The Lancet Neurology Commission Defeating Alzheimer's disease and other dementias

78 Pages·2016·2 MB·English

The Lancet Neurology Commission
Defeating Alzheimer’s disease and other dementias:
a priority for European science and society
Bengt Winblad, Philippe Amouyel, Sandrine Andrieu, Clive Ballard, Carol Brayne, Henry Brodaty, Angel Cedazo-Minguez, Bruno Dubois,
David Edvardsson, Howard Feldman, Laura Fratiglioni, Giovanni B Frisoni, Serge Gauthier, Jean Georges, Caroline Graff, Khalid Iqbal, Frank Jessen,
Gunilla Johansson, Linus Jönsson, Miia Kivipelto, Martin Knapp, Francesca Mangialasche, René Melis, Agneta Nordberg, Marcel Olde Rikkert,
Chengxuan Qiu, Thomas P Sakmar, Philip Scheltens, Lon S Schneider, Reisa Sperling, Lars O Tjernberg, Gunhild Waldemar, Anders Wimo,
Henrik Zetterberg
Executive summary private investment in the care of patients and the search Lancet Neurol 2016; 15: 455–532
Alzheimer’s disease (AD) is the leading cause of dementia, for AD therapeutics. See Comment pages 451 and 452
and because the primary risk factor for AD is old age, the Europe is well placed to take the world lead, in Department of Neurobiology,
prevalence of the disease is increasing dramatically with partnership with international organisations, to develop Care Sciences and Society,
ageing populations worldwide. Even in high-income new approaches to prevent or cure AD and other Center for Alzheimer Research,
Division of Neurogeriatrics
countries, the cost of medical care and associated societal dementias and to provide models of compassionate care
(Prof B Winblad MD,
burdens of dementia threaten to become overwhelming for patients. As the cost of care increases, funds must not A Cedazo-Minguez PhD,
as more people live into old age. In view of the lack of be shunted from basic research, clinical research, and Prof C Graff MD, G Johansson,
progress in developing a cure for AD and the rapidly drug-discovery programmes. In fact, a substantial increase L Jönsson MD,
Prof M Kivipelto MD,
increasing costs of dementia, policy makers and in long-term funding for multidisciplinary research
Prof T P Sakmar MD,
governments have a powerful incentive to provide more programmes is absolutely essential to reduce the burden L O Tjernberg PhD,
resources to develop AD therapeutics. The Lancet of individual suffering and the enormous societal cost of Prof A Wimo MD) and
Neurology Commission was formed with the overarching AD. Only targeted increases in research investment will Department of Neurobiology,
Care Sciences and Society,
aim to provide information and expert recommendations provide any hope of finding a cure for AD or developing
Center for Alzheimer Research,
to policy makers and political leaders about the growing strategies to delay the onset or slow the progression of the Division of Translational
problem of AD and related dementias of ageing. disease. Alzheimer Biology
The past two decades have seen remarkable (Prof A Nordberg MD), Karolinska
Institutet, Huddinge, Sweden;
improvements in the quality of care for patients with AD, Introduction
Department of Geriatric
with a research-driven shift to more personalised and Dementia encompasses a range of neurological disorders Medicine, Karolinska University
integrated team-oriented care. Epidemiological and characterised by memory loss and cognitive impairment. Hospital, Huddinge, Sweden
genetic studies have identified many factors that increase Alzheimer’s disease (AD) is the most common form of (Prof B Winblad, Prof C Graff,
Prof M Kivipelto,
the risk of AD. Prevention studies have highlighted the dementia, accounting for 50–70% of cases. The most
Prof A Nordberg); Centre
possibility of targeting risk and protective factors to delay common early symptom of dementia is difficulty in Hospitalier Régional
onset, with the promise of reducing the overall prevalence remembering recent events. As the disorder develops, a Universitaire de Lille, Institut
Pasteur de Lille, INSERM U1167
of dementia. However, no treatment is yet available to halt wide range of other symptoms can emerge, such as
RID-AGE, Unité d’Epidémiologie
or reverse the underlying pathology of established AD. disorientation, mood swings, confusion, more serious
et de Santé Publique, Labex
Indeed, an effective therapy for AD is perhaps the greatest memory loss, behavioural changes, difficulties in DISTALZ, Lille, France (Prof P
unmet need facing modern medicine. Basic biomedical speaking and swallowing, and problems with walking. Amouyel MD); Department of
Epidemiology and Public
research has provided insights into the causes and Progressive accumulation of disability, with deterioration
Health, Faculty of Medicine,
pathogenesis of AD and other neurodegenerative in multiple cognitive domains, interferes with daily
Toulouse University Hospital,
diseases, but improved understanding of disease functioning, including social and professional Toulouse, France
mechanisms will be needed to develop safe and effective functioning.1 Thus, dementia substantially affects the (Prof S Andrieu MD); Wolfson
Centre for Age-Related Diseases,
disease-modifying treatments. Nonetheless, several drugs daily lives of patients, their families, and wider society.
King’s College London, London,
are currently in late phases of clinical development. Increasing age is the most important risk factor for AD UK (Prof C Ballard MD);
The Commission considered a range of challenges that and other dementias, and as life expectancy increases Cambridge Institute of Public
need to be addressed to reduce the burden of dementia, and demographic ageing occurs in populations around Health, University of
Cambridge, Cambridge, UK
and these challenges are discussed in detail in the main the world, the number of people with dementia is
(Prof C Brayne MD); Centre for
sections of our report: health economics (section 1), expected to increase. In 2015, almost 47 million people Healthy Brain Ageing and
epidemiology (section 2), prevention (section 3), genetics worldwide were estimated to be affected by dementia, Dementia Collaborative
(section 4), biology (section 5), diagnosis (section 6), and the numbers are expected to reach 75 million by Research Centre, University of
New South Wales, Sydney, NSW,
treatment (sections 7, 8), care (section 9), and ethics 2030, and 131 million by 2050, with the greatest increase
Australia (Prof H Brodaty MD);
(section 10). In panel 1 we summarise the key findings of expected in low-income and middle-income countries.2 Institut de la Mémoire et de la
the Commission, with recommendations about how In 2012 and 2015, the World Health Organization (WHO) Maladie d’Alzheimer, IM2A,
patient care and related research—from basic to clinical— presented reports in which it acknowledged this trend— INSERM, Institut du Cerveau et
de la Moelle Épinière,
in AD and other dementias should be organised in the sometimes described in terms of a fast-growing
UMR-S975, Groupe Hospitalier
future. A concerted effort to tackle dementia is needed, epidemic—and concluded that AD and other dementias Pitié-Salpêtrière, Université
with a substantial overall increase in government and should be regarded as a global public health priority.3,4 Pierre et Marie Curie-Paris 6,
www.thelancet.com/neurology Vol 15 April 2016 455
The Lancet Neurology Commission
Paris, France
(Prof B Dubois MD); School of Panel 1: Key recommendations
Nursing and Midwifery, La
Trobe University, Melbourne, Progress in dementia care, treatment, and prevention with a high risk of AD). At more advanced stages of disease,
VIC, Australia 1 All individuals with Alzheimer’s disease (AD) should have ethical considerations relate to improved and more timely
(Prof D Edvardsson RN); access to reliable and timely diagnosis and treatment, decision making for end-of-life care.
Department of Nursing, Umeå
irrespective of social inequalities. Accurate and timely 8 Public awareness of AD and other dementias needs to be
University, Umeå, Sweden
(Prof D Edvardsson); Division of diagnosis is a prerequisite for cost-effective care with improved through outreach activities such as public lectures
Neurology, Faculty of available interventions. The cost-effectiveness of new and open-house sessions in clinical care settings, and
Medicine, University of British
therapies will be uncertain when they are introduced and information provided via mass media, social media, and
Columbia, Vancouver, BC,
should not be a limiting factor for treatment of this group. patient organisations.
Canada (Prof H Feldman MD);
Department of Neurobiology, 2 Guidelines for the provision of dementia care are needed in
Development of an improved infrastructure for research
Care Sciences and Society, all countries as part of national policy strategies or national
Center for Alzheimer Research, 9 Harmonised international databases are needed for
plans. Such frameworks should promote coordination
Aging Research Center, population-based longitudinal studies of ageing and
Karolinska Institutet, between health-care, social-care, and other relevant sectors dementia to further understand the burden (eg, prevalence,
Stockholm, Sweden (eg, welfare benefits and housing), and include affordable
incidence, mortality), natural history (eg, identification of
(Prof L Fratiglioni MD, long-term funding plans for dementia care that span these
Prof M Kivipelto, genetic and clinical markers for early detection), and
sectors.
F Mangialasche MD, C Qiu MD); pathogenesis of AD and other dementias (eg, potential
Geneva University Hospitals 3 An infrastructure is needed to enable the use of contributions of cardiovascular risk factors, nutrition,
and University of Geneva, non-pharmacological interventions (eg, psychosocial,
psychosocial stress, and frailty).
Geneva, Switzerland behavioural, and environmental interventions, including
(Prof G B Frisoni MD); IRCCS 10 For optimum use of genetics in pre-symptomatic and early
multidomain approaches) for which clear evidence of
Centro San Giovanni di Dio (preclinical or prodromal) diagnoses, current and future
Fatebenefratelli, Brescia, Italy benefit already exists. With guidance and advice from public
treatment approaches, and dementia prevention, DNA and
(Prof G B Frisoni); McGill Center health authorities, evidence-based interventions should be
clinical data from epidemiological studies, clinical settings,
for Studies in Aging, put into practice with appropriate training, support, and
Alzheimer’s Disease Research and clinical trials need to be collected and stored
maintenance of fidelity.
Unit, and Douglas Mental systematically; a legal framework is needed to regulate the
Health University Institute, 4 Prevention studies need to start in midlife and have a long
use of data for research and to protect affected individuals
Montreal, QC, Canada duration to identify windows of opportunity for effective
and their families.
(Prof S Gauthier MD); Alzheimer interventions. Many modifiable risk factors—including high
Europe, Luxembourg City, 11 Scientific collaboration among international research groups
blood pressure, obesity, physical inactivity, and unhealthy
Luxembourg (J Georges BA); demands the development of appropriate infrastructures to
Department of diet—are shared among dementias, including AD, and other
enable more effective use of existing data and rapid
Neurochemistry, Inge Grundke- major late-life chronic disorders, such as heart disease and
Iqbal Research Floor, New York stroke. Public health efforts to promote healthier lifestyles recruitment of participants in multinational interventional
State Institute for Basic trials. Increased collaboration among governments, and
in midlife have the potential to improve the general health
Research, Staten Island, NY, between public and private institutions, will help to
USA (Prof K Iqbal PhD); status of the population in old age.
accelerate and increase the power of clinical research.
Department of Psychiatry, 5 Available biological markers for AD—including cerebrospinal
University of Cologne, Cologne, fluid and brain imaging biomarkers—need to be validated 12 Redundant research in AD drug development could be
Germany (Prof F Jessen MD); avoided by increased openness. Detailed results, outcomes,
and standardised for use in research and clinical practice,
German Center for and databases of clinical trials should be made broadly
Neurodegenerative Diseases and the search for novel biomarkers with high predictive
available immediately after studies have been completed in
(DZNE), Bonn, Germany value at pre-dementia stages needs to be supported and
(Prof F Jessen); Personal Social a manner that is accessible to researchers and the general
improved. Simple biomarkers (eg, in blood) are needed for
Services Research Unit, London public.
use in general practice.
School of Economics and 13 Clinical drug development and clinical trials should be
Political Science, London, UK 6 The discovery of a cure or an effective therapy for AD
coordinated internationally. Budgets for drug discovery,
(Prof M Knapp PhD); remains imperative. Ambitious multidisciplinary
Radboudumc Alzheimer Centre development, and clinical trials should be increased to allow
programmes in basic research are needed to learn more
and Department of Geriatric international cohorts, ethical and regulatory frameworks,
about the causes and pathological mechanisms of AD and to
Medicine, Radboud University and standardised methods to be established, which will
Medical Center, Nijmegen, identify new, valid treatment targets.
facilitate clinical trials and accelerate progress.
Netherlands (R Melis PhD, 7 Ethical considerations are of increasing importance as
Prof M Olde Rikkert MD); 14 Public, private, and corporate funding decisions should be
diagnosis and treatment shift to earlier disease stages, with
Laboratory of Chemical Biology based on evidence and scientific merit, rather than being
& Signal Transduction, The a risk of false-positive cases. Important ethical questions driven by advocacy, opinion, persuasion, or corporate
Rockefeller University, New need to be addressed in disclosing the genetic status of
considerations.
York, NY, USA (Prof T P Sakmar); patients (eg, in families with causal mutations or individuals
Department of Neurology and
Alzheimer Center, VU
University Medical Center,
Similar policy declarations have been made by the in 2015.2 The direct costs of medical and social care,
Neuroscience Campus,
Amsterdam, Netherlands European Union5 (EU) and by some individual countries. $487 billion,2 represent 0·65% of the aggregated global
(Prof P Scheltens MD); The global economic costs of dementia were estimated gross domestic products (GDP)—an enormous economic
Department of Psychiatry and to be more than US$600 billion in 2010,6 and $818 billion impact for a single group of disorders, especially given
456 www.thelancet.com/neurology Vol 15 April 2016
The Lancet Neurology Commission
that 87% of the costs occur in high-income countries. of this Commission—written by leading health-care the Behavioral Sciences and
Care for people with dementia is provided by several professionals representing the areas of health economy, Department of Neurology,
sectors in society, with the social-care (long-term care epidemiology, genetics, biology, diagnosis, treatment, Keck School of Medicine,
Leonard Davis School of
and home services) and informal-care (provided by non- care, and ethics—is to inform, guide, and stimulate public
Gerontology of the University
professional caregivers) sectors accounting for the debate about the growing burden of dementia in Europe, of Southern California, Los
greatest proportion of costs—even greater than the cost with a focus on AD as the leading cause of dementia. Angeles, CA, USA
(Prof L S Schneider MD); Center
of direct medical care.6 In cost-of-illness studies, total
for Alzheimer Research and
societal cost estimates for dementia in Europe in 2010 Section 1. Health economics of Alzheimer’s disease
Treatment, Department of
were between $238·6 billion6 and €105·6 billion.7 AD has a substantial economic impact for each person Neurology, Brigham and
The economic costs of caring for a growing number of and family affected. A 2011 study8 of a multinational Women’s Hospital and
Massachusetts General
people with AD and other dementias are formidable, but (Spain, Sweden, the UK, and the USA) sample of
Hospital, Harvard Medical
the combined economic and societal burden of dementia 1222 patients estimated that societal costs amount to
School, Boston, MA, USA
is more daunting still, corresponding to the aggregate about €14 500 per year in patients at home with a high (Prof R Sperling MD); Danish
burden of people with dementia and their next of kin. No level of autonomy in activities of daily living (ADL), but Dementia Research Centre,
Department of Neurology,
cure or substantial symptom-relieving treatment is rises up to €72 500 per year in patients who need
Rigshospitalet, University of
available for AD or other dementias, and the progressive residential care. In 2014, the direct cost of AD for payers Copenhagen, Copenhagen,
nature of dementia can profoundly affect the lives of in the USA alone was estimated to be $214 billion.9 For Denmark (Prof G Waldemar MD);
patients and their families over many years. The impact comparison, the global direct cost (resources used for Clinical Neurochemistry
Laboratory, Department of
of this terminal disorder is already enormous, and in prevention and treatment) and indirect cost (resources
Neuroscience and Physiology,
view of the predicted rise in prevalence (proportion of the lost owing to morbidity or mortality, such as lost work The Sahlgrenska Academy at
population with the disorder) over the next few decades, productivity) of cancer was estimated at $290 billion in the University of Gothenburg,
AD and other dementias represent a huge challenge for 2010, the estimate for diabetes was $472 billion, and that Mölndal, Sweden
(Prof H Zetterberg MD); and UCL
any society. for all cardiovascular disease (including cerebrovascular
Institute of Neurology, Queen
To tackle the global burden of dementia and its disease) was $863 billion.10 Square, London, UK
economic and societal ramifications, substantially For diabetes, the direct costs amounted to 80% of the (Prof H Zetterberg)
increased investment in research is needed to accelerate global economic burden of the disease (almost 90% in Correspondence to:
the discovery and development of effective treatments, high-income countries) in 2010. Thus, indirect costs Prof Bengt Winblad, Department
of Neurobiology, Care Sciences
coupled with a broad, evidence-based public health constituted a small proportion of the overall economic
and Society, Center for Alzheimer
approach to disease prevention. Progress in under- burden.10 These substantial direct costs reflect the Research, Division of
standing the causes and disease mechanisms of AD and availability of effective medical therapy to manage glucose Neurogeriatrics, Karolinska
other dementias is needed to underpin new diagnostic control, prevent complications when possible, and treat Institutet, SE-141 57, Huddinge,
Sweden
and therapeutic strategies. Importantly, there is an complications when they occur. By contrast, only 16% of
bengt-winblad-
opportunity and a need to shift the treatment- costs for AD were direct medical costs, 41·7% were [email protected]
development paradigm: to establish stronger proof of informal-care costs, and 42·3% were social-care costs
concept before launching expensive phase 3 trials, to (section 9).10 Thus, the costs of AD are driven mainly by
develop multimodal combination treatment approaches, compensating for lost function rather than treatment or
and to allow precompetitive data sharing to accelerate prevention. The entire global market for pharmaceuticals
learning and improve the likelihood of success. and diagnostics for AD was estimated to be $10 billion in
At present, awareness about the many challenges of 2015, or roughly 1% of the total costs of the disease.11 This
dementia that need to be (and can be) addressed varies highlights not only the absence of effective therapy for AD
substantially among patients and their family members, (section 7), but also the opportunity for new treatment
health-care professionals, politicians, and other options to provide benefit by improving health outcomes
stakeholders. It is essential that new knowledge from and shifting from indirect to direct costs.
research is quickly translated into clinical practice and
disseminated broadly. In all education programmes, Costs of diagnosing AD
health-care professionals should be made aware of the Insufficient diagnostic services remain a major barrier to
best available evidence-based care. Our public-sector the provision of appropriate care for patients with
representatives and policy makers are ultimately dementia. Although disease-modifying treatments are
responsible for ensuring that clinical and basic research not available at present, timely and correct diagnosis is a
advances are effectively implemented into public health prerequisite for access to support services (eg, help with
policy. Such an aim demands that our research agenda is living arrangements) and symptomatic treatment
broad and engages a wide range of sectors. Policy makers (sections 6–9).
in Europe must support universal access to better It is estimated that only 20–50% of patients living with
diagnosis, care planning, and evidence-based treatment. dementia have a documented diagnosis in primary care,
Simultaneously, European countries must implement and this proportion is substantially lower in low-income
For more on the SveDem
disease-prevention programmes and provide incentives and middle-income countries.12 On the basis of data from
registry see http://www.ucr.
for drug development and clinical trials. The overall aim the Swedish Dementia Registry (SveDem), the average uu.se/svedem/
www.thelancet.com/neurology Vol 15 April 2016 457
The Lancet Neurology Commission
cost of diagnosing a case of AD in primary care was a case of AD, and a calculation of the cumulative costs as
estimated to be €753, whereas the corresponding cost in each new diagnostic procedure is added, starting in
specialist care was €1298 in 2010.13 Table 1 presents an primary care and transitioning to specialist care.13 Even
example from Sweden of the costs involved in diagnosing though the maximum diagnostic cost (assuming all
available diagnostic procedures are done) is more than
Unit cost (€) Cumulative €5000, which is high compared with the costs of
cost (€) diagnosing other common chronic disorders for which
Primary care diagnostic biomarkers are available (eg, diabetes), this
Visit to family physician 122 122 cost would be only a small fraction of the lifetime costs of
care incurred by a patient with AD.
Routine blood tests 33 156
The economic costs for individuals with dementia who
CT 200 356
remain undiagnosed are largely borne by caregivers and
Visit to occupational therapist 144 500
by patients themselves. With the possible future
Specialist care
availability of effective treatments, early identification of
Visit to specialist physician 367 867
AD pathological changes becomes even more important.
Neuropsychological testing 422 1289
The cost-effectiveness of treatment will ultimately
EEG 100 1389
depend on the strategy for identification of patients
CSF tests 622 2011
eligible for that treatment.
MRI 289 2300
SPECT 378 2678
Indirect and intangible costs of AD
PET 1711 4389
Methodological challenges exist in measuring the costs
Analyses of amyloid markers 1166 5555
of informal care for patients with AD, both in the
According to level of primary and specialist care, and cumulative cost as each new estimation of the amount of time spent caring for a
diagnostic procedure is added.13 Costs in Swedish kronor have been converted to patient and in how this time should be valued. Studies
euros on the basis of the exchange rate €1=9kr. Figures are rounded to the
have suggested that caregivers would be prepared to pay
nearest euro. CT=computed tomography. EEG=electroencephalography.
CSF=cerebrospinal fluid. MRI=magnetic resonance imaging. SPECT=single- between £59 and £144 per hour, depending on the
photon emission computed tomography. PET=positron emission tomography. country of study, for reductions in the time spent on
caregiving tasks.14 In addition to the direct and indirect
Table 1: Costs of diagnosing a case of Alzheimer’s disease
economic costs of AD, the associated burden of illness
includes the intangible costs of reduced quality of life
Panel 2: QALYs and DALYs explained and mortality. In health-economic evaluations, these
costs are often quantified in terms of quality-adjusted life
One quality-adjusted life-year (QALY) corresponds to a year spent in perfect health. Years
years (QALYs; panel 2).
spent in less than perfect health states (eg, with Alzheimer’s disease) are assigned a
Health utility weights for disease states in AD (panel 2)
weight (health utility), calculated on the basis of preferences for the health state. A
calculated with the Health Utilities Index (in which
weight of 1 signifies perfect health, whereas a weight of 0 means that the health state is
1 equals perfect health and 0 is equivalent to death) range
equivalent to death. Weights below 0 are also theoretically possible (ie, a health state
from 0·69 in mild disease to 0·14 in severe disease.15
worse than death).
Using a different instrument, EuroQoL’s EQ-5D, weights
The disability-adjusted life year (DALY) is a construct that, like the QALY, summarises have been estimated as ranging from 0·69 in mild
morbidity and mortality in terms of a single index. The number of DALYs is calculated as: dementia to 0·33 in severe dementia.16 For comparison,
the population mean health utility weight in the age group
DALYs = YLL + YLD
65–74 years is 0·78 and the utility weight for legal
YLL is years of life lost—an estimate of the average years a person would have lived if he or
blindness has been estimated as 0·26.17 DEMQoL is an
she had not died prematurely. The formula for YLL (without including social preferences) is:
instrument that, unlike the Health Utilities Index and the
YLL = N × L EQ-5D, was specifically developed to measure quality of
life in dementia, and a tariff linking responses on the
N is number of deaths in a particular population and L is the standard life expectancy at
DEMQoL to health utilities has been developed.18 Most
age of death (in years) for that population.
studies have relied on proxy assessments of the health
YLD is years of life with disability. To estimate the YLD for a particular disease over a
status of patients with AD. The agreement between
specific period, the number of incident cases in that period is multiplied by the mean
patient and proxy ratings with the EQ-5D and DEMQoL
disease duration (until remission or death) and a disability weight reflecting the severity
has varied across studies; however, agreement is generally
of the disease on a scale from 0 (perfect health) to 1 (dead). The basic formula for YLD
poorer in severe disease states. The quality of life of
(again, without applying social preferences) is:
caregivers themselves can also be affected. Studies have
YLD = I × DW × L shown an increased prevalence of depression in caregivers
of patients with AD.19 However, no direct link between
I is the number of incident cases, DW is disability weight, and L is the average duration of
caregiver health utilities and the severity of dementia in
disease.
the patient whom they care for was noted using the
458 www.thelancet.com/neurology Vol 15 April 2016
The Lancet Neurology Commission
EQ-5D.16 More specific and sensitive instruments are
Total DALYs due to AD and Proportion of GDP per Intangible
needed to measure the potential disutility associated with
DALYs other dementias DALYs due to person cost (US$
caregiving. (millions) (millions) dementia (%) (US$) billion)
WHO has estimated the disability weights (where 0
World 1523 11·16 0·7% ·· 550
equals no disability and 1 equals complete disability) in
High income 122 4·39 3·6% 38 182 503
AD and other dementias as 0·082 for mild dementia,
Upper-middle income 121 1·04 0·9% 7289 23
0·346 for moderate dementia, and 0·438 for severe
Lower-middle income 452 3·73 0·8% 1924 22
dementia.20 In 2012, AD and other dementias were
Low income 828 2·00 0·2% 596 4
estimated to be the cause of 18 million disability-adjusted
life years (DALYs) globally—years lost because of ill Data obtained from the World Bank. Intangible costs are valued at three times the GDP per person per DALY.
health, disability, or early death (panel 2). This is just DALY=disability-adjusted life year. AD=Alzheimer’s disease. GDP=gross domestic product.
0·7% of all DALYs; however, in European women aged Table 2: DALYs due to, and intangible cost of, Alzheimer’s disease and other dementias in world regions
70 years or older, AD causes 6% of DALYs.21 according to World Bank income level
Valuing each DALY at three times the gross domestic
GDP per person, the intangible cost of illness of AD and of drug therapy—it is crucial that the long-term value of
other dementias is around $550 billion (table 2).22 Thus, investment in medical care is recognised.
the intangible cost of dementia might be almost as high The main value of therapies that affect the long-term
as the total direct and indirect costs of care for AD. course of disease will lie in shortening the time spent in
the severe stages of dementia. However, because this
Current challenges and future goals outcome is not being studied in trials of new drugs, value
New treatment modalities and strategies for prevention will need to be estimated through forecasting models
and care will be key to reversing the increasing prevalence before treatments are even introduced in clinical practice.
(and associated morbidity) of AD (section 2). As new The accuracy of such models depends on the availability
options for diagnosis and treatment become available of long-term, high-quality data for disease progression
(sections 6, 7), they will undergo two stages of assessment, rates, costs, and health outcomes. Several epidemiological
the first by regulatory agencies to determine risk and studies have followed up patients with AD longitudinally
benefit, and the second by health technology assessment from diagnosis until the end stages (eg, the Swedish
(HTA) agencies and payer organisations to determine National Study on Aging and Care [SNAC]23 and the
value relative to the current standard of care and to European Alzheimer’s Disease Consortium–Impact of For more on the European
inform coverage and reimbursement decisions. Tools are Cholinergic Treatment Use [EADC-ICTUS]24 studies). Far Alzheimer’s Disease
Consortium see http://www.
needed that allow determination of the value of these new fewer data are available from the very early phases of AD,
eadc.info/
technologies with a sufficient degree of certainty to make before the onset of dementia. New therapies are being
correct coverage decisions. If a new treatment receives assessed in preclinical states of dementia, and thus new
regulatory approval but faces negative reimbursement data sources are needed to model accurately the long-term
decisions owing to inadequate demonstration of value, benefits of these treatments.
uptake of the new treatment will be low and patients and Results from economic models are highly contingent
caregivers will miss out on potential treatment benefits. on assumptions about long-term treatment benefits that
An important issue in establishing the value of new will not be immediately available from clinical trials. For
treatments for AD is that the benefits will largely fall instance, the potential impact of treatment on overall
outside the health-care sector, because most of the mortality has important implications for costs of care.25 If
potentially preventable costs of dementia relate to long- treatment improves survival but prolongs the time spent
term care and burden on informal caregivers. Increasing with severe dementia, it might bring only marginal health
availability of treatment options with the potential to benefits for patients but increase care costs substantially.
change the long-term course of AD will probably However, if late-stage morbidity is compressed and
necessitate substantial upfront investments in diagnosis patients spend proportionally more time in less severe
and medical expenditure, at least in the short term, and the states, cost savings could be substantial. Thus, the goal of
full benefits could take years or decades to be realised. The therapy is not merely to slow disease progression, but to
benefits of reducing the need for informal caregiving will minimise the time spent with severe dementia and
not appear on any budget and cannot easily offset maximise the time with conserved cognitive resources,
treatment costs. Furthermore, for funding decisions a autonomy in ADL, and quality of life.
short time horizon is sometimes used or discounting Patients who receive new therapies will need to be
applied, such that the value of future costs and effects is followed up in clinical practice, and data will need to be
decreased (relative to current costs and effects) to reflect gathered for resource use and health outcomes to gain
negative time preferences. Although it is common for further understanding of the value provided as new
budgeting constraints to prevent the flow of funds between treatment options are implemented. Few countries have
so-called silos—eg, savings made through reduced need the infrastructure available at present to follow up
for long-term care being used to finance increasing costs patients prospectively, as can be done through SveDem.13
www.thelancet.com/neurology Vol 15 April 2016 459
The Lancet Neurology Commission
(2) The aim should be to offer accurate, reliable, and
timely diagnosis to patients to provide cost-effective care
with available therapies and to realise the potential value
of new disease-modifying therapies.
5000–10 000 (3) The cost-effectiveness of new therapies will be
10 000–50 000 uncertain when they are introduced, because experience
50 000–100 000
100 000–500 000 of long-term benefits will be limited, whereas upfront
500 000–1 000 000 treatment costs can be substantial. Follow-up with data
1 000 000–15 000 000
collection in clinical practice on resource use and patient-
relevant outcomes should be done routinely to facilitate
the assessment of treatment benefits and cost-
effectiveness in clinical practice.
Section 2. Epidemiology of Alzheimer’s disease
and dementia
The burden of AD and other dementias, which is
projected to surge in the coming decades, poses a
serious threat to the sustainable development of
economies and the social welfare systems of Europe.
Epidemiological studies generate knowledge about the
occurrence (eg, prevalence and incidence), distribution
(eg, demographic, geographical, and temporal
variations), determinants (eg, genetic and non-genetic
risk or protective factors), health economics (eg, costs
of health care and cost-effectiveness of treatment and
intervention), and intervention strategies (eg, thera-
peutic and preventive interventions) of AD and other
dementias. Such studies are therefore key to
understanding and tackling the challenges of this
Figure 1: Number of people with dementia in 28 European countries in 2013
Estimates of the total number of people with dementia in each of 28 European countries were obtained from devastating disorder. In EU countries, knowledge about
Alzheimer Europe.26 the number of people with dementia is available, but
fewer data have been reported on the prevalence of
Furthermore, data collected might not immediately be dementia in eastern European countries (figure 1).26 To
relevant for other countries because of international cope with the challenges of AD and other dementias,
differences in care organisation and delivery. policy makers need this information, which will help to
Observational studies, such as EADC-ICTUS, in which guide the design and development of care and social
data are gathered across several countries will be an welfare systems, and allow appropriate use of scarce
important addition. resources for the care of people with dementia.
Specialist terms that are key to our discussion are
Summary and recommendations defined in panel 3.27,28
The societal costs of AD will increase substantially as Although AD diagnosed by current clinical criteria
global prevalence increases. Despite some evidence of a (section 6) accounts for 50–70% of all dementia cases,
decrease in incidence (the number of individuals who autopsy-verified studies have suggested that mixed
develop a disorder during a particular period) in Europe dementia, with vascular and neurodegenerative AD
and the USA, a substantial increase in prevalence seems pathology, accounts for most dementia cases. Additionally,
unavoidable as people live longer. At present, only about AD with onset before age 65 years (early-onset AD)
16% of costs associated with AD are direct (related to accounts for up to 5% of all cases. Most of the early-onset
resources used for prevention and treatment); most costs AD cases are familial AD—a rare form of AD caused by
are indirect, including care and societal costs. New mutations in the amyloid precursor protein (APP),
approaches to diagnose and treat AD should be assessed presenilin 1 (PSEN1), or PSEN2 genes (section  4).29
in the context of new paradigms for cost–benefit analysis Patients with non-familial (sporadic) early-onset AD have
to optimise the use of resources and improve quality of no reliable family history and usually have an older age of
life for patients with AD. onset than do patients with familial early-onset AD.30
(1) Economic assessments of new methods to diagnose Late-onset sporadic AD (from 65 years of age) is the most
and treat AD should include all costs of the disorder and common form of AD, accounting for about 95% of all
adopt a broad measure of outcome that captures full cases. The enormous costs of medical and social care for
societal benefits of treatment. patients with early-onset and late-onset AD depend on
460 www.thelancet.com/neurology Vol 15 April 2016
The Lancet Neurology Commission
Panel 3: Definitions
Allele: any of the alternative genetic variants of a specific gene forecasts from the previous round and the reasons they
or locus. provided for their judgments. Through discussion and
reconsideration of their answers to the stated questions, a
Attributable fraction of risk: the fraction of cases that would
consensus is achieved.
be avoided if a risk factor could be totally suppressed.
Epigenetic modifications: variations in genetic make-up that
Autosomal dominant: a mode of inheritance in which a single
do not include the DNA sequence (code) itself, such as DNA
copy of a mutant allele located on one of the 22 pairs of
methylation (methyl groups added to the nucleotide cytosine)
autosomes (non-sex chromosomes) is sufficient to cause a
and modification (eg, acetylation) of proteins that bind to the
disease. In diseases with mendelian autosomal dominant
DNA. Such variations, which can be heritable, make the DNA
transmission, which does not depend on the sex of the carrier
more or less accessible for activation (transcription).
parent, each child of an affected parent has a one in two (50%)
risk of inheriting the disease. Implicit memory: an aspect of memory in which previous
experiences help with the performance of a task even though
Brain reserve: the brain’s ability to tolerate age-related or
there is no conscious awareness of these experiences.
disease-related pathology before the threshold is reached for
clinical symptoms to appear. Brain reserve is directly related to Life-course approach: in epidemiology, a life-course approach
brain size, number of neuronal cells, or density of synapses, such is used to study the biological, physical, and social hazards
that a large brain or large number of cells is able to tolerate during gestation, childhood, adolescence, young adulthood,
more pathology.27 and midlife that might affect risks for chronic diseases and
health outcomes in later life. The approach aims to identify the
Cerebral small vessel disease: a cerebrovascular disease
underlying biological, behavioural, and psychosocial processes
characterised by a range of neuroimaging, pathological, and
that operate across the lifespan.
associated clinical features. Signs of cerebral small vessel disease
on conventional magnetic resonance imaging (MRI) scans Locus: in genetics, a locus is a specific location or position of a
include small subcortical infarcts, white matter hyperintensities, gene or DNA sequence on a chromosome, analogous to the
lacunes, prominent perivascular spaces, and cerebral specific coordinates of a geographical location on a map.
microbleeds.28
Mediterranean diet: a modern nutritional recommendation
Codominance: an additive relation between variants of one based on traditional dietary patterns of the Mediterranean
gene (alleles), in which an increased effect on phenotype is region. Key components of the diet include olive oil, vegetables,
noted with increasing number of alleles (ie, two copies of the and fish, with moderate consumption of dairy products (mostly
allele result in a more severe phenotype than one copy of the as cheese and yoghurt) and low consumption of meat products.
allele).
Minor allele frequency (MAF): the frequency of the less
Cognitive reserve: the brain’s ability to perform cognitive tasks common allele (genetic variant) in the population. The term
adequately despite neuropathological damage to the brain. usually refers to the less common of two different alleles of a
Cognitive reserve represents an enhanced ability to use brain single-nucleotide polymorphism.
networks more efficiently or to recruit alternative networks. It
Population attributable risk (PAR): the proportion of cases
is associated with high education, mentally stimulating
that would not occur in a population if a factor were completely
activity, physical and mental leisure activities, and rich social
eliminated from the population. The PAR or population
networks.27
attributable fraction (%) in a population depends on the
Cognitive stimulation: an intervention for people with prevalence of the risk factor (P) and the strength of its
e
dementia that offers various interactions and activities that are association (relative risk) with the disease (RR). The formula is:
e
designed to keep the brain active. The notion that cognitive
P (RR–1)
stimulation is beneficial for people with dementia is based on PAR = e e
the use-it-or-lose-it philosophy. [1 + Pe (RRe–1)]
Confounder: a factor related to both an exposure of interest Precision medicine: an approach to health care, also known as
and an outcome (eg, a disease). The factor (confounder) might personalised medicine, in which choices for treatment and
explain all or part of an association between an exposure and an prevention are tailored to the individual. When a trait or
outcome; a spurious relation between exposure and outcome disease is influenced by genetic make-up, health-care decisions
might be inferred if the confounder is not taken into account. can potentially be made on the basis of the specific genetic
background of the individual (ie, genomics). The notion can be
Delphi consensus: a structured method to achieve expert
extended to transcriptomics, proteomics, metabolomics, and
consensus. Experts answer several iterations of questions, with
so on.
a facilitator providing an anonymous summary of the experts’
(Panel continues on next page)
www.thelancet.com/neurology Vol 15 April 2016 461
The Lancet Neurology Commission
(Panel 3 continued from previous page)
Reality orientation: a programme designed to improve Single-nucleotide polymorphism (SNP): a genetic variation in
cognitive function in people with dementia. The aim is to use a single-nucleotide base pair. The DNA sequence (code) of the
verbal interaction, aids such as calendars and clocks, and human genome is made up of billions of nucleotide base pairs.
sensory stimuli such as distinctive sights, sounds, and smells to Generally there are two alleles for each SNP.
improve orientation and sensory awareness.
Somatic mutation: acquired genetic variation that occurs
Reminiscence therapy: a therapeutic approach in which tools during cell division (mitosis) in the cells of the body and is not
such as life histories, shared memories, and familiar objects transmitted to the next generation because for trans-
from past periods are used to improve wellbeing, usually in a generational transmission the mutation has to be present in
group setting. the gonadal cells.
disease severity (section 1);31 however, prevalence data of not been completely clarified, largely as a result of the
dementia according to severity or stage are scarce.32,33 short periods of follow-up for most studies.51–53
Furthermore, knowledge about the effect of potential
Living with dementia compensatory factors (eg, social engagement, cognitive
Several population-based studies have suggested that training, and mentally stimulating activity) is still poor.
people aged 65 years or older survive a median of In many countries, health-care policy aims to avoid or
3–9 years after a diagnosis of dementia, with some living postpone admission of patients with dementia to nursing
for as long as 20 years.34–42 Clinical deterioration of people homes and institutions. Informal care (eg, home care
with dementia, and particularly of people with AD, is provided by family and friends) tends to be less costly than
progressive, although the rate of decline in mental and formal care (eg, care provided in nursing homes or
physical function can vary. According to WHO, people institutions) for the social security system,54 although this
can generally expect to be in the mild or early stage of is not necessarily true when the costs are assessed from a
dementia (eg, forgetful, some language difficulties, and societal perspective.55 In addition to health-care and social-
mood changes) for the first year or two, the moderate or care policies, the proportion of people with dementia
middle stage (eg, very forgetful, increasing difficulty with living at home depends on several factors, including the
speech, and help needed with self-care activities) from characteristics of patients (eg, severity of cognitive and
the second to the fourth or fifth years, and the severe or functional disability) and caregivers (eg, perceived burden
late stage (eg, serious memory disturbances and nearly and coping strategies), and cultural factors.
total dependence and inactivity) from the fifth year Worldwide, most people with AD and other dementias
For more on the Kungsholmen onwards.3 Data from the Kungsholmen Project of are cared for at home, usually by a spouse or a daughter.
Project see http://www. community dwellers aged 75 years or older in central In low-income and middle-income countries, the
kungsholmenproject.se/
Stockholm showed that people with incident dementia estimated proportion of people with dementia living at
(ie, cases newly diagnosed during the study) spend a few home is around 94%, compared with around 66% in
months in the very mild stage of dementia, around high-income countries.56 The proportion of people with
2 years in the mild phase, 1–2 years in the moderate dementia cared for at home is higher in rural than in
stage, and a year in the severe stage.43 urban areas.57 A longitudinal study in Australia showed
Women with dementia live longer than men, because that several baseline clinical features of dementia
they tend to survive longer in the severe stage.43,44 More predicted a shorter time before admission to an
than 50% of dementia cases are estimated to reach the institution, such as lower cognitive and functional ability,
severe stage within 3 years. A population-based study45 of more neuropsychiatric symptoms, and use of
prevalent dementia cases (ie, those diagnosed at the start antipsychotic drugs.58 Moreover, greater deterioration in
of the study) showed an increase in the proportion of these factors within the first 3 months after baseline was
severe dementia from 19% at baseline to 48% after also predictive of shorter time to admission to an
3 years, and 78% after 7 years. By contrast, in a population- institution, which suggests that rate of disease progression
based prospective study46 of dementia progression (Cache is an important factor.
County), 40–50% of patients with incident AD deteriorated
slowly in cognitive and functional ability (eg, a decline of Dying with dementia
1 point per year on the Mini-Mental State Examination Several follow-up studies have consistently shown that
[MMSE] score and the Clinical Dementia Rating Sum of the extent to which dementia shortens life expectancy
Boxes). Although several studies have been done,45,47–50 the depends on age at onset, sex, and dementia subtype.44
For more on the Cognitive effect of cognitive decline on specific tasks of self-care Data from the UK Medical Research Council Cognitive
Function and Ageing Studies ADL (eg, eating, dressing, toileting) or instrumental ADL Function and Ageing Study (MRC CFAS) showed that
see http://www.cfas.ac.uk/
(IADL; eg, shopping, cooking, basic housework) has still the prevalence of dementia and severe cognitive
462 www.thelancet.com/neurology Vol 15 April 2016
The Lancet Neurology Commission
impairment in the period before death rises steeply with Temporal and geographical variations
age; by age 90 years, around 60% of people died with The age-standardised prevalence of dementia for people
dementia or severe cognitive impairment.59,60 Finally, not aged 60 years or older is 5–7% in most regions of the
only dementia shortens life expectancy: a subtle world. In the past decade, the work of the 10/66 Dementia For more on the 10/66
decrement in global cognitive function, even in the Research Group has contributed to understanding of the Dementia Research Group see
http://www.alz.co.uk/1066/
absence of clinically recognised impairment, is also epidemiology of dementia in low-income and middle-
strongly associated with shorter survival.61 income countries, such as Brazil, India, and China.69–71
The potential years of life lost (YLL)—ie, the average Systematic reviews and meta-analyses provide more
number of additional years a person would have lived if precise global and regional estimates of dementia
he or she had not died prematurely—because of dementia prevalence.3,5,72,73 They also show similar patterns of age-
in people aged 75 years or older has been estimated at specific prevalence of AD and dementia across worldwide
3–5 years.43,44 A Swedish study of people aged 75 years or regions, although substantial variations are evident
older suggested that the impact of dementia on lifespan among the oldest old (90 years or older; figure 3).72–75
(YLL 3·41) is similar to that of cardiovascular disease Higher prevalence and incidence of dementia and AD in
(YLL 3·58) but lower than that of cancer (YLL 4·40).43 women than in men, especially among the oldest old,
Mortality risk in patients with dementia or cardiovascular
disease is twice as high as that of people without these
8 Mean survival time
disorders, whereas patients with a diagnosis of cancer
Years of life lost
have a mortality risk three times higher than that of
people without cancer.43 Furthermore, the estimated years 6 5·4 5·7
lived with or lost because of one of these disorders is most 4·84·9 4·7
dependent on age at diagnosis, being higher among the Years 4 3·8 3·4 3·2
younger old (those aged 75–84 years) than in the oldest 2·8 2·7 2·8
old group (85 years or older; figure 2).43 This finding is 2 1·8
supported by a 2014 study in the USA showing that the
mortality risk for AD was higher for younger old
0
participants than for the oldest old participants (relative Dementia CVD Cancer Dementia CVD Cancer
risk 4·30 vs 2·77; p<0·05).62
75–84 years ≥85 years
AD and other dementias are substantially under-
reported on death certificates and medical records, Figure 2: Mean survival time and years of life lost to dementia, cardiovascular
although the situation has improved in the past disease, and cancer
20–30 years as a result of increasing awareness of the Data are stratified by two age groups.43 In people aged 75 years or older, the
effect of dementia on lifespan is similar to that of CVD, but lower than that of
disease among health professionals and the public. The
cancer. Years of life lost is an estimate of the average additional years a person
contribution of dementia to mortality is difficult to assess would have lived if he or she had not died prematurely. It is an alternative to
solely on the basis of death certificates, because dementia death or mortality rates, but gives more weight to deaths that occur among
young people. Years of life lost can be estimated from the number of deaths
is rarely thought of as an immediate or an underlying
multiplied by a standard life expectancy at the age at which death occurs.
cause of death in this context.63 Indeed, older people
CVD=cardiovascular disease.
often have different chronic and acute illnesses that
might be related to the dementia process64 and a direct or
80 China
indirect cause of death. A population-based study
UK
estimated that the population attributable risk (%) of 70 Eastern Asia
death owing to AD was about 36% for people aged USA
60 Western Europe
75 years or older, and that in the USA, AD might Latin America
contribute to almost as many deaths as does heart disease %) 50 Asia-Pacific
or cancer.62 Similarly, in a US nationwide study of nce ( 40
iensdtiimviadtueadl sto a cgoemd p65ri syee a3r2s% o ro fo aldlle dr,e datehasth ins w20it1h0 ,A wDit hw tehree Prevale 30
proportion projected to reach 43% by 2050.65 In 2013, the
20
US Alzheimer’s Association reported that AD was the For more on the Alzheimer’s
sixth leading cause of death across all ages, and the fifth 10 Association see https://www.
leading cause of death for people aged 65 years or older alz.org/
0
in the USA.66 In the UK, the rank (among all other 60–64 65–69 70–74 75–79 80–84 85–89 ≥90
diseases) of the age-standardised YLL for AD increased Age (years)
from 24th in 1990, to 10th in 2010.67 When death with
Figure 3: Age-specific prevalence of dementia by world region and in major
dementia is examined, the proportion of deaths
countries
attributable to dementia reached around one-third in Patterns of age-specific prevalence of dementia are similar across worldwide
people aged 85 years or older.68 regions, but vary substantially among the oldest old (age ≥90 years).72–75
www.thelancet.com/neurology Vol 15 April 2016 463
The Lancet Neurology Commission
have been reported in several studies in Europe and Asia, incidence of dementia among community-dwelling older
although data about sex differences have been less people.68,84,86 Given the diversity in social service systems
consistent in North American studies.76 and economic development across Europe, epi demio-
Study of the secular trends and geographical variations logical studies of dementia and AD in eastern and middle
of dementia occurrence and their determinants is crucial European countries are needed.98,99
for policy development in a world that faces a rapid
increase in the absolute number and proportion of older Asia-Pacific region
adults in the population. Thus, there has been increasing In mainland China, the prevalence of dementia and AD
interest in investigating the time trends of dementia increased steadily across all age groups of people aged
occurrence (eg, incidence and prevalence; table 3)68,77–92 and 55 years or older from the 1990s to 2010,89 although the
possible geographical differences in dementia distribution reported trends might be attributable partly to
in the past few years.74 Although findings from various methodological variations during the periods of study
regions across the world have not been consistent, the (eg, diagnostic criteria, age range, and sampling
results of several population-based community surveys methods).90 The number of people with dementia was
point to a stable or declining age-specific prevalence or estimated to have increased by 63·5% from 2000 to 2010
incidence of dementia among elderly people in Europe in China—compared with an average increase of 46·5%
and North America.93–95 Identification of temporal and worldwide during almost the same period72,73—largely
geographical variations in the prevalence and incidence of owing to the fast pace of population ageing in China.
dementia will help to establish modifiable risk and Rural and urban differences in the prevalence of
protective factors for dementia disorders, and could help dementia and AD are supported by a large-scale study
to shape public health policy in Europe and elsewhere. from China,100 which suggested that early experience of,
or exposure to, rural living (with low education and
North America socioeconomic status) might contribute to the association
A decline in the prevalence of dementia and cognitive between rural life and an increased risk of late-life
impairment has been reported in a few studies from the dementia and AD. In Hong Kong, a systematic review88
USA,77,96,97 and another study suggested a stable age- showed that the prevalence of clinically diagnosed
adjusted prevalence of dementia and AD in African dementia among community-dwelling people aged
American people aged 70 years or older from 1992 to 70 years or older increased from 4·5% in 1995, to 9·3%
2001.78 Additionally, several population-based studies in 2005–06. In Japan, the population-based Hisayama
from the USA have shown a decline (2–3% per annum) study91 suggested that the age-specific prevalence of all-
in the incidence of dementia and AD from the 1990s cause dementia and specific AD significantly increased
through the 2000s.79,80 More recently, two studies from from the early 1990s to 2005 in a general population of
the USA provide direct evidence supporting the declining elderly people. After all methodological variations were
trend of age-specific incidence of dementia starting even carefully assessed, an increasing prevalence of dementia
from the 1970s.81,82 in Japan was confirmed by a systematic review.92 These
findings suggest that previous estimates of dementia
Europe burden and long-term trends in dementia occurrence
Two population-based surveys68,85 in Sweden showed a across the world, especially in the Asia-Pacific region,
stable age-specific prevalence of dementia over the past were probably underestimates.101
20–30 years. Repeated cross-sectional surveys83 in 1988
and 1994 in Spain suggested an age-standardised stable Determinants of temporal and geographical variations
prevalence of dementia in women but a decreased Many factors can affect estimates of the occurrence of
prevalence in men. Finally, the large-scale MRC CFAS dementia, so it is no surprise that temporal trends vary
study86 provided evidence that a cohort effect might exist within and between countries. For instance, the upward
in the age-specific prevalence of dementia among trend in the prevalence of dementia from the 1990s to 2010
community residents, such that later-born populations in China is consistent with the time trends for increasing
had a lower likelihood of prevalent dementia than those prevalence of stroke and ischaemic heart disease, and
born earlier in the past century, whereas the prevalence related lifestyle and metabolic risk factors (eg, smoking,
of dementia among older people living in care settings physical inactivity, obesity and overweight, hypertension,
increased. However, the study showed no evidence of diabetes), over similar periods,102 together with a fast pace
variations in the incidence or prevalence of dementia of population ageing in China. Similarly, a substantial
across five regions in England and Wales. A systematic reduction in the prevalence of dementia in England from
review74 revealed evidence of geographical variations in 1991 to 2011, and the suggested reduction of dementia risk
the incidence or prevalence of dementia and, specifically, in the Netherlands and Sweden, imply that changes in
a higher risk of AD in rural as opposed to urban areas. health behaviours (eg, smoking cessation, physical
Studies from the Netherlands, Sweden, and England activity), improved management of cardiov ascular risk
have also provided evidence suggesting a declining factors (eg, hypertension, high cholesterol), and reduced
464 www.thelancet.com/neurology Vol 15 April 2016