this situation has led to a rapid increase in the proportion of dementia sufferers within the population. The causes of these disorders are complex. Workers in epidemiology have had to develop risk models in parallel with changing knowledge of biological risk factors. Dementias are now thought to be the end result of a complex interaction of genetic risks, biological changes attributable to several underlying associated and non-
1764
associated pathologies (including disorders which may have occurred in young adulthood), environmental trauma, hormonal changes, and effects of medication. Potential targets for treatment include neurotransmitter function, A production and deposition, and reduction of secondary risk factors such as arterial hypertension and hypolipidaemia. Although there is no definitive effective treatment in view, cholinergic therapies have had mild short-term success in stabilising cognitive loss and, along with psychotropic drugs, reducing associated behavioural disorders. Treatment of depression also reduces the rate of loss of ability to do daily activities. Although such contributions are modest at the individual level, clinical intervention to prolong patients’ autonomy, even if only for a few months, will have a substantial effect on the public health burden of Alzheimer’s disease. High rates of morbidity in professional and family care-givers have led to the development of respite services, and better adaptations of institutional care to the needs of dementia patients and their families. Many promising research avenues are yet to be explored: properly powered genetic studies, neuroimaging and other biomarker techniques for diagnosis and disease monitoring, targeting of other non-cholinergic neurotransmitters, and wider assessment of treatments for behavioural and psychological symptoms of dementia, and strategies to support carers. Improved diagnosis, wider recognition, and the prospects for disease modification make the future management of Alzheimer’s disease an exciting specialty. Conflict of interest statement None declared.
Acknowledgments There was no funding source.
References 1 2
3
4
5 6
7
8 9 10 11 12
13
14 15
Lancet Conference Writing Committee. The challenge of the dementias. Lancet 1996; 347: 1303–07. Hofman A, Rocca WA, Brayne C. The prevalence of dementia in Europe: a collaborative study of 1980–1990 findings. Int J Epidemiol 1991; 20: 736–48. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 1987; 76: 465–79. Ritchie K, Kildea D. Is senile dementia age-related or ageing-related?— evidence from a meta-analysis of dementia prevalence in the oldest old. Lancet 1995; 346: 931–34. Osuntokun BO, Ogunniyi AO, Lekauwa UG. Alzheimer’s disease in Nigeria. Afr J Med Sci 1992; 21: 71–77. Chandra V, Ganguli M, Pandav R, Johnston J, Belle S, DeKosky ST. Prevalence of Alzheimer’s disease and other dementias in rural India: the Indo-US study. Neurology 1998; 51: 1000–08. Zhang M, Katzman R, Salmon D, et al. The prevalence of dementia and Alzheimer’s disease in Shanghai, China: impact of age, gender and education. Ann Neurol 1990; 27: 428–37. Barclay LL, Zemcov A, Blass JP, Sansone J. Survival in Alzheimer’s disease and vascular dementias. Neurology 1985; 35: 834–40. Akesson HO. A population study of senile and arteriosclerotic psychoses. Hum Hered 1969; 19: 546–66. Mölsä PK, Marttila RJ, Rinne UK. Epidemiology of dementia in a Finnish population. Acta Neurol Scand 1982; 65: 541–52 . Burns A, Lewis G, Jacoby R, Levy R. Factors affecting survival in Alzheimer’s disease. Psychol Med 1991; 21: 363–70. Katzman R, Aronson M, Fuld P, et al. Development of dementing illnesses in an 80 year old volunteer cohort. Ann Neurol 1989; 25: 317–24. Corder E, Saunders AM, Risch NJ. Protective effect of apoliprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 1994; 7: 180–84. Skoog I, Lernfelt B, Landahl S, et al. 15-year longitudinal study of blood pressure and dementia Lancet 1996; 347: 1141–45. Corder E, Saunders A, Strittmatter W, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993; 261: 921–23.
THE LANCET • Vol 360 • November 30, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
16 Henderson AS, Easteal S, Jorm AF, et al. Apolipoprotein E allele 4 dementia, and cognitive decline in a population sample. Lancet 1995; 346: 1387–90. 17 Wade JPH, Mirsen TR, Hachinski VC, Fisman M, Lau C, Merskey H. The clinical diagnosis of Alzheimer’s disease. Arch Neurol 1987; 44: 24–29. 18 Mortimer JA, French LR, Schuman LM, Hutton JT. Head injuries in Alzheimer’s disease and vascular dementia. Neurology 1985; 35: 1804. 19 Tang MX, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 1996; 348: 429–32. 20 Poirier J. Apolipoprotein E in the brain and its role in Alzheimer’s disease. J Psychiatry Neurosci 1996; 21: 128—34. 21 Dupuy AM, Mas E, Ritchie K, et al. The relationship between Apolipoprotein E4 and lipid metabolism is impaired in Alzheimer’s disease. Gerontology 2001; 47: 213–18. 22 Stern Y, Alexander GE, Prohovnik I, Mayeux R. Inverse relationship between education and parietotemporal perfusion deficit in Alzheimer’s disease. Ann Neurol 1992; 32: 371–75. 23 Rocca W, Hofman A, Brayne C. The prevalence of vascular dementia in Europe: facts and fragments from 1980–1990 studies. Ann Neurol 1991; 30: 817–24. 24 Skoog I. Status of risk factors for vascular dementia. Neuroepidemiology 1998; 17: 2–9. 25 Erkinjuntti T. Vascular dementia: an overview. In: O’Brien J, Ames D, Burns A, eds. Dementia. Oxford: Oxford University Press, 2000. 26 Slooter A, Tang M, Van Duijn C, et al. Apolipoprotein E 4 and the risk of dementia with stroke. JAMA 1997; 277: 818–21. 27 Chapman J, Wang N, Treves T, Korczyn A, Bornstein N. ACE, MTHFR, Factor V Leiden and APOE polymorphisms in patients with vascular and Alzheimer’s dementia. Stroke 1998; 29: 1401–04. 28 Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer’s disease: the nun study. JAMA 1997; 277: 813–17. 29 American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th edn) Washington APA, 1994. 30 McKeith IG, Galasko D, Kosaka K. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies. Neurology 1996; 47: 1113–24. 31 Serby M, Samuels SC. Diagnostic criteria for dementia with Lewy bodies reconsidered. Am J Geriatr Psychiatry 2001; 9: 212—16. 32 Lund and Manchester Groups. Clinical and neuropathological criteria for fronto-temporal dementia. J Neurol Neurosurg Psychiatry 1994; 57: 416–18. 33 Skoog I, Hesse C, Aevarsson O, et al. A population study of ApoE genotype at the age of 85: relation to dementia, cerebrovascular disease and mortality. J Neurol Neurosurg Psychiatry 1998; 64: 37–43. 34 Duda JE, Lee VM, Trojanowski JQ. Neuropathology of synuclein aggregates. J Neurosci Res 2000; 61: 121–27. 35 Heutink P. Untangling tau-related dementia. Hum Mol Genet 2000; 9: 979–86. 36 Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 1999; 66: 137–47. 37 Kirby M, Lawlor BA. Biologic markers and neurochemical correlates of agitation and psychosis in dementia. J Geriatr Psychiatry Neurol 1995; 8 (suppl 1): S2–7. 38 Hardy J. Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 1997; 20: 154–59. 39 Nunan J, Small DH. Regulation of APP cleavage by - - and gamma-secretases. FEBS Lett 2000; 483: 6–10. 40 Haass C, De Strooper B. Review: neurobiology—the presenilins in Alzheimer’s disease—proteolysis holds the key. Science 1999; 286: 916–19. 41 Schenk D, Barbour R, Dunn W, et al. Immunization with amyloidbeta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400: 173–77. 42 Janus C, Pearson J, McLaurin J, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 2000; 408: 979–82. 43 Morgan D, Diamond DM, Gottschall PE, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 2000; 408: 982–85. 44 Wilcock DM, Gordon MN, Ugen KE, et al. Number of A inoculations in APP+PS1 transgenic mice influence antibody titers, microglial activation, and congophilic plaque levels. DNA Cell Biol 2001; 20: 731–36 45 Paglini G, Peris L, Mascotti F, Quiroga S, Caceres A. Tau protein function in axonal formation. Neurochem Res 2000; 25: 37–42. 46 Nagy Z, Esiri MM, Jobst KA, et al. Relative roles of plaques and tangles in the dementia of Alzheimer’s disease: correlations using three sets of neuropathological criteria. Dementia 1995; 6: 21–31.
THE LANCET • Vol 360 • November 30, 2002 • www.thelancet.com
47 Avila J. Tau aggregation into fibrillar polymers: taupathies. FEBS Lett 2000; 476: 89–92. 48 Lovestone S, Reynolds CH. The phosphorylation of tau: a critical stage in neurodevelopmental and neurodegenerative processes. Neuroscience 1997; 78: 309–24. 49 Alvarez G, Muñoz-Montaño JR, Satrústegui J, Avila J, Bogónez E, Díaz-Nido J. Lithium protects cultured neurons against -amyloidinduced neurodegeneration. FEBS Lett 1999; 453: 260–64. 50 Mudher A, Lovestone S. Alzheimer’s disease—do tauists and baptists finally shake hands? TINS 2002; 25: 22–26. 51 Hardy J. Apolipoprotein E in the genetics and epidemiology of Alzheimer’s disease. Am J Med Genet 1995; 60: 456–60. 52 Zubenko GS, Hughes HB, Stiffler JS, Hurtt MR, Kaplan BB. A genome survey for novel Alzheimer disease risk loci: Results at 10-cM resolution. Genomics 1998; 50: 121–28. 53 Myers A, Holmans P, Marshall H, et al. Susceptibility locus for Alzheimer’s disease on chromosome 10. Science 2000; 290: 2304–05. 54 Kehoe P, Wavrant-De Vrieze F, et al. A full genome scan for late onset Alzheimer’s disease. Hum Mol Genet 1999; 8: 237–45. 55 Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 1999; 66: 137–47. 56 Wilkinson D. Drugs for treatment of Alzheimer’s disease. Int J Clin Pract Int 2001; 55: 129–34. 57 Van Den Berg CM, Kazmi Y, Jann MW. Cholinesterase inhibitors for the treatment of Alzheimer’s disease in the elderly. Drugs Aging 2000; 16: 123–38. 58 Livingston G, Katona C. How useful are cholinesterase inhibitors in the treatment of Alzheimer’s disease? A number needed to treat analysis. Int J Geriatr Psychiatry 2000; 15: 203–07. 59 Davis KL, Mohs RC, Marin D, et al. Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA 1999; 281: 1401–06. 60 McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebocontrolled international study. Lancet 2000; 356: 2031–06. 61 Laakso MP, Partanen K, Riekkinen P, et al. Hippocampal volumes in Alzheimer’s disease with and without dementia, and in vascular dementia. Neurology 1996; 46: 678–81. 62 Barber R, Gholkar A, Scheltens P, et al. Apolipoprotein E 4 allele, temporal lobe atrophy and white matter lesions in late-life dementias. Arch Neurol 1999; 56: 961–65. 63 Scheltens P, Barkhof F, Valk J, et al. White matter lesions on magnetic resonance imaging in clinically diagnosed Alzheimer’s disease. Brain 1992; 115: 735–48. 64 Harris GJ, Lewis RF, Satlin A, et al. Dynamic susceptibility contrast MRI of regional cerebral blood volume in Alzheimer’s disease. Am J Psychiatry 1996; 153: 721–24. 65 Harris GJ, Lewis RF, Satlin A, et al. Dynamic susceptibility contrast MRI of regional cerebral blood volume in Alzheimer’s disease: a promising alternative to nuclear medicine. Am Soc Neuroradiol 1998; 19: 1727–32. 66 Fox NC, Cousens S, Scahill R, Harvey RJ, Rossor MN. Using serial registered brain magnetic resonance imaging to measure disease progression in Alzheimer’s disease power calculations and estimates of sample size to detect treatment effects. Arch Neurol 2000; 57: 339–44. 67 Fox NC, Warrington EK, Freeborough PA, et al. Presymptomatic hippocampal atrophy in Alzheimer’s disease. A longitudinal MRI study. Brain 1996; 119: 2001–07. 68 Huang W, Alexander GE, Daly EM, et al. High brain myo-inositol levels in the pre-dementia phase of Alzheimer’s disease in adults with Down’s syndrome. Am J Psychiatry 1999; 156: 195–202. 69 Tariot PN, Mack JL, Patterson MB, et al. The behaviour rating scale for dementia of the consortium to establish a registry for Alzheimer’s disease. Am J Psychiatry 1995; 152: 1349–57. 70 Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioural changes in Alzheimer’s disease. Neurology 1996; 46: 130–35. 71 Stern Y, Mayeux R, Sano M, Hauser WA, Bush T. Predictors of disease course in patients with probable Alzheimer’s disease Neurology 1987; 37: 1649–53. 72 Mortimer JA, Ebbitt B, Jun SP, Finch MD. Predictors of cognitive and functional progression in patients with probable Alzheimer’s disease. Neurology 1992; 42: 1689–96. 73 Reisberg B, Ferris SH, Torossian C, Kluger A, Monteiro I. Pharmacologic treatment of Alzheimer’s disease: a methodologic critique based upon current knowledge of symptomatology and relevance for drug trials. Int Psychogeriat 1992; 4 (suppl 1): 9–42. 74 Burns A. Psychiatric symptoms and behavioural disturbances in the dementias. J Neural Trans 1997; 51 (suppl): 27–35.
1765
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
75 Ritchie K, Gilham C, Ledésert B, Touchon J, Kotzi PO. Depressive illness, depressive symptomatology and regional cerebral blood flow in elderly people with sub-clinical cognitive impairment. Age Ageing 1999; 28: 385–91. 76 Fitz AG, Teri L. Depression, cognition and functional ability in patients with Alzheimer’s disease. J Am Geriatr Soc 1994; 42: 1994. 77 Auer SR, Monteiro IM, Reisberg B The empirical behavioural pathology in Alzheimer’s disease (E-BEHAVE-AD) rating scale. Int Psychogeriatr 1996; 8: 247–66. 78 Cummings JL The neuropsychiatric inventory: assessing psychopathology in dementia patients. Neurology 1997; 48: 510–16. 79 Allen NH, Gordon S, Hope T, Burns A. Manchester and Oxford Universities Scale for the Psychopathological Assessment of Dementia (MOUSEPAD). Br J Psychiatry 1996; 169: 293–307. 80 Tariot PN. CERAD Behaviour rating scale for dementia. Int Psychogeriatr 1996; 8 (suppl 3): 317–20. 81 Finkel I, Costa e Silva J, Cohen G, Miller S, Sartorius N. Behavioral and psychological signs and symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. Int Psychogeriatr 1996; 8 (suppl 3): 497–500. 82 Brodaty H, Hadzi-Pavlovic D. Psychosocial effects on carers of living with persons with dementia. Aust NY J Psychiat 1990; 24: 351–61. 83 Schultz R, Williamson G. A two-year longitudinal study of depression amongst Alzheimer’s care-givers. Alz Dis Assoc Dis 1997; 11: 117–24. 84 Harper S, Lund D. Wives husbands and daughters caring for institutionalized and non-institutionalized dementia patients: toward a model of care-giver burden Int J Aging Hum Dev 1990; 30: 241–62.
1766
85 Cahill S, Shapiro M. I think he might have hit me once: aggression towards care-givers in dementia care. Aust J Ageing 1993; 12: 10–15. 86 Homer A, Gilleard C. Abuse of elderly people by their carers. BMJ 1990; 301: 1359–62. 87 Pillemer K, Suitor J. Violence and violent feelings: what causes them among family care-givers? J Gerontol 1992; 47: 165–72. 88 McCallum J. Elder abuse: the new social problem? Mod Med Aust 1993; 9: 74–83. 89 Brodaty H, Gresham M, Luscombe G. The Prince Henry Hospital dementia care givers’ training programme Int J Geriatr Psychiat 1997; 12: 183–92 90 Ritchie K, Ledésert B. The families of the institutionalized dementing elderly. A preliminary study of stress in a French care-giver population. Int J Geriatr Psychiat 1992; 7: 5–14 91 Lindesay J, Briggs K, Lawes M, MacDonald A, Herzberg J. The Domus philosophy: a comparative evaluation of residential care for the demented elderly. Int J Geriat Psychiat 1991; 6: 727–36. 92 Ritchie K, Colvez A, Ankri J, Ledesert B, Gardent H, Fontaine A. The evaluation of long-term care for the dementing elderly: a comparative study of hospital and collective non-medical care in France. Int J Geriatr Psychiatry 1992; 7: 549–57. 93 Marshall M. State of the art dementia care. London: Centre for Policy on Ageing, 1997. 94 Armstrong M. Factors affecting the decision to place a relative with dementia into residential care. Nurs Stand 2000; 14: 33–37. 95 Steeman E, Abraham IL, Godderis J. Risk profiles for institutionalization a cohort of elderly people with dementia or depression. Arch Psychiatr Nurs. 1997; 11: 295–303.
THE LANCET • Vol 360 • November 30, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.