The Lancet Commissions
www.thelancet.com Vol 396 August 8, 2020	 413
Dementia prevention, intervention, and care: 2020 report of
the Lancet Commission
Gill Livingston, Jonathan Huntley, Andrew Sommerlad, David Ames, Clive Ballard, Sube Banerjee, Carol Brayne, Alistair Burns,
Jiska Cohen-Mansfield, Claudia Cooper, Sergi G Costafreda, Amit Dias, Nick Fox, Laura N Gitlin, Robert Howard, Helen C Kales, Mika Kivimäki,
Eric B Larson, Adesola Ogunniyi,Vasiliki Orgeta, Karen Ritchie, Kenneth Rockwood, Elizabeth L Sampson, Quincy Samus, Lon S Schneider,
Geir Selbæk, LindaTeri, Naaheed Mukadam
Executive summary
The number of older people, including those living with
dementia, is rising, as younger age mortality declines.
However, the age-specific incidence of dementia has fallen
in many countries, probably because of improvements in
education, nutrition, health care, and lifestyle changes.
Overall, a growing body of evidence supports the nine
potentially modifiable risk factors for dementia modelled
by the 2017 Lancet Commission on dementia prevention,
intervention, and care: less education, hypertension,
hearing impairment, smoking, obesity, depression, physical
inactivity, diabetes, and low social contact. We now add
three more risk factors for dementia with newer, convincing
evidence. These factors are excessive alcohol consumption,
traumatic brain injury (TBI), and air pollution. We have
completednewreviewsandmeta-analysesandincorporated
these into an updated 12 risk factor life-course model of
dementia prevention. Together the 12 modifiable risk
factors account for around 40% of worldwide dementias,
which consequently could theo­retically be prevented or
delayed. The potential for prevention is high and might
be higher in low-income and middle-income countries
(LMIC) where more dementias occur.
Our new life-course model and evidence synthesis has
paramount worldwide policy implications. It is never too
early and never too late in the life course for dementia
prevention. Early-life (younger than 45 years) risks,
such as less education, affect cognitive reserve; midlife
(45–65 years), and later-life (older than 65 years) risk factors
influence reserve and triggering of neuropathological
developments. Culture, poverty, and inequality are key
drivers of the need for change. Individuals who are most
deprived need these changes the most and will derive the
highest benefit.
Policy should prioritise childhood education for all.
Public health initiatives minimising head injury and
decreasing harmful alcohol drinking could potentially
reduce young-onset and later-life dementia. Midlife systolic
blood pressure control should aim for 130 mm Hg or
lower to delay or prevent dementia. Stopping smoking,
even in later life, ameliorates this risk. Passive smoking is
a less considered modifiable risk factor for dementia.
Many countries have restricted this exposure. Policy
makers should expedite improvements in air quality,
particularly in areas with high air pollution.
We recommend keeping cognitively, physically, and
socially active in midlife and later life although little
evidence exists for any single specific activity protecting
against dementia. Using hearing aids appears to reduce
the excess risk from hearing loss. Sustained exercise in
midlife, and possibly later life, protects from dementia,
perhaps through decreasing obesity, diabetes, and
cardio­vascular risk. Depression might be a risk for
dementia, but in later life dementia might cause
depression. Although behaviour change is difficult and
some associations might not be purely causal, individuals
have a huge potential to reduce their dementia risk.
In LMIC, not everyone has access to secondary
education; high rates of hypertension, obesity, and
hearing loss exist, and the prevalence of diabetes and
smoking are growing, thus an even greater proportion of
dementia is potentially preventable.
Amyloid-β and tau biomarkers indicate risk of progression
to Alzheimer’s dementia but most people with
normal cognition with only these biomarkers never
develop the disease. Although accurate diagnosis is important
for patients who have impairments and functional
concerns and their families, no evidence exists to support
pre-symptomatic diagnosis in everyday practice.
Our understanding of dementia aetiology is shifting,
with latest description of new pathological causes. In the
oldest adults (older than 90 years), in particular, mixed
dementia is more common. Blood biomarkers might hold
promise for future diagnostic approaches and are more
scalable than CSF and brain imaging markers.
Wellbeing is the goal of much of dementia care. People
with dementia have complex problems and symptoms in
many domains. Interventions should be individualised
and consider the person as a whole, as well as their family
carers. Evidence is accumulating for the effectiveness, at
least in the short term, of psychosocial interventions
tailored to the patient’s needs, to manage neuropsychiatric
symptoms. Evidence-based interventions for carers can
reduce depressive and anxiety symptoms over years and
be cost-effective.
Keeping people with dementia physically healthy is
important for their cognition. People with dementia
have more physical health problems than others of the
same age but often receive less community health care
and find it particularly difficult to access and organise
care. People with dementia have more hospital
admissions than other older people, including for
illnesses that are potentially manageable at home. They
have died disproportionately in the COVID-19 epidemic.
Hospitalisations are distressing and are associated with
poor outcomes and high costs. Health-care professionals
Lancet 2020; 396: 413–46
Published Online
July 30, 2020
https://doi.org/10.1016/
S0140-6736(20)30367-6
Division of Psychiatry
(Prof G Livingston MD,
J Huntley PhD,A Sommerlad PhD,
Prof C Cooper PhD,
S G Costafreda PhD,
Prof R Howard MD,V Orgeta PhD,
Prof E L Sampson MD,
N Mukadam PhD), Dementia
ResearchCentre, UK Dementia
Research Institute
(Prof N Fox MD), and
Department of Epidemiology
and Public Health
(Prof M Kivimäki FMedSci),
UniversityCollege London,
London, UK;Camden and
Islington NHS Foundation
Trust, London, UK
(Prof G Livingston, J Huntley,
A Sommerlad, Prof C Cooper,
S G Costafreda, Prof R Howard,
N Mukadam); Barnet, Enfield,
and Haringey Mental Health
Trust, London, UK
(Prof E L Sampson); National
Ageing Research Institute and
Academic Unit for Psychiatry of
Old Age, University of
Melbourne, Royal Melbourne
Hospital, Parkville,VIC,
Australia (Prof D Ames MD);
University of Exeter, Exeter, UK
(Prof C Ballard MD); Faculty of
Health: Medicine, Dentistry and
Human Sciences, University of
Plymouth, Plymouth, UK
(Prof S Banerjee MD); Cambridge
Institute of Public Health,
University ofCambridge,
Cambridge, UK
(Prof C Brayne MD); Department
ofOld Age Psychiatry,
University of Manchester,
Manchester, UK
(Prof A Burns MD); Department
of Health Promotion, School
of Public Health, Sackler
Faculty of Medicine
(Prof J Cohen-Mansfield PhD),
Heczeg Institute on Aging
(Prof J Cohen-Mansfield),
and MinervaCenter for
Interdisciplinary Study of End
of Life (Prof J Cohen-Mansfield),
The Lancet Commissions
414	 www.thelancet.com Vol 396 August 8, 2020
should consider dementia in older people without
known dementia who have frequent admissions or who
develop delirium. Delirium is common in people with
dementia and contributes to cognitive decline. In
hospital, care including appropriate sensory stimulation,
ensuring fluid intake, and avoiding infections might
reduce delirium incidence.
Acting now on dementia prevention, intervention, and
care will vastly improve living and dying for individuals
with dementia and their families, and thus society.
Introduction
Worldwide around 50 million people live with dementia,
and this number is projected to increase to 152 million
by 2050,1
rising particularly in low-income and middleincome
countries (LMIC) where around two-thirds of
people with dementia live.1
Dementia affects individuals,
their families, and the economy, with global costs
estimated at about US$1 trillion annually.1
We reconvened the 2017 Lancet Commission on
dementia prevention, intervention, and care2
to identify
the evidence for advances likely to have the greatest
impact since our 2017 paper and build on its work. Our
inter­disciplinary, international group of experts presented,
debated, and agreed on the best available evidence.
We adopted a triangulation framework evaluating the
consistency of evidence from different lines of research
and used that as the basis to evaluate evidence. We have
Key messages
•	 Three new modifiable risk factors for dementia
•	 New evidence supports adding three modifiable risk
factors—excessive alcohol consumption, head injury,
and air pollution—to our 2017 Lancet Commission on
dementia prevention, intervention, and care life-course
model of nine factors (less education, hypertension,
hearing impairment, smoking, obesity, depression,
physical inactivity, diabetes, and infrequent social
contact).
•	 Modifying 12 risk factors might prevent or delay up to
40% of dementias.
•	 Be ambitious about prevention
•	 Prevention is about policy and individuals.
Contributions to the risk and mitigation of dementia
begin early and continue throughout life, so it is never
too early or too late. These actions require both public
health programmes and individually tailored
interventions. In addition to population strategies,
policy should address high-risk groups to increase
social, cognitive, and physical activity; and vascular
health.
•	 Specific actions for risk factors across the life course
•	 Aim to maintain systolic BP of 130 mm Hg or less in
midlife from around age 40 years (antihypertensive
treatment for hypertension is the only known effective
preventive medication for dementia).
•	 Encourage use of hearing aids for hearing loss and
reduce hearing loss by protection of ears from excessive
noise exposure.
•	 Reduce exposure to air pollution and second-hand
tobacco smoke.
•	 Prevent head injury.
•	 Limit alcohol use, as alcohol misuse and drinking more
than 21 units weekly increase the risk of dementia.
•	 Avoid smoking uptake and support smoking cessation
to stop smoking, as this reduces the risk of dementia
even in later life.
•	 Provide all children with primary and secondary
education.
•	 Reduce obesity and the linked condition of diabetes.
Sustain midlife, and possibly later life physical activity.
•	 Addressing other putative risk factors for dementia,
like sleep, through lifestyle interventions, will improve
general health.
•	 Tackle inequality and protect people with dementia
•	 Many risk factors cluster around inequalities, which occur
particularly in Black, Asian, and minority ethnic groups
and in vulnerable populations.Tackling these factors will
involve not only health promotion but also societal
action to improve the circumstances in which people live
their lives. Examples include creating environments that
have physical activity as a norm, reducing the population
profile of blood pressure rising with age through better
patterns of nutrition, and reducing potential excessive
noise exposure.
•	 Dementia is rising more in low-income and middleincome
countries (LMIC) than in high-income countries,
because of population ageing and higher frequency of
potentially modifiable risk factors. Preventative
interventions might yield the largest dementia
reductions in LMIC.
For those with dementia, recommendations are:
•	 Provide holistic post-diagnostic care
•	 Post-diagnostic care for people with dementia should
address physical and mental health, social care, and
support. Most people with dementia have other illnesses
and might struggle to look after their health and this
might result in potentially preventable hospitalisations.
•	 Manage neuropsychiatric symptoms
•	 Specific multicomponent interventions decrease
neuropsychiatric symptoms in people with dementia
and are the treatments of choice. Psychotropic drugs are
often ineffective and might have severe adverse effects.
•	 Care for family carers
•	 Specific interventions for family carers have long-lasting
effects on depression and anxiety symptoms, increase
quality of life, are cost-effective and might save money.
Tel Aviv University,Tel Aviv,
Israel; Department of
Preventive and Social
Medicine, Goa Medical College,
Goa, India (A Dias MD);
Institute of Neurology,
National Hospital for
Neurology and Neurosurgery,
University College London
Hospitals NHS Foundation
Trust, London, UK (Prof N Fox);
Center for Innovative Care in
Aging (Prof L N Gitlin PhD), and
Department of Psychiatry
and Behavioral Sciences
(Q Samus PhD), Johns Hopkins
University, Baltimore, MA,
USA; Department of
Psychiatry and Behavioral
Sciences, UC Davis School of
Medicine, University of
California, Sacramento, CA,
USA (Prof H C Kales MD); Kaiser
Permanente Washington
Health Research Institute,
Seattle, WA, USA
(Prof E B Larson MD);
University College Hospital,
Ibadan, Nigeria
(Prof A Ogunniyi MBChB);
Inserm, Unit 1061,
Neuropsychiatry:
Epidemiological and Clinical
Research, La Colombière
Hospital, University of
Montpellier, Montpellier,
France (Prof K Ritchie PhD);
Centre for Clinical Brain
Sciences, University of
Edinburgh, Edinburgh, UK
(Prof K Ritchie); Centre for the
Health Care of Elderly People,
Geriatric Medicine Dalhousie
University, Halifax, NS, Canada
(Prof K Rockwood MD);
Department of Psychiatry and
the Behavioural Sciences and
Department of Neurology,
Keck School of Medicine,
Leonard Davis School of
Gerontology of the University
of Southern California,
Los Angeles, CA, USA
(Prof L S Schneider MD);
Norwegian National Advisory
Unit on Ageing and Health,
Vestfold HospitalTrust,
Tønsberg, Norway
(Prof G Selbæk MD); Institute
of Clinical Medicine, Faculty of
Medicine, University of Oslo,
Oslo, Norway (Prof G Selbæk);
Geriatric Department, Oslo
University Hospital, Oslo,
Norway (Prof G Selbæk);
Department Psychosocial and
Community Health, School of
Nursing, University of
Washington, Seattle, WA, USA
(Prof L Teri PhD)
The Lancet Commissions
www.thelancet.com Vol 396 August 8, 2020	 415
summarised best evidence using, where possible, goodquality
systematic reviews, meta-analyses, or individual
studies, where these add important knowledge to the
field. We performed systematic literature reviews and
meta-analyses where needed to generate new evidence for
our analysis of potentially modifiable risk factors for
dementia. Within this framework, we present a narrative
synthesis of evidence including systematic reviews and
meta-analyses and explain its balance, strengths, and
limitations. We evaluated new evidence on dementia risk
in LMIC; risks and protective factors for dementia; detection
of Alzheimer’s disease; multimorbidity in dementia;
and interventions for people affected by dementia.
Nearly all the evidence is from studies in highincome
countries (HIC), so risks might differ in other
countries and interventions might require modification
for different cultures and environments. This notion also
underpins the critical need to understand the dementias
related to life-course disadvantage—whether in HICs or
LMICs.
Our understanding of dementia aetiology is shifting.
A consensus group, for example, has described hippocampal
sclerosis associated with TDP-43 proteinopathy,
as limbic-predominant age-related TDP-43 encephalopathy
(LATE) dementia, usually found in people older
than 80 years, progressing more slowly than Alzheimer’s
disease, detectable at post-mortem, often mimicking or
comorbid with Alzheimer’s disease.3
This situation
reflects increasing attention as to how clinical syndromes
are and are not related to particular underlying pathologies
and how this might change across age. More work
is needed, however, before LATE can be used as a valid
clinical diagnosis.
The fastest growing demographic group in HIC is the
oldest adults, those aged over 90 years. Thus a unique
opportunity exists to focus on both human biology, in
this previously rare population, as well as on meeting
their needs and promoting their wellbeing.
Prevention of dementia
The number of people with dementia is rising.
Predictions about future trends in dementia prevalence
vary depending on the underlying assumptions and
geographical region, but generally suggest substantial
increases in overall prevalence related to an ageing
population. For example, according to the Global
Burden of Diseases, Injuries, and Risk Factors Study,
the global age-standardised prevalence of dementia
between 1990 and 2016 was relatively stable, but with an
ageing and bigger population the number of people
with dementia has more than doubled since 1990.4
However, in many HIC such as the USA, the UK, and
France, age-specific incidence rates are lower in more
recent cohorts compared with cohorts from previous
decades collected using similar methods and target
populations5
(figure 1) and the age-specific incidence
of dementia appears to decrease.6
All-cause dementia
incidence is lower in people born more recently,7
proba­bly
due to educational, socio-economic, health care, and lifestyle
changes.2,5
However, in these countries increasing
obesity and diabetes and declining physical activity
might reverse this trajectory.8,9
In contrast, age-specific
dementia prevalence in Japan, South Korea, Hong Kong,
and Taiwan looks as if it is increasing, as is Alzheimer’s
in LMIC, although whether diagnostic methods are
always the same in comparison studies is unclear.5–7
Modelling of the UK change suggests a 57% increase in
the number of people with dementia from 2016 to 2040,
70% of that expected if age-specific incidence rates
remained steady,10
such that by 2040 there will be
1·2 million UK people with dementia. Models also
suggest that there will be future increases both in the
number of individuals who are independent and those
with complex care needs.6
Figure 1: Incidence rate ratio comparing new cohorts to old cohorts from five studies of dementia incidence5
IIDP Project in USA and Nigeria, Bordeaux study in France, and Rotterdam study in the Netherlands adjusted for
age. Framingham Heart Study, USA, adjusted for age and sex. CFAS in the UK adjusted for age, sex, area, and
deprivation. However, age-specific dementia prevalence is increasing in some other countries. IID=Indianapolis–
Ibadan Dementia. CFAS=Cognitive Function and Ageing Study. Adapted fromWu et al,5
by permission of Springer
Nature.
Population Hazard ratio
incidence ratio (95%CI)
Rotterdam (age 60–90 years)
2000 vs 1990
2000 vs 1990
2000 vs 1990
Bordeaux (clinical diagnosis, age ≥65years)
1999 vs 1988
1999 vs 1988
1999 vs 1988
Bordeaux (algorithmic diagnosis, age ≥65years}
1999 vs 1988
1999 vs 1988
1999 vs 1988
CFAS (age ≥65 years)
2008 vs 1991
2008 vs 1991
2008 vs 1991
IIDP (African American age ≥70 years)
2001 vs 1992
IIDP (Yoruba age ≥70 years)
2001 vs 1992
Framingham heart study (age ≥60years)
1986–91 vs 1977–83
1992–98 vs 1977–83
2004–08 vs 1977–83
1986–91 vs 1977–83
1992–98 vs 1977–83
2004–08 vs 1977–83
1986–91 vs 1977–83
1992–98 vs 1977–83
2004–08 vs 1977–83
Total
Men
Women
Total
Men
Women
Total
Men
Women
Total
Men
Women
Total
Total
Total
Total
Total
Men
Men
Men
Women
Women
Women
0·8 (0·6–1·0)
0·7 (0·4–1·2)
0·8 (0·5–1·1)
0·9 (0·7–1·1)
1·2 (0·8–1·9)
0·9 (0·7–1·2)
0·6 (0·5–0·8)
1·1 (0·7–1·8)
0·6 (0·5–0·8)
0·8 (0·6–1·0)
0·6 (0·4–0·9)
1·0 (0·7–1·3)
0·4 (0·3–0·5)
0·8 (0·6–1·1)
0·8 (0·6–1·0)
0·6 (0·5–0·8)
0·6 (0·4–0·8)
1·0 (0·6–1·6)
0·9 (0·6–1·4)
0·6 (0·4–1·1)
0·7 (0·5–1·0)
0·5 (0·4–0·7)
0·5 (0·4–0·8)
1·00·5 2·00·25 4·0
Decreased incident
dementia
Increased incident
dementia
Correspondence to:
Prof Gill Livingston, Division of
Psychiatry, University College
London, LondonW1T 7NF, UK
g.livingston@ucl.ac.uk
The Lancet Commissions
416	 www.thelancet.com Vol 396 August 8, 2020
In our first report, the 2017 Commission described a
life-course model for potentially modifiable risks for
dementia.2
Life course is important when considering
risk, for example, obesity and hypertension in midlife
predict future dementia, but both weight and blood
pressure usually fall in later life in those with or developing
dementia,9
so lower weight and blood pressure
in later life might signify illness, not an absence of
risk.11–14
We consider evidence on other potential risk
factors and incor­porate those with good quality evidence
in our model.
Figure 2 summarises possible mechanisms of protection
from dementia, some of which involve increasing
or maintaining cognitive reserve despite pathology and
neuropathological damage. There are different terms
describing the observed differential susceptibility to agerelated
and disease-related changes and these are not
used consistently.15,16
A consensus paper defines reserve
as a concept accounting for the difference between an
individual’s clinical picture and their neuropathology.
It, divides the concept further into neurobiological
brain reserve (eg, numbers of neurones and synapses at a
given timepoint), brain maintenance (as neurobiological
capital at any timepoint, based on genetics or lifestyle
reducing brain changes and pathology development
over time) and cognitive reserve as adaptability enabling
preser­vation of cognition or everyday functioning in
spite of brain pathology.15
Cognitive reserve is changeable
and quantifying it uses proxy measures such as education,
occupational complexity, leisure activity, residual
approaches (the variance of cognition not explained by
demographic variables and brain measures), or identification
of functional networks that might underlie such
reserve.15–20
Early-life factors, such as less education, affect the
resulting cognitive reserve. Midlife and old-age risk factors
influence age-related cognitive decline and triggering of
neuropathological developments. Consistent with the
hypothesis of cognitive reserve is that older women are
more likely to develop dementia than men of the same
age, probably partly because on average older women have
had less education than older men. Cognitive reserve
mechanisms might include preserved metabolism or
increased connectivity in temporal and frontal brain
areas.17–21
People in otherwise good physical health can
sustain a higher burden of neuropathology without
cognitive impairment.22
Culture, poverty, and inequality
are important obstacles to, and drivers of, the need for
change to cognitive reserve. Those who are most deprived
need these changes the most and will derive the highest
benefit from them.
Smoking increases air particulate matter, and has
vascular and toxic effects.23
Similarly air pollution might
act via vascular mechanisms.24
Exercise might reduce
weight and diabetes risk, improve cardiovascular function,
decrease glutamine, or enhance hippocampal
neurogenesis.25
Higher HDL cholesterol might protect
against vascular risk and inflammation accompanying
amyloid-β (Aβ) pathology in mild cognitive impairment.26
Dementia in LMIC
Numbers of people with dementia in LMIC are rising
faster than in HIC because of increases in life expectancy
and greater risk factor burden. We previously calculated
that nine potentially modifiable risk factors together
are associated with 35% of the population attributable
fraction (PAFs) of dementia worldwide: less education,
high blood pressure, obesity, hearing loss, depression,
diabetes, physical inactivity, smoking, and social isolation,
assuming causation.2
Most research data for this
calcu­lation came from HIC and there is a relative absence
of specific evidence of the impact of risk factors on
dementia risk in LMIC, particularly from Africa and
Latin America.27
Calculations considering country-specific prevalence of
the nine potentially modifiable risk factors indicate PAF
of 40% in China, 41% in India and 56% in Latin America
with the potential for these numbers to be even higher
depending on which estimates of risk factor frequency
are used.28,29
Therefore a higher potential for dementia
prevention exists in these countries than in global
estimates that use data predominantly from HIC. If not
currently in place, national policies addressing access to
education, causes and management of high blood
pressure, causes and treatment of hearing loss, socioeconomic
and commercial drivers of obesity, could be
implemented to reduce risk in many countries. The
higher social contact observed in the three LMIC regions
provides potential insights for HIC on how to influence
this risk factor for dementia.30
We could not consider
other risk factors such as poor health in pregnancy
of malnourished mothers, difficult births, early life
malnutrition, survival with heavy infection burdens
alongside malaria and HIV, all of which might add to
the risks in LMIC.
Diabetes is very common and cigarette smoking
is rising in China while falling in most HIC.31
A
Figure 2: Possible brain mechanisms for enhancing or maintaining cognitive reserve and risk reduction of
potentially modifiable risk factors in dementia
• Mantain frequent exercise
• Reduceoccurrenceofdepression
• Avoid excessive alcohol
• Minimise diabetes
•Treat hypertension
• Prevent head injury
• Stop smoking
• Reduce air pollution
• Reduce midlife obesity
Reduced neuropathological
damage (amyloid or
tau-mediated, vascular or
inflammatory)
•Treat hearing impairment
• Mantain frequent social contact
• Attain high level of education
Increased and maintained
cognitive reserve
Preventing dementia
The Lancet Commissions
www.thelancet.com Vol 396 August 8, 2020	 417
meta-analysis found variation of the rates of dementia
within China, with a higher prevalence in the north and
lower prevalence in central China, estimating 9·5 million
people are living with dementia, whereas a slightly later
synthesis estimated a higher prevalence of around
11 million.30,32
These data highlight the need for more
focused work in LMIC for more accurate estimates of
risk and interventions tailored to each setting.
Specific potentially modifiable risk factors for
dementia
Riskfactorsinearlylife(education),midlife(hypertension,
obesity, hearing loss, TBI, and alcohol misuse) and later
life (smoking, depression, physical inactivity, social
isolation, diabetes, and air pollution) can contribute to
increased dementia risk (table 1). Good evidence exists
for all these risk factors although some late-life factors,
such as depression, possibly have a bidirectional impact
and are also part of the dementia prodrome.33,34
In the next section, we briefly describe relevant newly
published and illustrative research studies that add to
the 2017 Commission’s evidence base, including risks
and, for some, mitigation. We have chosen studies
that are large and representative of the populations, or
smaller studies in areas where very little evidence exists.
We discuss them in life-course order and within the
life course in the order of magnitude of population
attributable factor.
Education and midlife and late-life cognitive stimulation
Education level reached
Higher childhood education levels and lifelong higher
educational attainment reduce dementia risk.2,35–37
New
work suggests overall cognitive ability increases, with
education, before reaching a plateau in late adolescence,
when brain reaches greatest plasticity; with
relatively few further gains with education after
age 20 years.38
This suggests cognitive stimulation is
more important in early life; much of the apparent
later effect might be due to people of higher cognitive
function seeking out cognitively stimulating activities
and education.38
It is difficult to separate out the
specific impact of education from the effect of overall
cognitive ability,38,39
and the specific impact of later-life
cognitive activity from lifelong cognitive function and
activity.39,40
Cognitive maintenance
One large study in China tried to separate cognitive
activity in adulthood from activities for those with more
education, by considering activities judged to appeal to
people of different levels of education.40
It found people
older than 65 years who read, played games, or bet
more frequently had reduced risk of dementia (n=15 882,
odds ratio [OR]=0·7, 95% CI 0·6–0·8). The study
excluded people developing dementia less than 3 years
after baseline to reduce reverse causation.
This finding is consistent with small studies of midlife
activities which find them associated with better late-life
cognition; so for example, in 205 people aged 30–64 years,
followed up until 66–88 years, travel, social outings,
playing music, art, physical activity, reading, and speaking
a second language, were associated with maintaining
cognition, independent of education, occupation, late-life
activities, and current structural brain health.41
Similarly,
engaging in intellectual activity as adults, particularly
problem solving, for 498 people born in 1936, was associated
with cognitive ability acquisition, although not the
speed of decline.42
Cognitive decline
The use it or lose it hypothesis suggests that mental
activity, in general, might improve cognitive function.
People in more cognitively demanding jobs tend to
show less cognitive deterioration before, and sometimes
after retirement than those in less demanding jobs.43,44
One systematic review of retirement and cognitive
decline found conflicting evidence.45
Subsequently, a
12-year study of 1658 people found older retirement age
but not number of years working, was associated with
lower dementia risk.46
Those retiring because of ill health
had lower verbal memory and fluency scores than those
retiring for other reasons.47
Another study found a
two-fold increase in episodic memory loss attributable to
retirement (n=18 575, mean age 66 years), compared to
non-retirees, adjusting for health, age, sex, and wealth.48
Similarly, in a cohort of 3433 people retiring at a mean
age of 61 years, verbal memory declined 38% (95% CI
22–60) faster than before retirement.44
In countries with
Relative risk for
dementia
(95% CI)
Risk factor
prevalence
Communality Unweighted
PAF
Weighted
PAF*
Early life (<45 years)
Less education 1·6 (1·3–2·0) 40·0% 61·2% 19·4% 7·1%
Midlife (age 45–65 years)
Hearing loss 1·9 (1·4–2·7) 31·7% 45·6% 22·2% 8·2%
TBI 1·8 (1·5–2·2) 12·1% 55·2% 9·2% 3·4%
Hypertension 1·6 (1·2–2·2) 8·9% 68·3% 5·1% 1·9%
Alcohol (>21 units/week) 1·2 (1·1–1·3) 11·8% 73·3% 2·1% 0·8%
Obesity (body-mass
index ≥30)
1·6 (1·3–1·9) 3·4% 58·5% 2·0% 0·7%
Later life (age >65 years)
Smoking 1·6 (1·2–2·2) 27·4% 62·3% 14·1% 5·2%
Depression 1·9 (1·6–2·3) 13·2% 69·8% 10·6% 3·9%
Social isolation 1·6 (1·3–1·9) 11·0% 28·1% 4·2% 3·5%
Physical inactivity 1·4 (1·2–1·7) 17·7% 55·2% 9·6% 1·6%
Diabetes 1·5 (1·3–1·8) 6·4% 71·4% 3·1% 1·1%
Air pollution 1·1 (1·1–1·1) 75·0% 13·3% 6·3% 2·3%
Data are relative risk (95% CI) or %. Overall weighted PAF=39·7%. PAF=population attributable fraction.TBI=traumatic
brain injury. *Weighted PAF is the relative contribution of each risk factor to the overall PAF when adjusted for
communality.
Table 1: PAF for 12 dementia risk factors
The Lancet Commissions
418	 www.thelancet.com Vol 396 August 8, 2020
younger compared to higher retirement ages, average
cognitive performance drops more.49
Cognitive interventions in normal cognition and mild
cognitive impairment
A cognitive intervention or cognition-orientated treatment
comprises strategies or skills to improve general
or spe­cific areas of cognition.50
Computerised cognitive
training programmes have increasingly replaced tasks that
were originally paper-and-pencil format with computerbased
tasks for practice and training.51
Three systematic reviews in the general population
found no evidence of generalised cognition improvement
from specific cognitive interventions, including computerised
cognitive training, although the domain trained
might improve.52–54
A meta-analysis of 17 controlled trials of at least 4 hours
of computerised cognitive training, (n=351, control n=335)
for mild cognitive impairment, found a moderate effect on
general cognition post-training (Hedges’ g=0·4, 0·2–0·5);55
however few high quality studies and no long-term high
quality evidence about prevention of dementia currently
exists. A meta-analysis of 30 trials of computerised,
therapy-based and multimodal interventions for mild
cognitive impairment found an effect on activities of daily
living (d=0·23) and metacognitive outcomes (d=0·30)
compared to control.56
A third systematic review identified
five high quality studies, four group-delivered and one by
computer, and concluded the evidence for the effects of
cognitive training in mild cognitive impairment was
insufficient to draw conclusions.53
A comprehensive, high
quality, systematic overview of meta-analyses of cognitive
training in healthy older people, those with mild cognitive
impairment and those with dementia, found that most
were of low standard, were positive and most reached
statistical significance but it was unclear whether results
were of clinical value because of the poor standard of the
studies and heterogeneity of results (figure 3).51
In the only randomised controlled trial (RCT) of
behavioural activation (221 people) for cognition in
amnestic mild cognitive impairment, behavioural activation
versus supportive therapy was associated with a
decreased 2-year incidence of memory decline (relative
risk [RR] 0·12, 0·02–0·74).57
Hearing impairment
Hearing loss had the highest PAF for dementia in our
first report, using a meta-analysis of studies of people
with normal baseline cognition and hearing loss present
at a threshold of 25 dB, which is the WHO threshold for
hearing loss. In the 2017 Commission, we found an
RR of 1·9 for dementia in populations followed up over
9–17 years, with the long follow-up times making reverse
causation bias unlikely.2
A subsequent meta-analysis
using the same three prospective studies measuring
hearing using audiometry at baseline, found an increased
risk of dementia (OR 1·3, 95% CI 1·0–1·6) per 10 dB of
worsening of hearing loss.58
A cross-sectional study
of 6451 individuals designed to be representative of the
US population, with a mean age of 59·4 years, found a
decrease in cognition with every 10 dB reduction in
hearing, which continued to below the clinical threshold
so that subclinical levels of hearing impairment (below
25 dB) were significantly related to lower cognition.59
Although the aetiology still needs further clarification,
a small US prospective cohort study of 194 adults
without baseline cognitive impairment, (baseline mean
age 54·5 years), and at least two brain MRIs, with a
mean of 19 years follow-up, found that midlife hearing
impair­ment measured by audiometry, is associated with
steeper temporal lobe volume loss, including in the
hippocampus and entorhinal cortex.60
Hearing aids
A 25-year prospective study of 3777 people aged 65 years
or older found increased dementia incidence in those
with self-reported hearing problems except in those
using hearing aids.61
Similarly, a cross–sectional study
found hearing loss was only associated with worse
cognition in those not using hearing aids.62
A US
nationally representative survey of 2040 people older
than 50 years, tested every two years for 18 years, found
immediate and delayed recall deteriorated less after
initiation of hearing aid use, adjusting for other risk
factors.63
Hearing aid use was the largest factor
protecting from decline (regression coefficient β for
higher episodic memory 1·53; p<0·001) adjusting for
protective and harmful factors. The long follow-up
times in these prospective studies suggest hearing aid
use is protec­tive, rather than the possibility that those
developing dementia are less likely to use hearing aids.
Hearing loss might result in cognitive decline through
reduced cognitive stimulation.
TBI
The International Classification of Disease (ICD) defines
mild TBI as concussion and severe TBI as skull fracture,
oedema, brain injury or bleed. Single, severe TBI is
associated in humans, and mouse models, with widespread
hyperphosphorylated tau pathology, and mice
with APOE ε4 compared to APOE ε3 allele have more
hippocampal hyper-phosphorylated tau after TBI.64,65
TBI is usually caused by car, motorcycle, and bicycle
injuries; military exposures; boxing, horse riding, and
other recreational sports; firearms; and falls.66
A nationwide
Danish cohort study of nearly 3 million people
aged 50 years or older, followed for a mean of 10 years,
found an increased dementia (HR 1·2, 95% CI 1·2–1·3)
and Alzheimer’s disease risk (1·2, 1·1–1·2).67
Dementia
risk was highest in the 6 months after TBI (4·1, 3·8–4·3)
and increased with number of injuries in people with
TBI (one TBI 1·2, 1·2–1·3; ≥5 TBIs 2·8, 2·1–3·8). Risk
was higher for TBI than fractures in other body areas
(1·3, 1·3–1·3) and remained elevated after excluding
The Lancet Commissions
www.thelancet.com Vol 396 August 8, 2020	 419
Figure 3: Pooled results of
meta-analyses investigating
objective cognitive
outcomes of cognitionoriented
treatment in older
adults with and without
cognitive impairment
K represents the number of
primary trials included in the
analysis. If a review reported
several effect sizes within each
outcome domain, a composite
was created and k denotes the
range of the number of
primary trials that contributed
to the effect estimate.
AMSTAR=A MeaSurement
Tool to Assess systematic
Reviews (max score 16).
Adapted from Gavelin et al,51
by permission of Springer
Nature.
AMSTAR Hedge's g (95% CI)K
Older adults
Papp et al (2009)
Metternich et al (2010)
Martin et al (2011)
Gross et al (2012)
Hindin et al (2012)
Karr et al (2014)
Kelly et al (2014)
Lampit et al (2014)
Toril et al (2014)
Shao et al (2015)
Melby-Lervåg et al (2016)
Wang et al (2016)
Weicker et al (2016)
Chiu et al (2017)
Mewborn et al ( 2017)
Smart et al (2017)
Tetlow et al (2017)
Bhome et al 2018)
Gates et al (2019a)
Mild cognitive impairment
Sherman et al (2017)
Martin et al (2011)
Wang et al (2014)
Hill et al (2017)
Mewborn et al (2017)
Gates et al (2019b)
Dementia
Huntley et al (2015)
Kurz et al (2011)
Woods et al (2012)
Huntley et al (2015)
Folkerts et al (2017)
Kim et al (2017)
Alves et al (2013)
Karr et al (2014)
Huntley et al (2015)
Song et al (2016)
Folkerts et al (2017)
Hill et al (2017)
Bahar-Fuchs et al (2019)
Parkinson's disease
Leung et al (2015)
Lawrence et al (2017)
Stroke
Rogers et al (2018)
Loetscher et al (2013)
Virk et al (2015)
das Nair et al (2016)
Mixed
Yang et al (2018)
Kurz et al (2011)
Hoefler et al (2016)
10
4–5
2–11
35
25
15
2–7
51
20
6–10
17
8
10–20
6–22
48
8
3–14
10
2–4
26
2–3
3–6
17
12
2–5
3
5–12
14
2–17
2–3
11
2–3
10
3
3–6
2
11
26
7
4–10
22
4–6
2–6
5
3–18
5
5–8
3·5
6
6
6·5
3·5
8·5
9
12·5
6
6
1
8·5
6·5
7
9
7·5
4
8
12·5
8
6
8
12
9
12·5
11·5
6
10·5
11·5
10·5
7
12
8·5
11·5
2·5
10·5
12
14
10
7·5
13
13
12
12
6
6
2·5
Critically low
Critically low
Critically low
Critically low
Critically low
Critically low
Critically low
Moderate
Critically low
Critically low
Critically low
Critically low
Critically low
Low
Moderate
Critically low
Critically low
Low
Low
Low
Critically low
Critically low
Moderate
Moderate
Low
Moderate
Critically low
Moderate
Moderate
Low
Critically low
Low
Critically low
Moderate
Critically low
Low
Moderate
Moderate
Moderate
Critically low
Moderate
Low
Moderate
Low
Low
Critically low
Critically low
0·16 (0·14 to 0·19)
0·48 (0·23 to 0·73)
0·47 (–0·44 to 1·38)
0·31 (0·22 to 0·39)
0·33 (0·13 to 0·52)
0·26 (0·10 to 0·42)
0·38 (0·05 to 0·72)
0·22 (0·15 to 0·29)
0·32 (0·19 to 0·45)
0·31 (0·05 to 0·57)
0·13 (–0·02 to 0·28)
0·38 (0·12 to 0·64)
0·38 (0·14 to 0·62)
0·32 (0·16 to 0·48)
0·31 (0·24 to 0·39)
0·37 (0·05 to 0·69)
0·16 (–0·11 to 0·43)
0·13 (0·01 to 0·25)
0·64 (–0·56 to 1·85)
0·45 (0·16 to 0·75)
0·60 (0·00 to 1·19)
0·32 (–0·04 to 0·69)
0·35 (0·20 to 0·50)
0·34 (0·21 to 0·47)
0·41 (–0·22 to 1·04)
0·28 (–0·12 to 0·68)
0·26 (0·08 to 0·43)
0·41 (0·25 to 0·57)
0·35 (0·11 to 0·58)
0·35 (0·05 to 0·65)
0·44 (0·28 to 0·60)
0·09 (–0·36 to 0·54)
0·20 (–0·07 to 0·47)
0·22 (–0·74 to 1·18)
0·33 (0·14 to 0·53)
1·16 (0·53 to 1·79)
0·26 (0·01 to 0·51)
0·42 (0·23 to 0·61)
0·23 (0·02 to 0·44)
0·31 (0·02 to 0·60)
0·48 (0·36 to 0·60)
0·28 (–0·10 to 0·66)
0·18 (–0·24 to 0·60)
0·23 (–0·23 to 0·69)
0·36 (0·10 to 0·62)
–0·01 (–0·64 to 0·62)
0·15 (–0·06 to 0·36)
–0·5 0 0·5 1·0 1·5
Cognitive training
Cognitive stimulation
Mixed cognition-oriented treatments
Favours control Favours intervention
The Lancet Commissions
420	 www.thelancet.com Vol 396 August 8, 2020
those who developed dementia within 2 years after TBI,
to reduce reverse causation bias.67
Similarly, a Swedish cohort of over 3 million people aged
50 years or older, found TBI increased 1-year dementia risk
(OR 3·5, 95% CI 3·2–3·8); and risk remained elevated,
albeit attenuated over 30 years (1·3, 1·1–1·4).68
ICD defined
single mild TBI increased the risk of dementia less than
severe TBI and multiple TBIs increased the risk further
(OR 1·6, 95% CI 1·6–1·7 for single TBI; 2·1, 2·0–2·2 for
more severe TBI; and 2·8, 2·5–3·2 for multiple TBI). A
nested case control study of early onset clinically diagnosed
Alzheimer’s disease within an established cohort also
found TBI was a risk factor, increasing with number and
severity.69
A stronger risk of dementia was found nearer
the time of the TBI, leading to some people with earlyonset
Alzheimer’s disease.
Military veterans have a high risk of occupational TBI,
and formal record keeping allows long-term follow-up.
A study of 178 779 veterans with TBI with propensitymatched
veterans without TBI found dementia risk was
associated with TBI severity (HR 2·4, 95% CI 2·1–2·7 for
mild TBI without loss of consciousness; 2·5, 2·3–2·8 for
mild TBI with loss of consciousness; and 3·8, 3·6–3·9
for moderate to severe TBI).70
Similarly women veterans
with TBI had increased risk of dementia compared to
those without TBI (1·5, 1·0–2·2). 71
A cohort study of 28 815 older adults with concussion,
found the risk of dementia doubled, with 1 in 6 developing
dementia over a mean follow-up of 3·9 years, although
those taking statins had a 13% reduced risk of dementia
compared to those who were statin-free. They suggest
future RCTs as statins might mitigate injury-related brain
oedema, oxidative stress, amyloid protein aggregation,
and neuroinflammation.72
The term chronic traumatic encephalopathy describes
sports head injury, which is not yet fully characterised
and covers a broad range of neuropathologies and
outcomes, with current views largely conjecture.73
The
evidence has subsequently been strengthened by a study
on Scottish former soccer players reporting that they are
more likely than controls to have Alzheimer’s disease
specified on their death certificates (HR 5·1, 95% CI
2·9–8·8) and to have been prescribed any dementiarelated
medications (OR 4·9, 95% CI 3·8–6·3) but not
on medical records.74
The study controlled for socioeconomic
class based on residential address, which in
footballers might be less linked to level of education.
Hypertension
Persistent midlife hypertension is associated with
increased risk of a late life dementia. In the Framingham
Offspring cohort comprising 1440 people, elevated systolic
blood pressure (≥140 mm Hg in midlife; mean age
55 years) was associated with an increased risk of
developing dementia (HR 1·6, 95% CI 1·1–2·4) over an
18 year follow-up period.12
In this study risk increased
further if hypertension persisted into later life (mean age
69 years; HR 2·0, 95% CI 1·3–3·1). In the same cohort,
people in late midlife (mean age 62 years) with ideal
cardiovascular parameters (current non-smoker, body
mass index [BMI] 18·5–25 kg/m², regular phy­sical activity,
healthy diet, optimum blood pressure <120/<80 mm Hg,
cholesterol, and normal fasting blood glucose) were
compared to people with at least one of these risks.75
Those with ideal cardiovascular parameters had a lower
10-year risk of all-cause dementia (HR 0·8, 95% CI
0·1–1·0), vascular dementia (0·5, 0·3–0·8) and clinically
diagnosed Alzheimer’s disease (0·8, 0·6–1·0). In a UK
cohort study of 8639 civil servants, a single measure of
systolic blood pressure of 130 mm Hg or higher at
age 50 years but not at age 60 or 70 years was associated
with increased risk of dementia (1·4, 1·1–1·7).13
In those
with persistent systolic blood pressure of  130 mm Hg or
higher, from mean age 45 to 61 years, dementia risk is
increased even if free of cardiovascular disease relative to
those without hyper­tension (1·3, 1·0–1·7).
A further cohort study has provided potential insights
into mechanisms, reporting that midlife hypertension,
defined as from age 40 years, was associated with
reduced brain volumes and increased white matter
hyperintensity volume but not amyloid deposition.76
Of note, blood pressure declines in later life and this
decline is associated with and, potentially caused by,
dementia development (HR 2·4, 95% CI 1·4–4·2).12,13,77
Antihypertensive drugs, aspirin, and statins
The US and Puerto Rico Systolic Blood Pressure
Intervention Trial (SPRINT) in 9361 hypertensive adults
aged 50 years and older, was stopped early because of
significantly fewer cardiovascular events and deaths
occurring in the intensive treatment arm (aiming for
systolic <120 mm Hg, n=4678) in comparison with
standard treatment (systolic <140 mm Hg, n=4683).78
Cognitive assessment continued after stopping the trial
intervention in SPRINT MIND.79
In the intensive compared
with the standard treatment group, there were
7·2 dementia cases as opposed to 8·6 cases per
1000 person-years (HR 0·8; 95% CI 0·7–1·0) within on
average 2 years from the end of the intervention period
and 5 years after baseline. Pre-specified secondary
outcomes were also reduced in the intensive arm for mild
cog­nitive impair­ment (14·6 vs 18·3 cases per 1000 personyears;
HR 0·8, 95% CI 0·7–1·0), combined mild cognitive
impairment or dementia (20·2 vs 24·1 cases per 1000
person-years; HR 0·9, 95% CI 0·7–1·0)79
making this the
first trial to suggest reduction of risk for mild cognitive
impairment. Those who were lost to follow-up were at
greater risk of dementia than those who continued but
follow-up rates did not differ according to intervention
group.80
Four meta-analyses of blood pressure medications to
lower high blood pressure with six studies overlap
have provided combined estimates of effects. All metaanalyses
suggest reduced dementia in those in the
The Lancet Commissions
www.thelancet.com Vol 396 August 8, 2020	 421
interventions arms for outcomes of any dementia as well
as clinically diagnosed Alzheimer’s disease. The first
included randomised controlled trials (RCTs) of any
drug to lower blood pressure and reported a reduction in
risk of around 10% at marginal significance (RR 0·9,
95% CI 0·9–1·0).81
Meta-regression showed risk lowered
more if the achieved systolic pressure differential was
larger between the intervention and control group. The
second included 15 trials and observational studies of
diuretics involving 52 599 people (median age 76 years)
with 6·1 years median follow-up (dementia HR 0·8,
95% CI 0·8–0·9 and Alzheimer’s disease 0·8, 0·7–0·9).82
The third included used individual participant data from
six observational studies; (dementia 0·9, 0·8–1·0 and
Alzheimer’s disease 0·8, 0·7–1·0; figure 4).83
The fourth
focused on people prescribed calcium channel blocker
only, included 10 RCTs and observational studies
comprising 75 239 hypertensive older adults (median
age 72 years, median follow-up 8·2 years) found lowered
dementia risk (RR 0·7, 95% CI 0·6–0·9).84
A 2019 metaanalysis
addressing which class of anti-hypertensive
drug to use to lower risk of either incident dementia or
cognitive decline, found over 50 000 participants in
27 studies and reported no consistent difference in effect
according to which class of drug was used.85
A Cochrane review reported good evidence that statins
given to older people at risk of vascular disease do not
prevent cognitive decline or dementia.86
One RCT found
100 mg aspirin versus placebo in 19 114 healthy adults
older than 65 years did not reduce dementia (HR 1·0,
95% CI 0·8–1·2), death, physical disability, or cardiovascular
disease over a period of 4·7 years.87
Physical inactivity, exercise, and fitness
Studies of physical activity are complex. Patterns of
physical activity change with age, generation, and
morbidity and are different across sex, social class, and
cultures. The studies suggest a complicated relationship
with the potential for both risk reduction and reverse
causation.
Meta-analyses of longitudinal observational studies
of 1–21 years duration showed exercise to be associated
with reduced risk of dementia.2
A further overview of
sys­tematic reviews concluded that there is convincing
Figure 4: Associations of antihypertensive medication use with incident dementia in those with high blood pressure
Adapted from Ding et al,83
by permission of Elsevier.
Hazard ratio
(95% CI)
p value for
heterogeneity
Dementia
cases, n
Studies
(individuals, n)
Angiotensin-converting enzyme inhibitors
Alone or in combination (vs no drug users)
Alone (vs no drug users)
Alone or in combination (vs other drug users)
Alone (vs other drug users)
Angiotensin II receptor blockers
Alone or in combination (vs no drug users)
Alone (vs no drug users)
Alone or in combination (vs other drug users)
Alone (vs other drug users)
β blockers
Alone or in combination (vs no drug users)
Alone (vs no drug users)
Alone or in combination (vs other drug users)
Alone (vs other drug users)
Calcium channel blockers
Alone or in combination (vs no drug users)
Alone (vs no drug users)
Alone or in combination (vs other drug users)
Alone (vs other drug users)
Diuretics
Alone or in combination (vs no drug users)
Alone (vs no drug users)
Alone or in combination (vs other drug users)
Alone (vs other drug users)
Any antihypertensive drugs
Alone or in combination (vs no drug users)
χ²=3·35, df=5; p=0·65, I²=0·0%
6 (12521)
6 (11112)
6 (7794)
6 (6385)
3 (5737)
3 (5073)
3 (4559)
3 (4039)
6 (12668)
5 (9826)
6 (7794)
5 (5544)
6 (12469)
6 (11174)
6 (7794)
6 (6639)
6 (12588)
6 (10623)
6 (7794)
6 (5961)
6 (14520)
1100
895
1080
875
595
476
720
629
1258
888
1080
752
1098
900
1080
908
1257
934
1080
782
1865
0·97 (0·82–1·15)
1·03 (0·83–1·27)
1·11 (0·96–1·29)
1·16 (0·93–1·46)
0·84 (0·58–1·21)
0·78 (0·5–1·22)
0·88 (0·71–1·09)
0·76 (0·53–1·09)
0·86 (0·75–0·98)
0·96 (0·77–1·20)
0·95 (0·83–1·10)
1·07 (0·89–1·30)
0·87 (0·75–1·01)
0·92 (0·75–1·14)
1·04 (0·86–1·24)
1·09 (0·89–1·35)
0·87 (0·76–0·99)
0·97 (0·76–1·24)
0·95 (0·83–1·09)
1·05 (0·83–1·33)
0·88 (0·79–0·98)
0·32
0·72
0·43
0·48
0·09
0·24
0·62
0·62
0·58
0·27
0·41
0·39
0·97
0·97
0·26
0·5
0·52
0·16
0·91
0·26
0·65
0·710·5 1·411·0
Increased incident
dementia
Decreased incident
dementia
The Lancet Commissions
422	 www.thelancet.com Vol 396 August 8, 2020
evidence for physical activity protecting against clinically
diagnosed Alzheimer’s disease.88
Since the 2017 Commission, the HUNT study of
28 916 participants aged 30–60 years has been published,
reinforcing the previous literature in this area. At least
weekly midlife moderate-to-vigorous physical activity
(breaking into a sweat) was associated with reduced
dementia risk over a 25-year period of follow-up (HR 0·8,
95% CI 0·6–1·1) but the confidence intervals were wide.89
In contrast the Whitehall Study reporting on the 28-year
follow-up of 10 308 people, found that more than
2·5 hours of self-reported moderate-to-vigorous physical
activity per week, lowered dementia risk over 10, but not
28 years.33
Very long-term studies are unusual; however,
one 44-year study recruited 191 women (mean age 50)
purposively to be representative of the Swedish population
and reported that 32% of the participants with low
baseline peak fitness, 25% with medium, and 5% with
high fitness developed dementia (high vs medium
HR 0·1, 95% CI 0·03–0·5, low vs medium 1·4, 0·7–2·8).90
An individual-level meta-analysis of 19 observational
studies of relatively younger adults included
404 840 participants’ data (mean baseline age 45·5 years;
mean follow-up duration 14·9 years), reporting an
increased incidence of all-cause dementia (HR 1·4,
95% CI 1·2–1·7) and clinically diagnosed Alzheimer’s
disease (1·4, 1·1–1·7) in those who were physically
inactive in the 10-year period before diagnosis.91
Notably,
however, no difference in dementia risk measured
10–15 years before time of dementia incidence was
found except in those with comorbid cardio-metabolic
disease (RR 1·3, 95% CI 0·8–2·1).
People might stop exercising due to prodromal dementia
so inactivity might be either a consequence or a cause or
both in dementia and might be more of a risk in those
with cardiovascular morbidity. As with other outcomes,
exercise might be required to be sustained and continue
nearer the time of risk.92
Trials of exercise
Since the 2017 Commission several meta-analyses and
systematic reviews have been published with three
high quality meta-analyses which we include. The first
included 39 RCTs with an unclear total number of
participants examining moderate or vigorous exercise
of any frequency lasting 45–60 min per session in
cognitively normal adults aged older than 50 years. This
analysis reported global cognitive improvements (standard
mean difference [SMD]=0·3, 95% CI 0·2–0·4) for
moderate or vigorous resistance (13 studies) or aerobic
exercise (18 studies) lasting 45–60 min per session with
no difference between them but no effect found for
yoga.93
A second meta-analysis of RCTs in people with
mild cognitive impairment found global cognition
improved in the intervention group (0·3, 0·1–0·5) with
aerobic exercise having a higher effect (0·6, 0·5–0·6).94
This study did not have dementia as an outcome
measure. A third meta-analysis of RCTs of longer term
exercise found five studies (four lasting 12 months and
one 24 months) with 2878 participants with normal
baseline cognition.95
The incidence of dementia was
3·7% (n=949) for exercisers and 6·1% (n=1017) for
controls (random effect RR 0·6, 95% CI 0·3–1·1; fixed
effect as no evidence of heterogeneity 0·7, 0·4–1·0).
The authors concluded that the study showed no
significant effect of exercise for reducing dementia, mild
cognitive impairment, or clini­cally significant cognitive
decline but was underpowered. WHO guidelines have
been published since the 2017 Commission, suggesting
specific activity levels drawing on these, and one further
systematic review which considered sex differences on
the effect of exercise.96,97
It concluded the evidence
points towards physical activity having a small, beneficial
effect on normal cognition, with a possible effect in
mild cognitive impairment, mostly due to aerobic
exercise.97
Evidence about the effect of specific types of
exercise, such as progressive muscle resistance training,
on dementia risk is scarce.
Diabetes
In the 2017 Commission we reported on diabetes as a
risk factor for dementia. Distinguishing between treated
and untreated diabetes as a risk factor for dementia is
challenging in observational studies. In a pooled metaanalysis
from over 2·3 million individuals with type 2
diabetes across 14 cohort studies, including 102 174 with
dementia, diabetes was associated with an increased
risk of any dementia (RR 1·6, 95% CI 1·5–1·8 for women
and 1·6, 1·4–1·8 for men).98
The risk of dementia
increased with the duration and severity of diabetes. The
effect of different diabetic medications on cognition or
dementia outcomes remains unclear as few studies have
investigated this area.99
However, one meta-analysis of
cohort studies of diabetes reported that, cross sectionally,
people with diabetes taking metformin had lower prevalence
of cognitive impairment (three studies OR 0·6,
95% CI 0·4–0·8) and, longitudinally, reduced dementia
incidence (six studies HR 0·8, 95% CI 0·4–0·9)
compared with those taking other medications or no
medication.100
However another analysis did not find a
protective effect of metformin for incident dementia
(three studies, RR 1·1, 95% CI 0·5–2·4) with possible
harm with insulin therapy (1·2, 1·1–1·4); but this did
not account for severity of diabetes of those with type 2
diabetes on insulin.99
A Cochrane review reported
intensive compared to standard diabetes control trials
with 5 year follow up (n=11 140), showing no impact on
cognitive decline (1·0, 95% CI 0·9–1·1) or dementia
(1·3, 0·9–1·9).101
Overall type 2 diabetes is a clear risk factor for
development of future dementia; however, whether any
particular medication ameliorates this risk is unclear.
Intensive diabetic control does not decrease the risk of
dementia.
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Combined cardiovascular risk factors
Studies of individual cardiovascular risk factors usually
control for other cardiovascular risks, which cluster in
individual people. This does not take into account the
combinations and contexts in which risk occurs. A
UK study of 7899 people aged 50 years followed up for
25 years, calculated a cardiovascular health score based
on four behaviour-related (smoking, diet, physical
activity, BMI) and three biological (fasting glucose,
blood cholesterol, blood pressure) metrics each coded
on a three-point scale (0, 1, 2).100
A better score was
associated with a lower risk of dementia (HR 0·9,
95% CI 0·9–1·0 per 1 point scale increment), for both
behaviour-related (HR/1 point increment in subscales
0·9, 95% CI 0·8–0·9) and biological subscales (0·9,
0·8–1·0), main­tained in people free of cardiovascular
disease over the follow-up (0·9, 95% CI 0·8–1·0). These
authors also reported an association of the score on the
scale with hippocampal atrophy and total brain volume
but not white matter hyperintensities. This finding
underlines the importance of clustering of cardio­vascular
risk factors in midlife, as studies of individual risk
factors in this sample had not shown a significant
association, when controlling for other individual risks.33
Excessive alcohol consumption
Heavy drinking is associated with brain changes,
cognitive impairment, and dementia, a risk known for
centuries.102
An increasing body of evidence is emerging
on alcohol’s complex relationship with cognition and
dementia outcomes from a variety of sources including
detailed cohorts and large-scale record based studies.
Alcohol is strongly associated with cultural patterns and
other sociocultural and health-related factors, making it
particularly challenging to understand the evidence base.
A French 5-year longitudinal study of over 31 million
people admitted to hospital, found alcohol use disorders
(harmful use or dependence as defined in ICD) were
associated with increased dementia risk, calculated
separately for men and women (women HR 3·3, 95% CI
3·3–3·4, men 3·4, 3·3–3·4).103
The relationship of
dementia with alcohol use disorders was particularly
clear in the earlier onset dementias (age less than
65 years) in which 56·6% had an alcohol use disorder
noted in their records (n=57 353; 5·2% all dementias).
A systematic review incorporating 45 studies of light to
moderate drinking using a variety of definitions reported
a reduced risk of dementia compared with not drinking
(RR 0·7; 95% CI 0·6–0·91).104
Risk was not reported
separately for men and women. Drinking less than 21 units
of alcohol per week (1 unit of alcohol=10 mL or 8 g
pure alcohol) might be associated with a lower risk of
dementia.105,106
A 5-year follow-up study of 13 342 men and
women volunteers from UK biobank aged 40–73 years who
drank, included few heavy drinkers and did not analyse
abstainers.106
The study reported that those who drank
more than 12 units per week declined slightly more in
reaction time in a perceptual matching task than those
who drank less (β2=−0·07, 95% CI −0·09 to −0·04).106
The UK Whitehall study with 23 years follow-up, included
9087 participants aged 35–55 years at baseline.107
Drinking
more than 21 units per week and long-term abstinence
were both associated with a 17% (95% CI 4–32 and
13–23 respectively) increase in dementia compared to
drinking less than 14 units. Drinking more than 14 units
was also associated with right sided hippocampal atrophy
on MRI.108
Weight control and obesity
Overweight is an emerging concern, given the changing
BMI across the world’s ageing population. New evidence
supports the relationship between increased BMI and
dementia from a review of 19 longitudinal studies
including 589 649 people aged 35 to 65 years, followed up
for up to 42 years. It reported obesity (BMI ≥30; RR 1·3,
95% CI 1·1–1·6) but not being overweight (BMI 25–30;
1·1, 1·0–1·2) was associated with late-life dementia.109
In
a further meta-analysis of individual level data from
1·3 million adults (aged ≥18 years), which included
two studies from the meta-analysis cited above,109
higher
body mass measured before probable preclinical and
prodromal dementia was associated with increased
dementia risk (RR 1·3, 1·1–1·7/5-unit increase in BMI).11
Weight loss in midlife and dementia risk
A meta-analysis of seven RCTs (468 participants) and
13 longitudinal studies (551 participants) of overweight
and obese adults without dementia, mean age 50 years,
found weight loss of 2 kg or more in people with BMI
greater than 25 was associated with a significant
improvement in attention and memory. All but one of
the studies included participants aged younger than
65 years. The RCTs reported memory improvement over
8–48 weeks (SMD=0·4, 95% CI 0·2–0·6) and short-term
longitudinal studies found improvement over a median
of 24 weeks (SMD=0·7, 95% CI 0·5–0·8); however, data
about the long-term effects or the effect of weight loss in
preventing dementia are absent.110
Smoking
Smokers are at higher risk of dementia than non-
smokers,2
and at a higher risk of premature death before
the age at which they might have developed dementia,
introducing some bias and uncertainty in the association
between smoking and risk of dementia.111,112
Stopping
smoking, even when older, reduces this risk. Among
50 000 men aged older than 60 years, stopping smoking
for more than 4 years, compared to continuing, substantially
reduced dementia risk over the subsequent 8 years
(HR 0·9; 95% CI 0·7–1·0).113
Worldwide, 35% of nonsmoking
adults and 40% of children are estimated to be
exposed to second-hand smoke;114
although literature on
the impact of this exposure and dementia risk is scarce.
One study indicated that in women aged 55–64 years,
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second-hand smoke exposure was associated with more
memory deterioration and the risk increased with
exposure duration even after controlling for other
confounding factors.115
Depression
Depression is associated with dementia incidence, with
a variety of possible psychological or physiological
mechanisms. It is also part of the prodrome and early
stages of dementia. Reverse causation is possible
whereby depressive symptoms result from dementia
neuropathology that occurs years before clinical dementia
onset. These explanations are not mutually exclusive.
As in diabetes, few studies considering depression as a
risk factor for dementia have distinguished between
treated and untreated depression. In a meta-analysis
of 32 studies, with 62 598 participants, with follow-up
from 2 to 17 years, a depressive episode was a risk factor
for dementia (pooled effect size 2·0, 95% CI 1·7–2·3).116
Meta-regression analysis revealed a non-significant trend
for the association between depression and incident
dementia to be weaker when the length of follow-up was
longer. The Norwegian HUNT study, suggested that
symptoms of psychological distress predicted dementia
25 years later however with wide bounds of uncertainty
(HR 1·3, 95% CI 1·0–1·7).89
Two further studies differentiate
between late-life and earlier life depressive symptoms.
The UK Whitehall study, in a follow-up of
10 189 people, reports that in late life these symptoms
increase dementia risk but not at younger ages (follow-up
11 years HR 1·7; 95% CI 1·2–2·4; follow-up 22 years 1·0,
0·7–1·4). 34,117
A 14-year longitudinal study of 4922 initially
cognitively healthy men, aged 71–89 years, found depression
was associated with 1·5 (95% CI 1·2- 2·0) times the
incidence of dementia but this association was accounted
for by people developing dementia within 5 years of
depression.118
The use of antidepressants did not decrease
this risk.
A study of 755 people with mild cognitive impairment
and with a history of depression from the Australian
longitudinal Alzheimer’s Disease Neuroimaging Initiative,
considered the effect of selective serotonin-reuptake inhibitor
(SSRI) treatment, such as citalopram, known to
reduce amyloid plaque generation and plaque formation
in animal models.119
The study found that more than
4 years of such treatment was associated with delayed
progres­sion to clinically diagnosed Alzheimer’s disease.
People treated with antidepressants seem likely to differ
from those who are not treated. Thus, the question of
whether antidepressant treatment mitigates dementia risk
remains open.
Social contact
Social contact, now an accepted protective factor, enhances
cognitive reserve or encourages beneficial behaviours,
although isolation might also occur as part of the dementia
prodrome. Several studies suggest that less social contact
increases the risk of dementia. Although most people in
mid and later life are married, by the time they reach older
age, disproportionate numbers of women are widowed as
they outlive their husbands, thus reducing their social
contact. In these generations, marital status is therefore
an important contributor to social engagement. Additionally,
most marriages are in the relatively young, and
married people usually have more interpersonal contact
than do single people—this gives a long-term estimate
of the effect of social contact. A systematic review and
meta-analysis including 812 047 people worldwide found
dementia risk to be elevated in lifelong single (RR 1·4,
95% CI 1·1–1·9) and widowed people (1·2, 1·0–1·4),
compared with married people and the association was
consistent in different sociocultural settings.120
Studies
adjusted for sex and we do not know if a differential risk
between men and women exists. Differences persisted in
studies that adjusted for education and physical health so
might be attributable to married people having more
social contact, rather than solely because they tend to have
better physical health and more education, although
residual confounding is possible. A systematic review and
meta-analysis of 51 longitudinal cohort studies of social
isolation and cognition included 102 035 participants
aged 50 or more years at baseline, with follow-up of
2–21 years.121
High social contact (measured through
either or both of social activity and social network) was
associated with better late-life cognitive function (r=0·05,
95% CI: 0·04–0·065) and no differences according to sex
or length of time followed up.
A new meta-analysis found that in long-term studies
(≥10 years), good social engagement was modestly protective
(n=8876, RR=0·9, 95% CI 0·8–1·0); but loneliness
was not associated with dementia risk.122
No long term
(>10 years) studies of loneliness and dementia outcomes
have been done.
A UK 28-year follow-up study of 10 308 people found
that more frequent social contact at age 60 years was
associated with lower dementia risk over 15 years of
follow-up (HR for one standard deviation social contact
frequency 0·9, 95% CI 0·8–1·0). This finding suggests
more frequent social contact during late middle age is
associated with a modest reduction in dementia risk,
independent of socio-economic and other life­style
factors.123
A Japanese longitudinal cohort study of
13 984 adults aged older than 65 years with a mean of
10 years follow-up calculated a five-point social contact
scale based on: marital status; exchanging support with
family members; having contact with friends; participating
in community groups; and engaging in paid work.
It found the score to be linearly associated with reduced
dementia risk; those who scored highest on the five-point
scale were 46% less likely to develop incident dementia
compared with those in the lowest category.124
Despite clear cultural variation in the meaning and
perception of social isolation, findings of protective effect
of more social contact are largely consistent in different
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settings and for either sex across the studies and meta-
analyses.118,120,121
Social interventions
Little evidence of the effects of social interventions on
dementia exists but a systematic review of low quality
RCTs of 576 adults aged 60 or more years with normal
cognition found facilitated meeting and discussion
groups were associated with improved global cognition
and increased brain volume at follow-up.118
Air pollutants
Air pollution and particulate pollutants are associated
with poor health outcomes, including those related to
non-communicable diseases. Attention has turned to
their potential effect on the brain. Animal models
suggest airborne particulate pollutants accelerate neurodegenerative
processes through cerebrovascular and
cardiovascular disease, Aβ deposition, and amyloid
precursor protein processing.125,126
Although the higher
levels of dementia from air pollutants are still subject to
the potential for residual confounding, the effects on
animal models are evidence of physiological effects over
and above those driven by life-course deprivation.
High nitrogen dioxide (NO2) concentration (>41·5 µg/m³;
adjusted HR 1·2, 95% CI 1·0–1·3), fine ambient particulate
matter (PM)2·5 from traffic exhaust (1·1, 1·0–1·2)127–129
and
PM2·5 from residential wood burning (HR=1·6, 95% CI
1·0–2·4 for a 1 μg/m³ increase) are associated with
increased dementia incidence. Traffic often produces NO2
and PM2·5 and it is hard to separate their effects, although
evidence for additive effects of different pollutants
exists.127–129
A systematic review of studies until 2018
including 13 longitudinal studies with 1–15 years follow-up
of air pollutants exposure and incident dementia, found
exposure to PM2·5, NO2, and carbon monoxide were all
associated with increased dementia risk.24
The attributable
burden of dementia and excess death from PM2·5 in one
large 10-year US study was particularly high in Black or
African American individuals and socio-economically
disadvan­taged communities and related to particulate
PM2·5 concentrations above the US guidelines.130
Sleep
Mechanisms by which sleep might affect dementia
remain unclear, but sleep disturbance has been linked
with β-amyloid (Aβ) deposition,131,132
reduced glymphatic
clearance pathways activation,133
low grade inflammation,
increased Tau, hypoxia132,134
and cardiovascular disease.135
Sleep disturbance is hypothesised to increase inflammation
which raises Aβ burden, leading to Alzheimer’s
disease and further sleep disturbance.136
Two meta-analyses showed similar findings. The first
was a synthesis of longitudinal studies with an average of
9·5 years follow-up and the second reported crosssectional
and prospective cohort studies of mixed quality
with different methods of measuring sleep. Sleep
disturbances were defined broadly, often self-reported
and including short and long sleep duration, poor sleep
quality, circadian rhythm abnormality, insomnia, and
obstructive sleep apnoea. All these disturbances were
associated with a higher risk of all-cause dementia
(RR 1·2; 95% CI 1·1–1·3)137
and clinically diagnosed
Alzheimer’s disease (1·6, 1·3–1·9) compared with no
sleep disturbance, although not all cohort studies
excluded those with cognitive impairment or dementia at
baseline from their analyses.138
A U-shaped association
has been reported between sleep duration and risk of
mild cognitive impairment or dementia with higher risks
of dementia with less than 5 hours (HR=2·6; 95% CI
1·4–5·1) compared with more than 5 and less than 7 and
more than 10 hours sleep (2·2, 1·4–3·5) and risks for allcause
dementia and clinically diagnosed Alzheimer’s
disease being similar.135,139–141
The postulated mechanisms of reduced sleep leading
to accumulation of Alzheimer’s type pathology is
inconsistent with the evidence that both more sleep and
less sleep are associated with increased risk of dementia.
New onset late-life sleep disturbance, a few years before
clinical dementia, might be part of the natural history of
the dementia syndrome, appearing to be a risk factor, or
reflect other disorders, for example, mood disturbances or
cardiovascular disease.135,142
Hypnotic use might increase
risks although this is unclear and a 2018 study139
suggests
that findings of a connection were related to reverse
causality and confounders.143
When benzodiazepine use
was considered, in one study, sleep length was no longer
significant139
but not in all studies.135
Those taking
hypnotics were at greater risk of dementia than those who
did not regardless of sleep duration.139
Medication for
sleep disturbance might be harmful and benzodiazepines
are associated with falls, hospital admissions, and possibly
dementia.139,144
Diet
Nutrition and dietary components are challenging to
research with controversies still raging around the
role of many micronutrients and health outcomes in
dementia. Observational studies have focused on individual
components ranging from folate and B vitamins,
Vitamin C, D, E, and selenium amongst others as
potential protective factors.88
There has been a move
towards considering the evidence base for whole diets in
the last 5 years, particularly high plant intake such as in
the Mediterranean diet (high intake of vegetables,
legumes, fruits, nuts, cereals, and olive oil; low intake of
saturated lipids and meat) or the similar Nordic diet,
rather than individual nutrients, which might reduce
cognitive decline and dementia.145
One example is a
longitudinal cohort study of 960 partici­pants, ages
58–99 years, in which those reporting the highest intake
of green leafy vegetables, equivalent to 1·3 servings per
day, had less cognitive decline over 4·7 years than those
reporting the lowest intake (β=0·05 standardised units
The Lancet Commissions
426	 www.thelancet.com Vol 396 August 8, 2020
95% CI 0·02–0·07).146
The authors report this difference
as being equivalent to being 11 years younger. A further
prospective cohort study with three midlife dietary
assessments in 8255 people, followed up for a mean of
nearly 25 years, found neither healthy dietary pattern
nor Mediterranean diet protected from dementia, except
in those with cardiovascular disease, suggesting that diet
might influence dementia risk by protecting from the
excess risk of cardiovascular risk factors.147
Dietary interventions
As well as whole diets, there has been some interest in
multi-nutrient interventions. A systematic review and a
Cochrane review including RCTs of supplements (A, B,
C, D, and E; calcium, zinc, copper, and multivitamins
trials, n-3 fatty acids, antioxidant vitamins, and herbs)
found a lack of evidence for supplement use to preserve
cognitive function or prevent dementia in middleaged
(45–64 years) or older people (aged 65 years and
older).148,149
Cochrane reviews found no evidence for
beneficial effects on cognition of those with mild cognitive
impairment of supplementation with B vitamins
for 6 to 24 months150
or with vitamin E in preventing
progression from mild cognitive impairment to demen­
tia.151
A 24-month RCT of 311 people of a multi-nutrient
drink containing docosahexaenoic acid, vitamins B12,
B6, folic acid, and other nutrients; found no significant
effect on preventing cognitive deteriora­tion in
prodromal Alzheimer’s dis­ease.152
The authors comment
that the control group’s cognitive decline was much
lower than expected, leading to an inadequately powered
trial.
Meta-analysis of two RCTs with 471 participants
with normal cognition found the Mediterranean diet
improved global cognition compared to controls
(SMD 0·2, 95% CI 0·0–0·4).153
A further meta-analysis
identified five RCTs (n=1888) with a weak effect on
global cognition (SMD 0·2, 95% Cl 0·0–0·5)154
but no
benefit of Mediterranean diet for incident cognitive
impairment or dementia.
The WHO guidelines recommend a Mediterranean diet
to reduce the risk of cognitive decline or dementia, as it
might help and does not harm, but conclude Vitamins B
and E, polyunsaturated fatty acid, and multicomplex
supplementation should not be recommended.97
Trials of combination strategies to prevent
dementia
The FINGER RCT was a 2-year multidomain intervention
to prevent cognitive decline and dementia in
1260 people with cardiovascular risk factors aged
60–77 years, recruited from a Finnish national survey.
Similar multidomain studies were discussed in the 2017
Commission.2
FINGER found a small group reduction in
cognitive decline in the intervention group compared
with control (comprehensive neuropsychological test
battery Z score 0·02, 95% Cl 0·00–0·04) regardless of
baseline sociodemographic, socio-economic, cognitive,
or cardiovascular status.155
However, in a subgroup
analysis, greater beneficial effects were observed on
processing speed in individuals with higher baseline
cortical thickness in Alzheimer’s disease areas.156
The Healthy Ageing Through Internet Counselling in
the Elderly (HATICE) study recruited 2724 older people
(≥65 years) in the Netherlands, Finland, and France
with two or more cardiovascular risk factors.157,158
It
compared an interactive internet platform plus remote
support by a coach, aiming to improve self-management
of vascular risk factors, with a non-interactive
control platform with basic health information. A small
improvement in the cardiovascular risk composite
primary outcome was observed in the intervention
group compared with the control group at 18 months,
mainly through weight loss, and the dementia risk
score was slightly lower in those who received
the intervention (mean difference −0·15, 95% CI
−0·3 to −0·0). A larger effect was observed in the
younger age group (65–70 years) and those with the
lowest level of education, who had a higher baseline
risk, suggesting that targeting high-risk popula­tions
might be more effective. Several multi­domain preventive
trials are ongoing—for example, World Wide
FINGERS.
Total PAF calculation
We incorporated excessive alcohol consumption, TBI,
and air pollution into our life-course model of dementia,
as well as the original nine risk factors, because of the
updated evidence. To calculate new RRs for excessive
alcohol consumption, TBI and air pollution, we systematically
reviewed the literature and did new metaanalyses
for excessive alcohol consumption and TBI.
For the other nine factors, we used values for RR and
risk factors prevalence from our previous analysis and
calculated communality using the same method as in
the 2017 Commission.2
PAF calculation
We used a representative sample of over 10 000 UK
community-dwelling adults, to calculate communality
(clustering of risk factors) of 11 risk factors for which
data existed,159
to allow calculation of each factor’s
unique risk. As we could find no datasets measuring
TBI, with the other 11 risk factors of interest, we could
not calculate its communality. We therefore used the
mean of the other 11 communalities to calculate a
weighted PAF, so we could include TBI. We used
cohabitation as a proxy measure for social contact, and
urbanicity for air pollution exposure. Our analysis
found four principal components, explaining 55% of
the total variance between the eleven risk factors,
suggesting substantial overlap. The appendix (p 2)
shows the PAF formula and the steps in calculating
communality and we detail our new meta-analyses
See Online for appendix
For the WorldWide FINGERS
network see http://wwfingers.
com/
The Lancet Commissions
www.thelancet.com Vol 396 August 8, 2020	 427
next, which we used to update the figure and perform
our new calculations.
Incorporation of the new chosen risks in new
systematic reviews
Alcohol
We searched, from inception to Oct 29, 2019, Embase,
Allied, and Complementary Medicine, MEDLINE, and
PsycINFO terms “dementia” OR “dement*” OR “AD” OR
“VaD”, “Alzheimer*” AND “alcohol” OR “ethanol” OR
“alcohol*” OR “drink*” OR “drunk*” to update an earlier
review.160
We used inclusion criteria: original populationbased
cohort studies measuring drinking during midlife,
as alcohol intake tends to fall with age;161
alcohol
consumption quantified at baseline by units or number
of drinks (one drink, 1·5 units) per week; and all-cause
dementia ascertained at follow-up using validated clinical
measures. We contacted authors for additional data.162
Three studies met our inclusion criteria.107,162,163
We
converted HRs to RRs 164
and used raw data162
to calculate
RR,165
for our random effects meta-analysis using Generic
Inverse Variance Methods. The RR associated with
drinking—more than 21 units (168 g) of alcohol weekly—
compared with lighter drinking was 1·18 (95% Cl
1·06–1·31; figure 5). We used Health Survey England
figures for heavier drinking prevalence to calculate PAF
as we could not find a worldwide estimate. The weighted
PAF was 0·8.
TBI
To estimate the RR of TBI of all severities for all cause
dementia, we searched Embase, Medline, and PsycINFO
from Jan 1, 2016, to Oct 21, 2019, updating an earlier
search,166
using terms (“traumatic brain injury” or “head
injury” or “brain injury” or TBI) AND (neurodegeneration
or “cognitive dysfunction” or dementia or “Alzheimer’s
disease” or “Parkinson’s disease” or “frontotemporal
dementia”). We converted HR figures to RR.164,167
We
used inclusion criteria: original population-based cohort
studies, baseline TBI of all severities reported, and allcause
dementia ascertained at follow-up using validated
clinical measures. We combined four new studies meeting
inclusion criteria67,68,71,168
with the four studies meeting
criteria from the original review in a random effects meta-
analysis.166
The pooled RR was 1·84 (95% CI 1·54–2·20)
for all cause dementia from all severities of TBI (figure 6)
although there was heterogeneity in study-specific estimates,
possibly because of different popula­tions. We used
the TBI adult population prevalence of 12·1% from a metaanalysis
to calculate PAF.173
The weighted PAF was 3·4.
Figure 5: Meta-analysis of relative risk of dementia associated with drinking more than 21 units of alcohol per week in midlife compared to lighter
consumption of alcohol
Lower dementia risk Higher dementia risk
Log
(risk ratio)
Weight Risk ratio
IV, random, 95% CI
Total
Study or subgroup
Handing et al (2015)163
Jarvenpaa et al (2005)162
Sabia et al (2018)107
Total (95% CI)
Heterogeneity τ2
=0·00, χ2
=0·06, df=2 (p=0·97); I2
=0%
Test for overall effect z=3·00 (p=0·003)
0·17
0·29
0·16
SE
0·09
0·53
0·07
Drinking
>21 units per week
300
23
2232
2555
Total
Drinking
<21 units per week
9153
310
552
15015
37·3%
1·1%
61·1%
100·0%
1·19 (0·99–1·41)
1·34 (0·47–3·78)
1·17 (1.02–1·35)
1·18 (1·06–1·31)
0·01 0·1 1 10 100
Figure 6: Meta-analysis of relative risk of all-cause dementia associated with all severity midlife traumatic brain injury
Reduced risk Increased risk
Log
(risk ratio)
Weight Risk Ratio
IV, random, 95% CI
Study or subgroup
Abner et al (2014)169
Chu et al (2016)168
Fann et al (2018)67
Gardner et al (2014)170
Nordström et al (2014)171
Nordström et al (2018)68
Wang et al (2012)173
Yaffe et al (2019)71
Total (95% CI)
Heterogeneity τ2
=0·05, χ2
=579·69, df=7 (p<0·00001); I2
=99%
Test for overall effects: z=6·69 (p<0·00001)
–0·27
1·161
0·211
0·383
0·385
0·569
0·548
0·397
SE
0·353
0·098
0·012
0·021
0·107
0·0132
0·034
0·198
4·6%
13·0%
15·3%
15·2%
12·7%
15·3%
15·0%
8·9%
100·0%
0·76 (0·38–1·52)
3·19 (2·64–3·87)
1·23 (1·21–1·26)
1·47 (1·41–1·53)
3·99 (3·24–4·93)
1·77 (1·72–1·81)
1·73 (1·62–1·85)
1·49 (1·01–2·19)
1·84 (1·54–2·20)
0·2 0·5 1 2 5
The Lancet Commissions
428	 www.thelancet.com Vol 396 August 8, 2020
Pollution
A 2019 systematic review synthesised observational
studies, finding consistently increased risk of dementia
from air pollution, but heterogeneous comparator groups
precluded meta-analysis.24
We updated the search, using
the same search terms and searching MEDLINE,
Embase, and PsycINFO from Sept 20, 2018, (the end
date of the last search) to Oct 22, 2019. We included
longitudinal studies with assessment of all cause air
pollution exposure; use of formal assessment of cognitive
function at baseline; report of incident all-cause
dementia, data from adults (age ≥18 years); and a
minimum follow-up of 6 months. As meta-analysis was
not possible, we used data from the only study of allcause
air pollution with the outcome of all-cause
dementia, with low-moderate risk of bias. This
population-based, observational cohort was from Canada,
where pollutant concentrations are among the lowest
in the world and examined 2 066 639 people, with a
mean baseline age of 67 years.174
We calculated the RR
of dementia for those in the three highest quartiles
compared to the lowest was 1·09 (1·07–1·11). The
attributable fraction for exposure to the highest three
quartiles versus the lowest quartile of PM2·5 and NO2 was
6·1% (4·8–7·5). The weighted PAF was 2·3.
Table 1 displays the prevalence, commu­nality, relative
risk, unweighted and weighted PAFs adjusted for communality.
Figure 7 shows the updated life-course model
of potentially modifiable risk factors for dementia,
including the three new risk factors.
Strengths and limitations
This Commission is the most comprehensive ana­lysis to
date and updates the 2017 Commission with emerging
risk factor evidence convincing enough to calculate
PAF for potentially reversible risk factors. We reviewed
the literature systematically for the chosen risk factors
and provided illustrative new literature to update our
synthesis and identify data to calculate communality. We
find a hopeful picture with an estimate of around 40% of
all cases of dementia being associated with 12 potentially
modifiable risk factors.
We have made assumptions to calculate this new
model. We used global figures for dementia risk
although we know the risk factors prevalence varies
between countries and most global research is from
HIC, so LMIC are under-represented because of lack of
data. We have assumed a causal relationship between
risk factors and dementia, although we have been
cautious and not included risk factors with less good
evidence. No single database exists with all 12 risk factors
together, but we found 11 of the factors in a UK database
and used the mean figure for communality calculations
for TBI. We calculated communality for the other 11. We
do not know how far findings of communality in other
geographical populations might differ, or in those with a
differing distribution of age groups or sex. We found
that social isolation was not explicitly measured and had
to use proxies, such as cohabitation when considering
prevalence, which are approximate.
Specifically, evidence for the association of alcohol
misuse with dementia comes from HIC and future
studies from LMIC are needed to complete the picture.
Exposure to air pollution changes over a lifetime and is
inextricably linked to poverty and deprivation. However,
the effects on animal models suggests specific physiological
effects over and above those driven by life-course
deprivation. We also considered the overlap with education
for this and other risk factors and the correction for
education, strongly inversely linked to deprivation, will
address at least some of the confounding. However, the
results in one study which reported the effect of air
pollution on incident dementia showed very little
Figure 7: Population attributable fraction of potentially modifiable risk factors for dementia
Risk unknown
60%
Potentially
modifiable
40%
7%
8%
3%
2%
5%
4%
4%
2%
2%
%
1%
1%
1%
Later life
Diabetes
Air pollution
Physical inactivity
Social isolation
Depression
Smoking
Hearing loss
Percentage reduction in dementia prevalence
if this risk factor is eliminated
Less education
Traumatic brain injury
Hypertension
Alcohol
>21 units per week
Obesity
Midlife
Early life
The Lancet Commissions
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difference in estimates before and after adjustment for
education and other risk factors, suggesting little residual
confounding exists.174
We were also unable to metaanalyse
data on pollution and thus unlike the other
relative risks, the figure comes from only one study, from
an area of low pollution so is likely to be an underestimate.
The longitudinal evidence linking potentially modifiable
risk factors to dementia generally fulfils causality criteria
in observational data (strength, consistency, biological
plausibility, temporality, dose–response, coherence, and
quasi-experimental studies, for example, more education
or using hearing aids). When measuring a risk nearer to
the age of dementia onset, then it is more likely that
prodromal change affects, or even causes it. Alternatively, a
risk factor might act on preclinical pathology or even cause
dementia near the time of exposure. Thus, excessive
alcohol, and TBI are particularly important in young-onset
dementia, although many early onset dementias relate to
genetic risks. Risk factors might also matter more at a time
of higher biological vulnerability, which the studies we
have drawn on cannot establish. The length of exposure
required for risk or protection effect, and their interrelationships
as they change across life is unclear—it
seems probable that longer or more intense exposure has
stronger effects. Additionally, as our communality figures
show, risk factors overlap. We cannot establish from these
data if having multiple risk factors has an additive or
synergistic effect. Association does not prove causation,
however, as already noted, the reductions in prevalence
and incidence in several HIC suggests that at least some of
the risk factors estimated here do have a causal relationship
with the clinical expression of dementia.
Key points and recommendations
We judge that sufficient new evidence supports adding
three additional modifiable risk factors for dementia to
our 2017 Commission model (excessive alcohol, traumatic
brain injury, and air pollution). We have been able to add
updated evidence on the nine risk factors implicated in
the 2017 Commission (education, hypertension, hearing
impairment, smoking, obesity, depression, inactivity,
diabetes, and social contact). Reduction of these risk
factors might be protective for people with or without a
genetic risk, although study findings have not been
entirely consistent.175–178
As we noted in the 2017
Commission, others have previously calculated an estimate
of the risk associated with APOε4 at 7% taking into
account some other risk factors and this estimate
highlights how relatively important potentially modifiable
risk factors are in dementia.2,179
For some risk factors, the pattern of risk and the
individual’s other health, both physical and mental,
might be especially important. Currently, the evidence
suggests a Mediterranean or Scandinavian diet might
have value in preventing cognitive decline in people with
intact cognition, particularly as one component of a
healthy lifestyle, although how long the exposure has to
be or during which ages is unclear. We do not recommend
taking additional vitamins, oils, or mixed dietary supplements
as a means of preventing dementia as extensive
testing in trials has not led to signals of beneficial effects.
Data from RCTs on interventions to prevent cognitive
decline, all-cause dementia, or Alzheimer’s disease are
few. For some key life influences, only observational
data, particularly related to natural experiments such as
changing the statutory education age, are possible. These
influences should be investigated systematically wherever
possible. Others can theoretically be investigated but the
long follow-up required for midlife risk and protective
factors and non-random attrition in longer studies are
challenging. Using intermediate endpoints, such as
cognition, and dementia onset in research remains
uncertain because no intermediate markers with such a
close relationship to dementia outcomes exist that it
would be possible to predict with certainty for any given
individual, age, and sex. Overall, the evidence for treating
hypertension is strongest and high blood pressure
throughout midlife increases the risk of dementia even
without stroke.
Although a need for more evidence is apparent, recommendations
should not wait, as clear indications of ways
to reduce the chances of developing dementia without
causing harm will also lead to other health and wellbeing
benefits.
Our recommended strategies for dementia risk
reduction include both population-wide and targeted
interventions (panel). It is important to remember that
more socially disadvantaged groups, including Black,
Asian, and minority ethnic groups, are particularly at
risk.
Although we have more to learn about effectiveness,
avoiding or delaying even a proportion of potentially
modifiable dementias should be a national priority for all.
Interventions and care in dementia
Not all dementia will be preventable and we present the
latest evidence on intervention and care for dementia. To
date the emphasis has been on specific subtypes of
dementia, most notably on Alzheimer’s disease, which has
been conceptualised over the years in a variety of changing
diagnostic criteria—eg, DSM IV and DSM V.180,181
Intense
efforts have been put into biomarkers for early preclinical
detection of the disease process before it becomes
dementia. Biomarkers need to show reliability and validity,
and for dementias they also need to be very closely and
clearly related to clinical syndrome outcomes in the way
that, for example, human papillomavirus is for cervical
cancer, and hypertension has been for stroke.
Biomarkers and detection of Alzheimer’s disease
Markers of neurodegeneration linked to clinical dementia
include brain volume loss—ie, hippocampal volume loss
and entorhinal cortex and medial temporal cortical
thinning—seen in structural imaging. The most studied
The Lancet Commissions
430	 www.thelancet.com Vol 396 August 8, 2020
molecular markers are in Alzheimer’s disease and are
amyloid and tau, which PET and CSF detect clinically.
The prevalence of particular pathologies at different ages
is important in interpretation of such studies. So, for
example, population derived studies show increases in
plaques in the population from less than 3% at age
50–59 years to around 40% at age 80–89 years.182
Amyloid imaging
Amyloid imaging detects amyloid in the brain with high
sensitivity and specificity in both cognitively normal and
people with Alzheimer’s disease when the gold-standard
comparison is either neuropathology or clinical diag­nosis,
distinguishing Alzheimer’s disease from other neurodegenerative
conditions.183
Amyloid imaging is not a
diagnostic test for dementia. A US study of randomly
selected older people from the community recruited
1671 people (mean age of 71 years).182
The prevalence of
PET detected amyloid positivity increased from 2·7%
(95% CI 0·5–4·9) of people without cognitive impairment
aged 50–59 years to 41·3% (95% CI 33·4–49·2%) aged
80–89 years.182
In 10-year follow-up PET positivity was
associated with a higher probability of developing
Alzheimer’s disease compared with those who were
amyloid negative (HR 2·6, 95% CI 1·4–4·9). In participants
with mild cognitive impairment who were amyloid
positive the probability (HR 1·9, 95% CI 0·9–3·9) was
not very different to those who were amyloid negative
(1·6, 0·8–3·4).
Similarly, an 8-year follow-up study of 599 volunteers
(average age 70 years) in Australia found that cognitively
normal PET amyloid-positive people had an elevated
risk of developing Alzheimer’s disease compared with
amyloid negative (17·7% vs 8·1%; OR 2·4, 95% CI
1·5–4·0).184
Over 80% of the 266 people who were PET
amyloid-positive did not go onto develop a cognitive
impairment within 8 years, showing positive status
does not predict impairment for most people in a
timeframe that might be a useful prognostic window.
Follow-up at 5 years of amyloid-positive participants
with normal cognition or mild cognitive impairment
versus amyloid negative people found the same pattern
of increased risk (2·6, 1·4–4·9). Risk also increases per
1 year of age (HR 1·05, 95% CI 0·55–2·0/year), and
APOEε4 status (2·6, 1·4–5·0).184
Most people who are amyloid positive with no other
markers have not developed Alzheimer’s disease dementia
during their lifetime. A model of lifetime risks of people
who are amyloid positive without any other biomarkers
finds it to be 8·4% for a 90-year-old woman who is
cognitively normal at baseline, 23·5% for a 75-year-old
woman and 29·3% for a 65-year-old woman.185
The 10-year
risk is considerably less, so a 65-year-old woman with only
amyloid biomarkers but who is cognitively normal and
has no neurodegeneration has a 10-year Alzheimer’s
disease risk of 2·5% and a man 2·3%, but the risk is
higher with accompanying neurodegeneration (table 2).185
Overall, the knowledge of PET-measured amyloid and
tau status and MRI-derived cortical thickness in a general
population derived sample, only adds a small improvement,
which might not be clinically important for
predicting memory decline over a model with clinical and
genetic variables.186
Using amyloid PET in patients with cognitive impairment
of uncertain causes, results in changes to the
clinical diagnosis of Alzheimer’s disease187
and sometimes
to medication prescription. We do not know whether
PET use improves patient care or decreases care costs.
Many people have a mixed cause of dementia and a
positive result does not indicate only Alzheimer’s disease.
Fluid biomarkers
PET imaging is very costly (US$3000 in the USA) and
although used in some clinical settings remains the topic
of research to understand its usefulness in broader
populations. Fluid biomarkers—ie, blood and cerebrospinal
fluid tests—have become a more practical focus of
interest since it has become possible to measure specific
proteins linked to the proteins associated with the
neuropathologies of Alzheimer’s disease.188
A composite
blood biomarker for amyloid tested in a discovery dataset
and then a validation cohort of participants aged
60–90 years who were already taking part in studies in
Japan or Australia had areas under the receiver operating
Panel: Recommended strategies for dementia risk reduction
Risks are particularly high in more socially disadvantaged populations including in Black,
Asian, and minority ethnic groups.
Population-wide
•	 Prioritise childhood education for all, worldwide
•	 Implement social public health policies that reduce hypertension risk in the entire
population
•	 Develop policies that encourage social, cognitive, and physical activity across the life
course for all (with no evidence for any specific activities being more protective)
•	 Scrutinise the risks for hearing loss throughout the life course, to reduce the risk of
exposure to this risk factor
•	 Reduce the risk of serious brain trauma in relevant settings, including occupational
and transport
•	 National and international policies to reduce population exposure to air pollution
•	 Continue to strengthen national and international efforts to reduce exposure to
smoking, both for children and adults, and to reduce uptake and encourage cessation
Targeted on individuals
•	 Treat hypertension and aim for systolic blood pressure <130 mm Hg in midlife
•	 Use hearing aids for hearing loss; we need to help people wear hearing aids as many
find them unacceptable, too difficult to use, or ineffective
•	 Avoid or discourage drinking 21 or more units of alcohol per week
•	 Prevent head trauma where an individual is at high risk
•	 Stopping smoking is beneficial regardless of age
•	 Reduce obesity and the linked condition of diabetes by healthy food availability and
an environment to increase movement
•	 Sustain midlife, and possibly late-life physical activity
The Lancet Commissions
www.thelancet.com Vol 396 August 8, 2020	 431
characteristic curves of 96·7% for discovery and 94·1%
for validation. The blood biomarker had sensitivity and
specificityabove80%againstamyloidPETmeasurement188
and correlated with CSF concentrations of Aβ1–42. These
results are similar to other amyloid blood biomarkers189,190
and harmonisation to a common reference standard is
now vital. Although CSF Aβ1–42/1–40 ratio and amyloid
PET are now considered interchangeable,191
CSF tau
biomarkers have only correlated weakly with brain tau
as currently measured by radioligands.192
Neurofilament
light protein is measured in many cohorts; however, it is
non-specific. People with Huntington’s disease, multiple
sclerosis, mild cognitive impairment, and Alzheimer’s
disease might have raised blood neurofilament light concentrations,
which are a marker of neurodegeneration.193–195
Key points and conclusions
To be useful in clinical practice biomarkers must be well
understood in the populations to which they are going to
be applied, including the effects of age and sex on results.
There is now reasonable evidence that amyloid and tau
measured by PET or in fluid indicate increased risk for
development of cognitive impairment in older adults but
at the individual level prognostication is not possible as
most cognitively normal people with these markers
do not develop dementia within a clinically relevant
timeframe. Negative amyloid results can be useful for
ruling out current Alzheimer’s pathology in people with
cognitive impairment when the cause is uncertain and
show an individual is unlikely to develop Alzheimer’s
disease during the next few years. High neurofilament
light concentrations indicate a neuro­degenerative process
but not its cause. The value of biomarkers, in terms of
diagnostic value, has not been addressed in different
representative populations and particularly not in those
from LMIC. The potential advantages of blood biomarkers
are their low cost and their wider acceptability and
applicability in many settings. In many areas of medicine
more reliable diagnostic tests have improved research,
including epidemiological and public health research
and trials, to help distinguish cause from symptom
(tuberculosis from a fever) or assess risk factor and
disease (hyper­cholesterolaemia and ischaemic heart
disease). Those biomarkers developed for the underlying
biology of the dementia syndrome are subject to the same
assessment of value.
Principles of intervention in people with dementia
In the 2017 Commission, we discussed that when
concerns are raised by patients or family, an accurate
diagnosis is helpful. Such a diagnosis provides a
gateway to intervention and services where available, for
planning for possible futures, and support for family, as
well as to research. Unfortunately, these services are not
always available. National plans for dementia support
timely diagnosis and offer help to individuals and their
families.
We did not address screening of those not presenting
with concerns but rigorous systematic reviews by the
US Task Force on Prevention have found an absence
of evidence of benefit and harm.196
The first trial of
population screening took place in the USA, screening
4005 primary care patients aged 65 years or older. No
clear benefit or harm in terms of quality of life, mood, or
increasing diagnostic rates was found.197
Other strategies
might become more valuable in time such as sensitive
awareness of risk factors, when routine records suggest
an individual might be deteriorating cognitively.198
People with dementia have complex problems with
symptoms in many domains. Those providing support
and any interventions must consider the person as a
whole, as well as their context and their close carers,
whether family or friends. Individuals’ medical, cognitive,
psychological, environmental, cultural, and social needs
must be given consideration.2
In the context of under
provision of services, this notion is and will continue to
be a challenge. Dementia, as an illness which affects
cognition by definition, affects the ability to organise
activities and people with dementia often need help to do
what they enjoy—for example, listen to music, or go to
gardens and parks. Wellbeing is one of the goals of
dementia care.
Normal state 1 Amyloidosis
state 2
Neurodegeneration
state 3
Amyloidosis and
neurodegeneration
state 4
Mild cognitive impairment
and amyloidosis and
neurodegeneration state 5
Mild cognitive impairment
and neurodegeneration
state 6
60 years 0·2 (0·06–0·8) 1·3 (0·6–2·5) 3·6 (1·1–14·2) 7·1 (4·5–10·9) 93·5 (91·1–95·0) 57·2 (48·2–67·9)
65 years 0·5 (0·14–1·8) 2·5 (1·2–4·9) 4·3 (1·4–15·0) 10·7 (6·8–16·2) 91·7 (89·2–93·5) 55·4 (46·6–65·8)
70 years 1·1 (0·34–3·5) 4·7 (2·4–8·7) 5·5 (2·0–16·6) 15·5 (10·0–22·8) 88·6 (85·8–90·6) 52·2 (43·8–62·4)
75 years 2·2 (0·74–6·5) 7·8 (4·1–14·0) 7·3 (2·9–19·0) 20·8 (13·7–29·7) 83·8 (80·7–86·2) 47·4 (39·6–57·0)
80 years 3·7 (1·3–9·8) 11·1 (6·0–18·7) 9·3 (3·9–20·9) 24·4 (16·4–33·8) 75·8 (72·2–78·7) 40·0 (33·1–48·6)
85 years 4·7 (1·8–11·0) 11·5 (6·5–18·5) 9·7 (4·3–19·3) 23·1 (15·8–31·2) 63·7 (59·6–67·2) 30·0 (24·5–37·2)
90 years 3·8 (1·5–8·2) 8·2 (4·7–12·9) 7·1 (3·3–13·3) 16·8 (11·5–22·6) 46·7 (42·7–50·2) 19·1 (15·3–24·3)
Data are relative risk (95% CI) or %. Reproduced from Brookmeyer and Abdalla185
by permission of Elsevier.
Table 2:Ten-year risks by age of developing Alzheimer’s disease for women based on amyloidosis alone and in the presence of neurodegeneration and
mild cognitive impairment
The Lancet Commissions
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Interventions once a diagnosis has been made
Medication
Cholinesterase inhibitors have a useful, modest role
in improving cognition and activities of daily living in
patients with mild-to-moderate Alzheimer’s disease
and memantine can be prescribed in combination or
each drug used separately for moderate and severe
Alzheimer’s disease.2,199,200
However, although available in
most countries these drugs are no longer remunerated
in France because it is felt that they offer only a small
benefit while shifting clinician’s attention from other
interventions. Whether non-prescribing of this drug will
help patients by removing an intervention with known
benefit or be detrimental to them is unknown.201
No
advances have been reported in Aβ therapeutics, with
negative results from phase 3 trials of monoclonal
antibodies (eg, solanezumab, crenezumab) and inhibitors
of β-secretase, a protease involved in the production of
Aβ peptides.202
Aducanumab previously abandoned as
futile now has further unpublished results. Three
5HT6 antagonists and the calcium channel blocker
nilvadipine203,204
have also been ineffective. These drugs
also show substantial impact during treatments at socalled
therapeutic concentrations on the leakiness of
blood vessels. The long-term impact of such side-effects
is unknown. Anti-tau, anti-amyloid, and anti-inflammatory
drugs continue to be in focus and some argue that
pre-symptomatic interventions are necessary, especially if
targeting Aβ production, but no evidence of efficacy205
and
some evidence of worsening target symp­toms currently
exists.206
Cognitive training in people with dementia
A meta-analysis of 12 controlled trials of 389 people with
mild dementia, completing 4 or more hours of group-based
computerised cognitive training (mean age 66–81 years,
63·5% female participants), found a small, statistically
significant beneficial effect on overall cogni­tion, driven by
two trials of virtual reality or Video games (SMD=0·3,
95% CI 0·0–0·5), one with a low and one with a high risk
of bias.55
A Cochrane review207
found 33 trials of cognitive
training, only one of which over­lapped with the study
above, with around 2000 participants with mild-tomoderate
dementia, most with a high or uncertain risk of
bias.207
People completing cognitive training, compared
with usual treatment or non-specific activities, had
small-to-moderate effects on overall cogni­tion (SMD 0·4,
95% CI 0·2–0·6) and specific cognitive abilities such as
verbal fluency and improvements lasted for a few months
to 1 year. No direct evidence was observed to suggest that
cognitive training was better than cognitive stimulation
therapy.
Exercise and physical activity
The Dementia and Physical Activity RCT208
found moderate-to-high
intensity aerobic and strength exercise
training did not slow cognitive impairment in people
with mild-to-moderate dementia but improved physical
fitness. The US Reducing Disability in Dementia study209
implemented an at-home multicomponent intervention
including exercise education, training to increase pleasant
events, and activator-behaviour-consequence problemsolving
approach over 6 weeks by case managers in
255 community dwelling people with dementia older
than 60 years and their family carer and were able to
follow up 140 (54·9%). The study found increased
physical activity; days of taking 30 or more minutes of
exercise (effect size 0·6, 95% CI 0·4–0·8 after the
treatment and 0·3, 0·1–0·5 at 13 months) in a before and
after intervention comparison.
Interventions for neuropsychiatric symptoms of
dementia
Neuropsychiatric symptoms are common and often
clus­tered in people with dementia. These symptoms
might precede dementia and are associated with tau
and amyloid neuropathology.210
This suggests that underlying
neurobiological mechanisms might underpin
neuropsychiatric symptoms. However, other drivers
relating to the personal history and the environment of
the person with dementia are also likely to exist.
Neurodegeneration could lead to increased vulnerability
to stressors or triggers. Genetics, cognitive reserve,
resilience, medical comorbidities, and environment
including responses of carers might modify these
relationships. Needs and responses will also be
individual and relate to a person’s own social, cultural,
and historical context. First-line assessment and
management of neuropsychiatric symptoms should
focus on basic health: describe and diagnose symptoms;
look for causes such as pain (using validated pain
assessments might help), illness, discomfort, hunger,
loneliness, boredom, lack of intimacy and worry that
could cause the behaviours and alleviate these while
considering risks of harm.2
No new evidence of medication effectiveness for these
symptoms exists; risperidone in low doses (0·5 mg daily)
and some other antipsychotics are sometimes effective
but often ineffective and have adverse effects.2
Specific
initiatives have led to a decrease in antipsychotic
prescriptions for people with dementia, although often
replaced with other psycho­tropics (figure 8), such as
benzodiazepines, antidepres­sants, and mood stabi­
lisers.211
These psychotropics lack evidence of efficacy
for neuropsychiatric symptoms but show clear evidence
of possible harm; for example, trazodone and benzodiazepines
increase fall-related injuries.144
Major policy
changes should be assessed carefully, within and across
countries for unintended consequences (and perhaps
unexpected benefits) and their costs.
Evidence is slowly accumulating for the effectiveness, at
least in the short term, of person-centred evidence-based
psychosocial interventions. In Germany, a 6-month
The Lancet Commissions
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cluster RCT of nurse-delivered, supervised dementia care
management used a computer-assisted nurse assessment
to determine personalised intervention modules, then a
multi-disci­plinary team discussion and agreement with
the physician for 634 people (mean age 80 years) with
dementia living at home with a primary carer or alone.212
The mean mini mental state examination (MMSE) was 23,
only 38% had a formal diagnosis of dementia; the majority
of participants (51%) had mild dementia but some had
moderate and some severe dementia. The intervention
consisted of psychosocial management of treatment and
care, medi­cation management and carer support, and
education and discussion with a psychiatrist or neurologist.
The intervention, compared with care as usual, was
associated with better outcomes for neuropsychiatric
symptoms (Neuropsychiatric Inventory [NPI] score −7·5,
95% CI −11·1 to −3·8), however this effect could be because
of deterioration in care as usual (in the care as usual group
NPI increased from 7·2 to 15·2; in the intervention
group NPI increased from 7·6 to 8·2). This between-group
reduction in neuropsychiatric symptoms was greater than
that expected, extrapolating from other study results, with
antipsychotic medication. Effects on quality of life were
only apparent for those people living with a carer.
An eight-session home-based tailored activity programme
RCT, tailored both to the person with dementia
living at home and to a family member compared with
eight telephone-based education sessions, recruited
160 participants with 64% follow-up, imputing values
for the rest.213
The study reported a large reduction in
overall neuropsychiatric symptoms immediately after the
intervention, which were better in the group receiving
home-based tailored activity programme on the neuropsychiatric
inventory (mean difference in score 24·3,
Figure 8: Proportion of patients with a diagnosis of dementia prescribed an antipsychotic drug (A) and those prescribed an anxiolytic, hypnotic,
or antidepressant (B)
CPRD=Clinical Practice Research Datalink. Reproduced from Donegan et al,211
by permission of Elsevier.
0
5
10
15
20
25
A
PatientswithdementiaintheCPRDwitha
prescriptionforanantipsychoticdrug(%)
Any
Typical
Atypical
July–Sept,2005
Oct–Dec,2005
Jan–M
arch,2006
April–June,2006
July–Sept,2006
Oct–Dec,2006
Jan–M
arch,2007
April–June,2007
July–Sept,2007
Oct–Dec,2007
Jan–M
arch,2008
April–June,2008
July–Sept,2008
Oct–Dec,2008
Jan–M
arch,2009
April–June,2009
July–Sept,2009
Oct2009–Dec,2019
Jan–M
arch,2010
April–June,2010
July–Sept,2010
Oct–Dec,2010April–June,2011
July–Sept,2011
Oct–Dec,2011
Jan–M
arch,2012
April–June,2012Oct–Dec,2012
Jan–M
arch,2013
April–June,2013Oct–Dec,2013April–June,2014
July–Sept,2014
Oct–Dec,2014
Jan–M
arch,2015
April–June,2015
July–Sept,2013
Jan–M
arch,2014
Jan–M
arch,2011
July–Sept,2012
0
5
10
20
30
40
15
25
35
PatientswithdementiaintheCPRDwithaprescription
forananxiolytic,hypnotic,orantidepressant(%)
Quarter
Anxiolytics
Hypnotics
Antidepressants
B
The Lancet Commissions
434	 www.thelancet.com Vol 396 August 8, 2020
95% CI 3·1–45·6), and on functional dependence and
pain but this was not sustained 4 months later. Noncompleters
had more severe neuropsychiatric symptoms.
Depression
Since the 2017 Commission two new systematic reviews of
antidepressants to treat depression in dementia reported
moderate quality evidence that antidepressant treatment
for people with dementia does not lead to better control of
symptomatology compared with placebo.214,215
Agitation
Agitation is distressing for people with dementia and
those around them, and contributes substantially to the
overall costs as the level of agitation increases.216
The
body of evidence on this key behaviour is growing, mostly
focused on care-home settings. These findings are
valuable as these populations are most affected; however,
because many people with dementia reside at home a
major gap in knowledge remains.
Care home residents with agitation often find sitting
still difficult and therefore might not be included in
activities.217,218
Two new cluster RCTs of professionals
delivering multicomponent, interdisciplinary, interventions
in care homes successfully reduced agitation.
The WHELD study219
included participants with or
without neuropsychiatric symptoms and provided
person-centred care, aiming to improve communication
with people with dementia. It implemented social,
sensory experiences or other activities; educated about
antipsychotic review; and addressed physical problems,
finding lower Cohen Mansfield Agitation Inventory
(CMAI) at 9 months (MD −4·3 points, 95% CI
−7·3 to −1·2).219
The TIME study220
for people with
moderate-to-high levels of agitation consisted of a
manual-based comprehensive assessment of the resident
and structured case conference for the staff and
doctor, to create a tailored plan, and then implement
it. This intervention led to reduced agitation at 8 weeks
(NPI −1·1 points, 95% CI −0·1 to −2·1; CMAI
−4·7 points, −0·6 to −8·8) and 12 weeks (NPI −1·6,
−0·6 to −2·7; CMAI −5·9, −1·7 to −10·1).220
These effect
sizes are similar to those seen for medications, but
without harmful side-effects.2,221
A further RCT studied a
six-session intervention with staff in groups, teaching
staff to understand agitation as related to medical,
psychological, or social unmet needs and to implement
strategies to meet these needs, using the describe,
investigate, create, and evaluate approach.222
The intervention
did not reduce agitation symptoms, although it
was cost-effective, improving quality of life.223
Overall,
the current evidence for agitation in care homes
favours multi-component interventions by clinical staff,
including considering if drugs might harm, and not
drug interventions. Thus a major gap remains in
knowledge about people living at home who comprise
the majority of those with dementia.
Psychotic symptoms in dementia
People with dementia might be wrongly thought to have
delusions when they misremember, and new psychotic
symptoms are often due to delirium, thus thorough
assessment of symptoms is essential.2
Management of
psychosis in dementia should start with non-pharmacological
interventions; however, evidence for effectiveness
of these interventions for psychosis in dementia is
weaker than for agitation.224
Antipsychotics for psychosis
in dementia should be prescribed in as low a dose and
for the shortest duration possible.2
However, a Cochrane
review of antipsychotics withdrawal found two trials
with participants with dementia who had responded
to antipsychotic treat­ment. These reported that stopping
antipsychotics was associated with symptomatic
relapse225
suggesting the need for caution in any
medication withdrawal in this group. There was lowquality
evidence that, in general, discon­tinuation might
make little or no difference to overall neuropsychiatric
symptoms, adverse events, quality of life or cognitive
function.226
Apathy
Apathy might be conceptualised as the opposite of
engagement, comprising reduced interest, initiative,
and activity. Like people without dementia, those with
dementia engage more in preferred activities, but
require additional support to do so.227
A study in care
homes observed engagement increased during activities
in those who attended the groups.228
A Cochrane review
of the few people who had been in drug RCTs of
methylphenidate versus placebo for apathy in dementia
found small improvements on the apathy evaluation
scale (MD −5·0, 95% CI −9·6 to−0·4, n=145, three
studies, low-quality evidence) but not on the NPI apathy
subscale (MD −0·1, 95% CI −3·9 to 3·7, n=85, two
studies).229
Sleep
There is no evidence that medication for sleep in
dementia is effective230
and considerable evidence for
harm—ie, earlier death, increased hospitalisation, and
falls—exists.139,144
Test­ing of non-pharmacological interventions
is ongoing.231
Carers
Carer distress related to neuropsychiatric symptoms
rather than the dementia symptoms was associated in
one study with increased use and costs of health
services,232
high­lighting the need for effectively identifying,
educating, and supporting distressed carers. An
RCT233
reporting 6-year follow-up after the eight session
STrAtegies for RelaTives intervention—manual-based
coping intervention delivered by supervised psychology
graduates—found continuing effectiveness for depressive
symptoms in carers (adjusted MD −2·00; 95% CI
−3·4 to −0·6) and risk of case-level depression, with
The Lancet Commissions
www.thelancet.com Vol 396 August 8, 2020	 435
patient-related cost being approximately 3 times lower
than those who did not receive the intervention
(median £5759 vs £16 964 in the final year; p=0·07).233
Another US study234
followed up 663 people, mean age
77 years, 55% women. Caregiver depression rather than
symptoms of people with dementia predicted emergency
department use for people with dementia, with a 73%
(RR 1·73, 95% CI 1·3–2·3) increase.234
Functioning
A UK RCT of 14 sessions of cognitive rehabilitation
focused on individual goal attainment with therapy
delivered at home by an occupational therapist or nurse
to 475 participants with mild-to-moderate dementia
(MMSE ≥18 for inclusion; mean 24) and a family carer.235
Individuals had two or three goals; the most common was
engaging in activities (21% of goals). The intervention
group reported increased goal attainment over 3 and
9 months compared with usual treatment (effect size 0·8,
95% CI 0·6–1·0 at both 3 and 9 months).235
The treatment
did not improve participants’ quality of life, mood, selfefficacy,
cognition, carer stress, or health status and was
not cost-effective. A systematic review236
of RCTs without
meta-analysis for overall effect size, concluded that all
interventions which had improved functioning in people
living with dementia in the community have been
individual rather than group interventions. These were:
in-home physiotherapist delivered aerobic exercise (two
studies, larger one positive, 140 people with Alzheimer’s
disease; smaller study negative, 30 people with Alzheimer’s
disease), individualised cogni­tive rehabilitation (mild or
moderate dementia; two studies; 257 cognitive reserve
intervention groups and 255 controls), and in-home
activities-focused occupa­tional therapy (people with mild
to moderate dementia, three studies, 201 intervention,
191 controls) reduced functional decline compared to
controls but group-exercise and reminiscence therapies
were ineffective.236
People with dementia have other illnesses
Multimorbidity is a huge challenge in dementia, not
only because people with dementia have increased rates
of other illnesses, but also because they often find
it parti­cularly difficult to organise care. People with
dementia might forget to tell their family or health
professionals of symptoms, struggle to understand or
follow agreed plans, and are more likely to forget to
drink and eat, increasing falling and infection rates.237
People with dementia consult primary care less often238
and have fewer dental visits239
than those without
dementia and their family members, if involved,
often feel they lack knowledge to assist.240
Health-care
professionals need education to be more comfortable,
understanding, and positive in communicating with
people with dementia.241
Around 70–80% of people diagnosed with dementia in
primary care have at least two other chronic illnesses.242,243
People who are physically more frail are more likely to
have dementia, but the relationship between pathology
and symptoms in these people is comparatively weak
suggesting that dementia might be from other causes.22
Compared to the general older population, people with
dementia have increased rates of cerebro­vascular dis­
ease,243–246
stroke,247
Parkinson’s disease,243,245
dia­betes,245,247
skin ulcers, anxiety and depression,243,245
pneu­monia,
incontinence, and electrolyte disturbance.245
Multimorbidity
in people with dementia is associated with faster
functional decline248
and worse quality of life for people
with dementia and their family carers.249
Dementia and COVID-19
Severe acute respiratory syndrome coronavirus 2, was
first identified in patients with viral pneumonia in Hubei
province, China.250
Severity and mortality of the associated
disease (COVID-19) worsen with increasing age251
and
with pre-existing illnesses such as hypertension and
diabetes,252
and thus many people with dementia are at
particular risk. Death certificates from the UK indicate
that dementia and Alzheimer’s disease were the most
common underlying conditions, specified in 11 950 deaths
(25·6% of all deaths involving COVID-19) in March to
May, 2020.253
Many charities, practitioners, and academics
supporting people with dementia have issued guidance
based on current evidence and best practice, including
advance consideration of whether people would wish to
be hospitalised if they develop severe COVID-19. Concern
has been expressed that the illness and consequent
distancing might increase family carer stress, loneliness,
neuropsychiatric symptoms and use of psychotropic
medication, and lead to complications, including future
dementia. Interventions delivered remo­tely through
technology have also been implemented in some
places.254–257
People with dementia might struggle to adhere to
measures to reduce virus transmission, as they might
not understand or remember about required changes to
behaviour, such as physical distancing and hygiene,
leading to increased risk to themselves and their carers.258
They might additionally be vulnerable if they depend on
others for daily activities or personal care, as this
necessitates close personal contact.
This situation is particularly concerning in those care
homes, where many residents have dementia and where
many COVID-19 deaths have occurred in many
countries259–261
with reports of more than half of residents
being admitted to hospital. In US nursing homes, among
10 576 people with confirmed COVID-19, residents living
with dementia made up 52% of COVID-19 cases; yet,
accounted for 72% of all deaths (an increased risk
of 1·7).262
The number of people living together in care
homes means that the infection of an individual, either
staff or resident, could endanger more people than in
traditional or family households. Although evidence
exists that if staff are sufficiently and rigorously protected
The Lancet Commissions
436	 www.thelancet.com Vol 396 August 8, 2020
they are unlikely to develop COVID-19, many staff have
become unwell and some have died.263,264
Illness means
that there are fewer people to care for residents at a time
when they need particularly high levels of care. This
situation is par­ticularly relevant in the care of residents
with dementia, if they are expected to remain in their own
rooms, rather than eating and participating in activities
with others. Staff or residents might also be moved
between care homes and increase risk in other homes.261
Restrictions on visitors to private homes, care homes, and
hospitals might cause greater distress for people with
dementia and they might not understand why people are
wearing masks, recognise who is behind it, or understand
speech when lips are covered. Lack of restrictions means
that the visitors might also be at elevated risk.261
The impacts of COVID-19 on people with dementia
might be particularly severe in LMICs, due to smaller
health budgets for testing and protective equipment,
capacity of health-care systems, quality of care home
provision and patterns of workforce mobility.264
Thus, people with dementia are particularly vulnerable
to COVID-19 because of their age, multimorbidity, and
difficulties in maintaining physical distancing.250–252
We recommend rigorous public health measures of
protective equipment and hygiene, including not
moving staff or residents between care homes or
admitting new residents when their COVID-19 status is
unknown, should mitigate impacts on people with
dementia. It is also imperative that there is frequent and
regular testing of staff in care homes for infection,
ensuring staff have sick pay so that they do not come in
when symptomatic and interim care is being set up for
people discharged from hospital so that only those who
are COVID-19 free come to live in care homes. Resident
testing should encompass asymptomatic as well as
symptomatic people, when there is exposure within the
home to COVID-19. In the future, many homes might
be able to start to provide oxygen therapy so that those
who do not want to be admitted to hospital are still able
to access oxygen therapy. In addition, it is also important
to reduce isolation by providing the necessary equipment
and a brief training to relatives on how to protect
themselves and others from COVID-19; so that they can
visit their relatives with dementia in nursing homes
safely when it is allowed. Further evidence is needed
to inform responses to this and future public health
emergencies.
Hospital admissions
Hospitalisation in people with dementia is associated
with adverse, unintended consequences, including
distress, func­tional and cognitive decline, and high economic
costs.265–267
People with dementia have 1·4 to 4 times
more hospital admissions than others with similar
illnesses.266,268–270
A systematic review and meta-analysis including
34 studies of 277 432 people with dementia found that in
the six studies which compared the two groups, people
with dementia had increased hospital admissions
compared with those without dementia, after adjusting
for age, sex, and physical comorbidity (RR 1·4, 95% CI
1·2–1·7; figure 9).271
Hospitalisation rates in people with
dementia ranged from 0·37 to 1·26 per person-year in
high-quality studies. Admissions are often for conditions
that might be manageable in the community (potentially
preventable hospitalisations).268
People with dementia
experience longer and more frequent admissions and
readmissions; health-care expenditure for people with
moderate-severe dementia is around double that of
people without dementia.269,272,273
Early detection and
management of physical ill-health in people with
dementia, particularly of pain, falls, diabetes, incontinence,
and sensory impair­ment, is important.199,274,275
However, no intervention has successfully reduced
number of hos­pital admissions of community-dwelling
people with demen­tia,276
although education, exercise,
rehabilitation, and telemedicine have reduced admissions
for older people without dementia.277
High-quality care for people with dementia takes longer
than caring for others with the same condition.278
Recognition
of dementia in hospital inpatients is necessary for
optimum care,279
but dementia is often undetected or
unrecorded.280
In the UK however, detection rates have
increased over the past 10 years.281
Physical illness, delirium, and dementia
Dementia and delirium frequently occur together. In one
hospital inpatients’ survey nearly 35% of those older than
80 years experienced delirium; those with prior cognitive
impairment had 15 times the risk of devel­oping delirium
than those without (OR 15·3, 95% CI 5·2–45·4).282
People with delirium without known dementia are
more likely to be diagnosed with dementia in the future
than others, either because of pre-existing undiagnosed
dementia or cognitive impairment, present in 20·7%
(95% CI 11·9–29·5) and 37·8% (27·3–88·3) respectively
of one cohort, or because delirium has neurotoxic effects
and so precipitates dementia.283
People with similar
Figure 9: Systematic review and meta-analysis of hospitalisation rates of people with dementia compared to
those without dementia controlled for age and sex
Reproduced from Shepherd et al,271
by permission of Springer Nature.
Note: weights are from random effects analysis
Overall (I-squared=86·3%, p=0·000)
Tolppanen et al (2015)
Zhu et al (2015)
Pimoguet et al (2016)
Malone et al (2009)
Phelan et al (2012)
Albert et al (1999)
1·42 (1·21, 1·66)
RR (95% CI)
1·25 (1·22, 1·28)
1·46 (1·24, 1·94)
1·08 (0·75, 1·53)
1·68 (1·51, 1·86)
1·41 (1·23, 1·61)
2·30 (1·10, 4·60)
100·00%
Weight
25·03%
16·50%
10·78%
22·60%
21·15%
3·95%
Higher hospitalisation rate in people with dementia
1·00·5 2·0 5·0
The Lancet Commissions
www.thelancet.com Vol 396 August 8, 2020	 437
people diagnosed with Alzheimer’s disease had mixed
causes of dementia.299
Although Alzheimer’s disease
neuropathology was the commonest cause of dementia,
Alzheimer’s disease changes rarely occurred on their own,
so only 9% of people with dementia had pure Alzheimer’s
disease pathology.300
People who have Alzheimer’s disease
patho­logy without developing dementia tend to have
fewer age-related health deficits than those who develop it
with even low concentrations of plaques and tangles.301
A
moderation analysis showed that the relationship between
Alzheimer’s disease pathology and dementia status
differed according to level of frailty (adjusted for age, sex,
and education) with increasing frailty weakening the
relationship between Alzheimer’s disease pathology and
dementia (figure 10).22
As with delirium, some of this
additional health risk might be modifiable. This approach
suggests a new type of therapy focus on specific agerelated
processes that underpin many diseases of late life
might reduce the incidence or severity of dementia.
End-of-life care in dementia
The numbers of people dying with dementia are increasing
but the evidence for the best end-of-life care is scarce.
Trends in age-standardised death rates (3·6%) for dementia
increased slightly between 1990–2016, with pronounced
increases in the USA and Japan and decreases in western
Europe and central Latin America.4
Dementia is more
readily being included on death certificates, which
accounts for some of the rise. The increase might be
related to dementia manifesting at later ages, with higher
physical frailty22
leading to a faster decline.
Most people with dementia might die while still in the
mild-to-moderate stages whereas only about a quarter of
those dying with dementia have severe dementia.302,303
The trajectory of dementia is often unpredictable304
and palliative care initiation should reflect need not
prognosis.
neuropatho­logy show faster cognitive decline if they
develop delirium than if they do not.284
Additionally, older
people without dementia declined cognitively more than
twice as fast after an emergency hospital admission for
any cause, compared with those not admitted, suggesting
any severe illness is associated with cognitive decline.285
Risk factors for delirium in dementia include sensory
impairment, pain, poly­pharmacy, dehydration, intercurrent
illnesses, such as urinary tract infections or faecal
impaction, and an unfamiliar or changing environment.286
Delirium in older people should prompt consideration of
underlying dementia.
Most research on delirium prevention has been in
people without dementia. It suggests targeting hydration,
stopping medication predisposing to delirium, monitoring
the depth of anaesthesia, and sleep promotion.
However, no evidence for medication efficacy, including
cholinesterase inhibitors, antipsychotic medication, or
melatonin exists.287–289
The Hospital Elder Life Program290
—
an intervention to prevent delirium in those admitted to
hospital—reduces delirium incidence and includes people
who are cognitively impaired. This multidisciplinary
treatment consists of daily visits, orientation, therapeutic
activities, sleep enhancement, early mobilisation, vision
and hearing adaptation, fluid repletion, infection prevention
and management of constipation, pain, and
hypoxia, and feeding assistance.290
A network meta-analysis of drugs for prevention and
treatment of delirium did not include studies of people
with dementia, thus we cannot use this to recommend
drugs for people with dementia and delirium as this
research might be inapplicable to them.291
Little high-quality research exists on managing delirium
in dementia. One RCT compared care at a specialist
medical and mental health unit to usual care for
600 confused people older than 65 years, acutely admitted
to hospital and found no difference in the primary
outcome of days spent at home or in hos­pital, but
increased family satisfaction.292
A further RCT of
cognitively stimulating activities for people with delirium
in dementia did not improve the delirium.293
No definitive
evidence that any medication improves delirium in
people with dementia exists: cholinesterase inhibitors,
antipsychotics, and sedating benzodiazepines are inef­­
fective and antipsychotics and benzodiazepines are
associated with mortality and morbidity.265,288,294–297
Given
the risk of dementia in people who develop delirium, its
prevention, and possibly advances in its management,
might offer a means for dementia prevention.298
Link between very old age, frailty, and dementia
The fastest growing demographic group in most advanced
countries are people aged 90 years and older. One well
characterised post-mortem cohort of the oldest old
(n=1079; mean age 90 years) dying with dementia, found
that neuropathological features of Alzheimer’s disease
account for about half of the cognitive decline seen as
Figure 10: Moderation analyses of the relationship between Alzheimer’s
disease pathology and clinical diagnosis of Alzheimer’s dementia (adjusted
for age, sex, and education)
As frailty increased, the odds of a neuropathological diagnosis of Alzheimer
disease corresponding to a clinical diagnosis decreased. Reproduced from
Wallece et al,22
by permission of Elsevier.
Frailtyindex Odds ratio (95% Cl)
0 5
0
0·1
0·2
0·3
0·4
0·5
0·6
0·7
0·8
0·9
1·0
10 15 20
3·24 (1·74–6·02); p=0·0002
5·68 (3·70–8·71); p<0·0001
9·96 (5·35–18·62); p<0·0001
The Lancet Commissions
438	 www.thelancet.com Vol 396 August 8, 2020
Decision making about end of life is complex and
simple rules of thumb, co-designed with staff and carers,
provided clarity in some small studies.304
One RCT testing
decision-aids about families’ and doctors’ goals of care
for people with advanced dementia led to increased
palliative care content in care plans.305,306
In a 9-month UK
prospective study, 85 care home residents with advanced
dementia from 14 homes were likely to be living with
distressing symptoms, specifically agitation (54%) or
pain (61% on movement).304
Capacity to make abstract decisions, including about
the future, might be lost early in dementia.307
Therefore,
advance care planning, designed to empower people
with dementia and improve quality of dying, might
theoretically be something everyone should do before
developing dementia.308
However, people might not be
able to predict their future wishes. This might explain
why family carer proxies show only low-to-moderate
agreement with stated end-of-life treatment preferences
of people with dementia.309
Advance care planning might,
however, reduce carers’ uncertainty in decision making
and improve perceptions of quality of care.310
Partners of people dying with dementia experience
poorer mental health than those facing bereavement
from other causes311
possibly because of long and difficult
caring responsibilities. This might be ameliorated
through sensitive and timely information, particularly
regarding the progression of dementia,312
individually or
through family and staff case-conferencing.313,314
Conclusions
Knowledge about risk factors and potential prevention,
detection, and diagnosis of dementia is improving
although significant gaps remain.315
In this Commission
report, we have specified policy and individual changes
to delay the onset of cognitive impairment and dementia
and better ways to support and treat people with
dementia and their families and to improve their quality
of life.
Interventions, including organisation of the complex
physical illness and social needs, to support people
affected by dementia can have a huge effect when taken
as a whole. Our ambition is for worldwide provision of
resources for an adequate level of wellbeing to people
with dementia and their carers with a better evidence
base to guide individual care and policy making alike.
With good quality care, people can live well with dementia
and families can feel supported.
Contributors
GL, JH, AS, and NM contributed to literature searches and quality
assessments for systematic reviews. JH and NM performed meta-analyses.
GL, JH, AS, and NM conceived the new PAF calculation and NM led the
statistical analysis. GL, JH, AS, NM, DA, CLB, SB, AB, JC-M, CC, SGC,
NF, RH, HCK, EBL, VO, KRi, KRo, ELS, QS, LSS, and GS attended the
conference to discuss the content. GL, JH, EBL, AS, DA, and ELS wrote
first drafts of sections of the paper. GL wrote the first draft of the whole
paper and revisions of drafts. CBa reviewed and contributed to revision of
the final drafts. All authors contributed to sections of the reports and all
revised the paper for important intellectual content.
Declaration of interests
AS reports grants from Wellcome Trust (200163/Z/15/Z), outside the
submitted work. DA reports grants from Eli Lilly, during the conduct of
the study. CBa reports grants and personal fees from Aca-dia and
Lundbeck; and personal fees from Roche, Otsuka, Biogen, Eli Lilly,
and Pfizer, outside the sub-mitted work. SB reports grants and personal
fees from AbbVie, personal fees and non-financial sup-port from
Eli Lilly, and personal fees from Eleusis, Daval International,
Boehringer Ingelheim, Axovant Sciences, Lundbeck, and Nutricia,
outside the submitted work; and he has been employed by the
Department of Health for England. NF reports non-financial support
from Eli Lilly, outside the submitted work. LNG and her institutions
(Johns Hopkins University, Baltimore, MD, USA, Drexel University,
Philadelphia, PA, USA, and Thomas Jefferson University, Philadelphia,
PA, USA) are entitled to receive royalties from fees associated with
online training for the tailored activity program, which is an evidencebased
program referenced in the Review. RH reports grants from
Department of Health, NIHR HTA Programme, outside the submitted
work; and he is a Scientific Trustee of the charity Alzheimer’s Research
UK. MK reports grants from the UK Medical Research Council
(S011676, R024227), NordForsk (the Nordic Programme on Health and
Welfare, 75021) and the Academy of Finland (311492), outside the
submitted work. EBL reports other (royalties) from UpToDate, outside
the submitted work. KRo reports personal fees from Clinical Cardio
Day-Cape Breton University, Sydney, NS, Canada, CRUIGM-Montreal,
Jackson Laboratory, Bar Harbor, MA, USA (speaker fees), MouseAge,
Rome, Italy (speaker fees), Lundbeck, Frontemporal Dementia StudyGroup,
SunLife Insurance, Japan, outside the submitted work. He is a
President and Chief Science Officer of DGI Clinical, which in the last
5 years has contracts with pharma and device manufacturers (Baxter,
Baxalta, Shire, Hollister, Nutricia, Roche, Otsuka) on individualised
outcome measurement. In 2017, he attended an advisory board meeting
with Lundbeck. He is also Associate Director of the Canadian
Consortium on Neurodegeneration in Aging, which is funded by the
Canadian Institutes of Health Research, and with additional funding
from the Alzheimer Society of Canada and several other charities,
as well as, in its first phase (2013-2018), from Pfizer Canada and Sanofi
Canada. He receives career support from the Dalhousie Medical
Research Founda-tion as the Kathryn Allen Weldon Professor of
Alzheimer Research, and research support from the Canadian
Institutes of Health Research, the QEII Health Science Centre
Foundation, the Capital Health Research Fund and the Fountain Family
Innovation Fund of the QEII Health Science Centre Foundation.
LSS reports grants and personal fees from Eli Lilly, Merck, and Roche/
Genentech; personal fees from Avraham, Boehringer Ingelheim,
Neurim, Neuronix, Cognition, Eisai, Takeda, vTv, and Abbott; and
grants from Biogen, Novartis, Biohaven, and Washington University
DIAN-TU, outside the submitted work. The remaining authors declare
no conflict of interests.
Acknowledgments
We are partnered by University College London (UCL), the Alzheimer’s
Society, UK, the Economic and Social Research Council, and Alzheimer’s
Research UK, and would like to thank them for financial help.
These organisations funded the fares, accommodation, and food for the
Commission meeting but had no role in the writing of the manuscript or
the decision to submit it for publication. We would like to thank
Bernadette Courtney, Jacques Gianino, and Nuj Monowari, from UCL,
London, UK, for their administrative help, including managing finances,
booking rooms and food, and setting up a website supported by the
University College London Hospitals National Institute for Health
Research Biomedical Research Centre. We would like thank
Henrik Zetterberg for advice on biomarkers and dementia.
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