Content uploaded by Stewart W Mercer
Author content
All content in this area was uploaded by Stewart W Mercer on Nov 26, 2015
Content may be subject to copyright.
RESEARCH PAPER
Vascular comorbidities in younger people with
dementia: a cross-sectional population-based study
of 616 245 middle-aged people in Scotland
C A Heath,
1
S W Mercer,
2
B Guthrie
3
▸Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
jnnp-2014-309033).
1
Department of Neurology,
Ninewells Hospital, Dundee,
UK
2
Department of Primary Care,
University of Glasgow,
Glasgow, UK
3
Department of Primary Care
Medicine, University of
Dundee, Dundee, UK
Correspondence to
Dr Craig A Heath, Ninewells
Hospital, Dundee, DD1 9SY,
UK; craigheath@nhs.net
Received 22 July 2014
Revised 23 September 2014
Accepted 15 October 2014
Published Online First
18 November 2014
To cite: Heath CA,
Mercer SW, Guthrie B. J
Neurol Neurosurg Psychiatry
2015;86:959–964.
ABSTRACT
Introduction There is growing evidence of an
aetiological relationship between vascular risk factors
and the development of dementia in later life. Dementia
in the under-65s has historically been considered to be
more driven by genetic factors, but previous
epidemiological studies in the young have been relatively
small. This study aims to determine the prevalence of
vascular comorbidity in people aged <65 with dementia
in comparison to the general population.
Methods Analysis of routine clinical data from 314
(30%) general medical practices in Scotland.
Results From an overall population of 616 245
individuals, 1061 cases of ‘all-cause’dementia were
identified (prevalence 172/100 000 population, 95% CI
161 to 182). The prevalence of dementia was higher in
people with vascular morbidities, and prevalence
progressively increased from 129/100 000 in people with
no vascular comorbidity to 999/100 000 in people with
four or more (p=0.01). The strength of association was
greatest with a previous transient ischaemic attack (TIA)
or stroke and chronic kidney disease (adjusted OR=3.1
and 2.9, respectively). Statistically significant, but smaller
associations were seen with the presence of
hypertension, diabetes, ischaemic heart disease and
peripheral vascular disease (adjusted OR=1.4, 2.0,
1.9 and 2.2, respectively).
Discussions Vascular comorbid diseases were more
commonly recorded in people aged 40–64 with
dementia than those without. This finding indicates that
vascular disease may be more important in the aetiology
of young-onset dementia than previously believed, and is
of concern given the continuing rise in obesity and
diabetes internationally.
INTRODUCTION
Dementia is a growing global problem with an esti-
mated 25 million cases worldwide in 2005. The
costs of dementia to both individuals and society as
a whole are large, with healthcare-related cost
alone in the USA estimated at $200 billion per
year.
1
There is growing evidence to support a role
for both genetic and acquired risk factors for the
development of dementia in the elderly.
2
Consistent modifiable risk factors for the develop-
ment of Alzheimer’s and ‘all–cause’dementia in
older people are those associated with vascular
disease and include diabetes, hypertension and
obesity.
3–8
Less robust evidence supports an associ-
ation with smoking, chronic renal failure and psy-
chological stressors including depression.
9–11
Although, the prevalence of dementia rises expo-
nentially with age, it is well recognised in younger
people (usually arbitrarily defined as less than
65 years old). The importance of genetic factors in
dementia of young onset has commonly been
reported in the literature, but in clinical practice,
inherited dementia is relatively uncommon. A posi-
tive family history of autosomal dominant dementia
is seen in the minority of patients, even among
those attending national centres of excellence (per-
sonal communication Professor Martin Rossor,
National Hospital for Neurology and Neurosurgery,
London, UK), but the role of potentially modifiable
risk factors like vascular disease is unclear in this
population. There have been a limited number of
epidemiological studies of young onset dementia.
With few exceptions,
12
the primary aim has been to
estimate the prevalence and cause of dementia,
albeit often using data from selective populations,
for example, those attending hospital clinics. The
reported prevalence of dementia in the young varies
from 38 to 420 per 100 000 population, reflecting
heterogeneity in study design and study popula-
tion.
12–15
Alzheimer’s disease remains the most
common cause of dementia in younger people, but
dementia associated with movement disorders or
other neurodegenerative disorders are more com-
monly seen than in an older population. The rela-
tively small numbers included in previous research
in the young have rarely permitted an accurate
assessment of potential risk factors; thus, the relative
importance of modifiable risk factors in young onset
dementia remains unclear.
The aim of this study is to determine the preva-
lence of young onset dementia in a large popula-
tion sample, and the prevalence of vascular
comorbid conditions in people with young onset
dementia in comparison to the general population.
METHODS
The UK National Health Service (NHS) requires
registration with a general medical practice to
access healthcare services. UK general practitioners
(GPs) universally use electronic medical records
that include data on demography, the conditions an
individual has and prescribing. Patients with
dementia were identified from a data set of
1 751 841 people registered with 314 general prac-
tices in Scotland, covering approximately one-third
of the Scottish population. The data set used for
the analysis and definitions of the morbidities
defined have been fully reported elsewhere,
16
but
Heath CA, et al.J Neurol Neurosurg Psychiatry 2015;86:959–964. doi:10.1136/jnnp-2014-309033 959
Cognitive neurology
group.bmj.com on August 17, 2015 - Published by http://jnnp.bmj.com/Downloaded from
in brief, at the time of data extraction, participating practices
systematically used electronic medical records for registration of
patients, morbidity recording (including dementia) and prescrip-
tions. The data for this analysis are from all patients who were
alive and permanently registered with a participating practice on
31 March 2007. The data set is representative of all Scottish
patients in terms of age, sex and socioeconomic status.
Dementia is one of the conditions included in the UK Quality
and Outcomes Framework, under which GPs are paid to main-
tain accurate registers for common chronic conditions, and for
the delivery of specified care to people with those conditions.
This ensures that diagnoses are reviewed annually, and accuracy
of diagnosis is financially incentivised. Additional data extracted
were for age, sex, socioeconomic status defined by the Carstairs
Score of the postcode of residence grouped into equal fifths of
the population, and the presence of specified vascular and neu-
rodegenerative comorbidities.
The NHS National Research Ethics Service had previously
approved the anonymous use of these data for research pur-
poses; therefore, this study did not need individual ethics
approval.
Case definition
Dementia was defined as the presence ever of one of a specified
set of Read Codes (the standard morbidity coding used by NHS
general practices) or the prescription ever of an anticholinester-
ase inhibitor (detailed in see online supplementary appendix 1).
People with dementia were included if they were between 40
and 64 years old (inclusive) on 31 March 2007. The comparison
population consisted of people between ages 40–64 with no
record of dementia in the primary care record.
Prior to conducting the study, the accuracy of GP coding of
young onset dementia was examined in a set of eight practices
with a registered population of 51 147, where electronic
records were screened to identify cases of young onset dementia
using the same criteria as above, and the full primary care
record including free-text and hospital letters reviewed. In total,
17 350 people were aged between 40 and 64 years old, and 15
of them were coded as having dementia (estimated prevalence
of 86.5/100 000 population (95% CI 50.8 to 122.2). On
review, all diagnoses fulfilled Diagnostic and Statistical Manual
of Mental Disorders (DSM) IV criteria for gradual onset and
progressive impairment in memory function and at least one
other cognitive domain resulting in impairment of social and
occupational function.
Statistical analysis
The crude, age and gender-stratified prevalence of dementia was
estimated with 95% CIs calculated using Wilson’s method with
continuity correction. The proportion of people with and
without dementia who had a vascular comorbidity (hyperten-
sion, ischaemic heart disease (IHD), diabetes, peripheral vascu-
lar disease, stroke or transient ischaemic attack (TIA) or chronic
kidney disease (CKD) stage 3 or worse) was calculated and the
OR=estimated using logistic regression with and without adjust-
ment for age, sex and socioeconomic status. A Breslow Day test
for homogeneity of OR was undertaken to analyse the potential
effect modification of gender.
As a sense check to examine if known associations with
dementia were found, the analysis was repeated for the presence
of neurodegenerative disorders known to be associated with
dementia (Parkinson’s disease, multiple sclerosis and learning
disability).
A Mantel-Haenszel linear-by-linear association test was used
to test for linear association. All analyses were carried out in
IBM SPSS V.11.
RESULTS
Basic demographics
In total, 616 245 individuals aged between 40 and 64 inclusive
were identified from a total population of 1 751 841, of whom
1061 had a dementia diagnosis. People with dementia had a
mean age of 55.6 years (SD±6.9) and 657 (62%) were women.
Those without dementia were significantly younger (mean
age=51.2 SD±7.2) p<0.01) and 49.5% were women.
Prevalence rates
The overall prevalence of dementia in those between the ages of
40 and 64 was 172 (95% CI 161 to 172) per 100 000 popula-
tion (table 1). Prevalence increased with age from 75/100 000
population in those aged 40–44, to 399/100 000 identified
between the ages 60 and 64. Prevalence of dementia was
inversely related to socioeconomic status with lowest prevalence
noted in the most affluent. The overall prevalence in the most
affluent fifth of the population was 119 (95% CI 99 to 139) per
100 000 in comparison to 226 (95% CI 196 to 256) per
100 000 population in the least affluent fifth.
The prevalence of dementia was higher in people with vascu-
lar morbidities, and prevalence progressively increased with the
number of vascular comorbidities, from 129/100 000 in people
with no vascular comorbidity to 999/100 000 in people with
four or more (p=0.01).
Vascular comorbidities were common in people with demen-
tia, with 27% having hypertension, 9% IHD and 12% diabetes
(table 2). They were more common in people with dementia in
comparison to the general population. As expected given that
people with dementia were somewhat older than people
without, age adjustment reduced the crude associations seen,
but people with dementia were more likely to have all of the
vascular comorbidities examined, the strongest associations
being with stroke/TIA and CKD (adjusted OR=3.1, 95% CI 2.4
to 4.0; 2.9, 95% CI 2.1 to 4.0, respectively). Associations were
weaker but still statistically significant for other vascular
comorbidities, with adjusted ORs of 2.0 or more for diabetes
and peripheral vascular disease, and somewhat weaker associa-
tions with IHD and hypertension. In total, 59% of people with
dementia had no vascular comorbidity, compared with 79.4%
of people without dementia (adjusted OR=0.6, 95% CI 0.5 to
0.7), and people with dementia were much more likely to have
multiple vascular comorbidities. Analysis for linear trend
(linear-by-linear association=384, 1 df, p<0.001) demonstrates
association between the number of vascular comorbid condi-
tions and dementia with the greatest association identified in
those with four or more comorbidities (table 3).
Neurodegenerative and congenital disorders
As expected, people with dementia were much more likely to
have Parkinson’s disease and learning disability compared with
people without (adjusted OR=8.7, 95% CI 4.4 to 16.9 and 7.1,
95% CI 4.8 to 10.4, respectively) with a weaker association
with multiple sclerosis which was not significant after adjust-
ment (adjusted OR=1.8, 95% CI 0.9 to 3.4), although the
numbers are small for all these conditions (table 4).
DISCUSSION
To the best of our knowledge, this population-based study is the
largest prevalence study of young onset dementia to date, and
960 Heath CA, et al.J Neurol Neurosurg Psychiatry 2015;86:959–964. doi:10.1136/jnnp-2014-309033
Cognitive neurology
group.bmj.com on August 17, 2015 - Published by http://jnnp.bmj.com/Downloaded from
Table 1 Prevalence of dementia (per 100 000 population) in people aged 40–64 years by demographics and vascular morbidity
Number of individuals Number of cases
Prevalence of dementia per
100 000 population (95% CI)
All people aged 40–64 616 245 1061 172 (161 to 182)
Age group
40–44 143 010 108 75 (61 to 90)
45–49 134 880 127 94 (77 to 110)
50–54 118 914 162 136 (115 to 157)
55–59 113 029 240 212 (186 to 240)
60–64 106 304 424 399 (360 to 436)
Gender
Male 310 999 404 130 (117 to 142)
Female 305 246 657 215 (198 to 231
Socioeconomic status
Quintile 1 (affluent) 123 663 147 119 (99 to 139)
Quintile 2 136 549 175 128 (108 to 148)
Quintile 3 139 662 278 199 (179 to 219)
Quintile 4 114 056 230 202 (182 to 222)
Quintile 5 (deprived) 102 123 231 226 (196 to 256)
Vascular comorbidity
Stroke/TIA 8405 67 797 (607 to 987)
Chronic kidney disease 4850 40 825 (570 to 1079)
Ischaemic heart disease 21 513 99 460 (370 to 550)
Diabetes 30 620 129 421 (348 to 493)
Hypertension 92 542 287 310 (274 to 346))
Peripheral vascular disease 7056 38 539 (367 to 709)
Number of vascular comorbidities
None 488 251 630 129 (118 to 139)
One 96 994 257 265 (232 to 297)
Two 24 262 131 540 (447 to 632)
Three 5107 33 725 (491 to 957)
Four or more 1001 10 999 (382 to 1615)
Table 2 Prevalence of vascular morbidities in middle-aged people with and without dementia
Vascular comorbidity present
Number of individuals
without dementia
Number of individuals
with dementia
Crude OR
(95% CI)
*Adjusted OR
(95% CI)
†Adjusted OR
(95% CI)
Stroke/TIA
Yes 8338 67 4.9 (3.8 to 6.3) 3.3 (2.6 to 4.2) 3.1 (2.4 to 4.0)
No 606 846 994
CKD
Yes 4810 40 5.0 (3.6 to 6.8) 3.0 (2.1 to 4.1) 2.9 (2.1 to 4.0)
No 610 374 1021
IHD
Yes 21 414 99 2.9 (2.3 to 3.5) 1.9 (1.5 to 2.4) 1.9 (1.5 to 2.4)
No 593 770 962
Diabetes
Yes 30 491 129 2.6 (3.2 to 4.5) 2.1 (1.7 to 2.5) 2.0 (1.7 to 2.5)
No 584 693 932
Hypertension
Yes 92 255 287 2.1 (1.8 to 2.4) 1.4 (1.2 to 1.6) 1.4 (1.2 to 1.6)
No 522 929 774
PVD
Yes 7018 38 3.2 (2.3 to 4.5) 2.3 (1.7 to 3.2) 2.2 (1.6 to 3.1)
No 608 166 1023
*Adjusted for age and gender.
†Adjusted for presence of age/gender/neurodegenerative disorder/learning disability/socioeconomic status.
CKD, chronic kidney disease; IHD, ischaemic heart disease; PVD, peripheral vascular disease.
Heath CA, et al.J Neurol Neurosurg Psychiatry 2015;86:959–964. doi:10.1136/jnnp-2014-309033 961
Cognitive neurology
group.bmj.com on August 17, 2015 - Published by http://jnnp.bmj.com/Downloaded from
additionally, it examines the presence of multiple vascular
comorbidities in people with young onset dementia compared
with the general population. The large cohort examined
includes approximately one-third of the Scottish population,
and the cohort is known to be representative of the total popu-
lation in terms of age, sex and socioeconomic status.
16
The
overall reported prevalence was 172/100 000 population and is
close to the middle of the range of estimates in previous studies
but more precisely estimated.
12–15 17 18
There is variability in
prevalence estimates in the literature, which is likely due to het-
erogeneity in study design. In general terms, previous studies
have taken two forms: population-based studies and registry-
based studies. Population-based studies have tended to only
include those at greatest risk, typically a narrower and older age
range than this study and thus have reported higher prevalence
rates. Ott et al
14
only included people aged 55–65 years, and
the reported overall prevalence of 420/100 000 is consistent
with the estimated prevalence of 399/100 000 in this age group
within the current study. Registry-based studies have more accur-
ate case classification for those included, but are likely to have
lower case ascertainment. This is illustrated in a study by
Harvey et al
13
which was undertaken in two inner city London
Boroughs and provides the most accurate case classification to
date. The reported prevalence rate of 54/100 000 (CI 45 to 64)
in people aged 30–64 and 78/100 000 in people aged 40–64 is
considerably lower than the current study, but patients were
identified by health and social care referral at a time when elec-
tronic coding of dementia in primary care records was incom-
plete, and thus likely to lead to underascertainment. Finally, the
large population included within the current study allows preva-
lence to be estimated with reasonable precision, which is
important when examining rare diseases, with the CIs around
the estimated overall prevalence of 172/100 000 being relatively
narrow (95% CI 161 to 182).
This study shows a strong association between vascular
disease and dementia in those aged between 40 and 64. The
strength of association is greatest with a history of previous TIA/
stroke, but significant associations are also seen with CKD,
hypertension, diabetes, IHD and peripheral vascular disease,
and people with dementia were much more likely to have mul-
tiple comorbidities. Cerebrovascular disease has consistently
been associated with an increased risk of dementia in older
people with 10% of patients with stroke developing dementia.
19
In addition, the presence of white matter changes on MRI of
the brain, often termed ‘small vessel disease’, has been shown to
increase subsequent risk of dementia in individuals without
overt symptomatic strokes.
20
The mechanism by which cerebro-
vascular disease confers an increased risk of dementia remains
unclear; however, current opinion favours a complex interaction
between frank symptomatic strokes, pre-existing leucoaraiosis
and ongoing exposure to existing vascular risk factors, and
similar processes are likely to be at play in younger people.
The association between glucose metabolism and dementia in
the elderly has been investigated extensively with growing
robust evidence for an association between impairment of
glucose metabolism (including diabetes) and the development of
cognitive decline.
3–5
A number of observational studies have found a twofold
increase risk of dementia in comparison to controls. The largest
meta-analysis of people with type 2 diabetes demonstrates an
overall relative risk of 1.5 and 2.48 for those with Alzheimer’s
and vascular dementia, respectively.
21
People with diabetes
appear to have greater rate of cognitive decline in comparison
to controls prior to the development of dementia per se.
22 23
Interestingly, people in an older cohort with diabetes and add-
itional vascular risk factors were found to have a greater risk of
dementia than those who only have diabetes.
24
The mechanism
underlying the association between diabetes and dementia is
unclear. Long-term glycaemic control may be important but this
has not been definitively shown, and large-scale longitudinal
data will be required to examine this further.
Studies of the association between hypertension and the risk
of developing dementia have not always provided consistent
results, particularly when hypertension is identified in later
life.
25
Hypertension measured in middle age consistently seems
to increase the risk cognitive impairment in the elderly.
7
The
current study provides supportive evidence of an association
between hypertension and dementia in a younger cohort as
Table 4 Prevalence of neurodegenerative disorders and learning disability in middle-aged people with and without dementia
Presence of comorbid condition
Number of individuals
without dementia
Number of individuals
with dementia OR (95% CI) *Adjusted OR (95% CI)
Parkinson’s disease
Yes 389 9 13.5 (7 to 26.3) 8.7 (4.4 to 16.9)
No 614 795 1952
Learning disability
Yes 2679 27 6.5 (4.4 to 9.5) 7.1 (4.8 to 10.4)
No 612 705 1034
Multiple sclerosis
Yes 2525 9 2.1 (1.1 to 4.0) 1.8 (0.9 to 3.4)
No 612 659 1052
*Adjusted for age/gender/socioeconomic status.
Table 3 Association between increasing number of vascular
comorbid conditions and dementia
No vascular
comorbidities
Number of
individuals
without
dementia
Number of
individuals with
dementia (%)
Adjusted* OR
(95% CI)
None 488 251 630 (0.13) 1 (reference)
One 96 994 257 (0.26) 1.5 (1.3 to 1.7)
Two 24 262 131 (0.54) 2.8 (2.3 to 3.4)
Three 5107 33 (0.73) 3.1 (2.2 to 4.5)
Four or more 1001 10 (1) 4.6 (2.5 to 8.8)
*Adjusted for presence of age/gender/neurodegenerative disorder/learning disability/
socioeconomic status.
962 Heath CA, et al.J Neurol Neurosurg Psychiatry 2015;86:959–964. doi:10.1136/jnnp-2014-309033
Cognitive neurology
group.bmj.com on August 17, 2015 - Published by http://jnnp.bmj.com/Downloaded from
well. The associations between dementia, peripheral vascular
disease and CKD are less well established. A single Japanese
study found a positive association between stage 3 CKD and the
risk of dementia in an older cohort.
10
In addition, recent results
from the Edinburgh type 2 diabetes study suggest an increased
risk of dementia in those with reduced Ankle-Brachial Pulse
Index (APBI) in an older cohort.
26
Although the exact aetiology
remains unclear, it is likely that both disorders reflect wide-
spread disease within the vasculature, including the small cere-
bral vessels, thus the association found in this study is not
unexpected.
Like all cross-sectional studies, this analysis can only show
association rather than directly examine causality. Nordström
et al
12
recently reported the findings of a large cohort study
examining risk factors for the development of dementia in the
young by following up men identified from the Swedish
Military Service Conscription Register with baseline variables
measured at army entry and follow-up data (median follow-up
37 years) obtained from the Swedish National Hospital
Discharge Patient Register. The prevalence of dementia was
reported as 92/100 000 population with a median age at
follow-up of 54 years, but the study did not include women
(who make up over 60% of people with dementia in the current
study), those with pre-existing learning disability or movement
disorder. A history of hypertension and stroke conferred an
increased lifetime risk of dementia at follow-up, but angina in
the absence of myocardial infarction, CKD and peripheral vas-
cular disease were not examined. The risk of dementia was also
greatest in those with excessive alcohol intake at baseline,
although data on alcohol intake were incomplete. In the current
study, recording of alcohol intake was incomplete or poorly
quantified and not analysed.
The current study has the limitations common to all cross-
sectional studies and those using routine clinical data. Dementia
may be misdiagnosed or under-recorded in this population,
although referral to a specialist dementia service would be
routine clinical practice in the UK, particularly in the young. In
addition, accurate recording is financially incentivised and a case
note review of patients identified using the same electronic data
case definition suggests that coding is accurate. Nonetheless, it is
possible that there is under-recording of dementia, although we
believe this is less likely in younger people than the very old.
27
If
there is under-recording, then it is unlikely to alter the findings
since young onset dementia is rare, so misclassifying a proportion
of true cases as not having dementia will not meaningfully
change the control group characteristics. Additionally, it is
important to recognise that cross-sectional analyses can examine
association but cannot establish causality, and it is possible that
the causal relationship is because people with dementia are better
screened for vascular disease rather than because vascular disease
is a cause of dementia in this population. However, there has
been extensive improvement activity for many years to promote
case finding for hypertension and diabetes with financial incen-
tives to regularly measure blood pressure in all middle-aged
people, and most of the other conditions are diagnosed after an
individual develops symptoms making better screening of people
newly diagnosed with dementia unlikely to explain the findings.
Nonetheless, causality will be better established using longitu-
dinal methods.
Historically, genetic factors have been considered to be the
most important cause of dementia in the young. Genetic factors
in dementia have been investigated extensively with the role of
ApoE4 established. The presence of ApoE4 confers an increased
risk of dementia and appears to influence age of onset.
28–30
However, genetic testing including ApoE status is not routine
clinical practice, precluding their examination in this study.
This study provides evidence to support an association
between vascular risk factors, or evidence of existing vascular
disease, and the risk of dementia in those between the ages of
40–64. These findings are likely to have significant implications
for developed and developing countries given the exponential
rise in obesity and diabetes. The relative importance of acquired
risk factors in comparison to genetic predisposition remains
unclear. The most plausible explanation is that the age of onset
and overall risk of dementia is likely to reflect a complex inter-
action between both genetic and acquired risk factors.
The association between vascular disease and the risk of
dementia in the young provides an opportunity for potential
intervention and, perhaps, prevention. It is possible that people
at higher risk of dementia would benefit from more aggressive
vascular risk factor reduction than the general population, but
establishing this definitively would require large clinical trials
with very long follow-up, and analysis using observational data
is more feasible (although also more prone to confounding).
Large population-based longitudinal studies with careful ascer-
tainment of dementia type are needed to examine the relative
importance of acquired and genetic risk factors, improve diag-
nosis and allow prediction of prognosis in younger people with
dementia.
Contributors Each author has made a substantial contribution to the design,
acquisition and analysis of data. A final draft of the paper was agreed on prior to
submission.
Funding CAH was supported by National Health Service Career Research
Fellowship scheme, and data set creation was supported by Scottish Government
Chief Scientist Office Applied Research Programme Grant 07/01.
Competing interests None.
Ethics approval The NHS National Research Ethics Service had previously
approved the anonymous use of these data for research purposes.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES
1 Alzheimer’s Association. 2010 Alzheimer’s disease facts and figures. Alzheimers
Dement 2010;6:158–94.
2 Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer’s disease. Nat Rev Neurol
2011;7:137–52.
3 Ott A, Stolk RP, van Harskamp F, et al. Diabetes mellitus and the risk of dementia:
The Rotterdam Study. Neurology 1999;53:1937–42.
4 Leibson CL, Rocca WA, Hanson VA, et al. The risk of dementia among persons with
diabetes mellitus: a population-based cohort study. Ann N Y Acad Sci
1997;826:422–7.
5 Luchsinger JA, Tang MX, Stern Y, et al. Diabetes mellitus and risk of Alzheimer’s
disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol
2001;154:635–41.
6 Knopman D, Boland LL, Mosley T, et al. Cardiovascular risk factors and cognitive
decline in middle-aged adults. Neurology 2001;56:42–8.
7 Launer LJ, Masaki K, Petrovitch H, et al. The association between midlife blood
pressure levels and late-life cognitive function. The Honolulu–Asia Aging Study.
JAMA 1995;274:1846–51.
8 Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer’s disease risk
with obesity, diabetes, and related disorders. Biol Psychiatry 2010;67:505–12.
9 Ott A, Slooter AJ, Hoffman A, et al. Smoking and risk of dementia and Alzheimer’s
disease in a population-based cohort study: the Rotterdam Study. Lancet
1998;351:1840–3.
10 Sasaki Y, Marioni R, Kasai M, et al. Chronic kidney disease: a risk factor for
dementia onset: a population-based study. The Osaki-Tajiri Project. J Am Geriatr
Soc 2011;59:1175–81.
11 Breno S, Diniz BS, Butters MA, et al. Late-life depression and risk of vascular
dementia and Alzheimer’s disease: systematic review and meta-analysis of
community-based cohort studies. Br J Psychiatry 2013;202:329–35.
12 Nordström P, Nordström A, Eriksson M, et al. Risk factors in late adolescence for
young-onset dementia in men: a nationwide cohort study. JAMA Intern Med
2013;173:1612–18.
Heath CA, et al.J Neurol Neurosurg Psychiatry 2015;86:959–964. doi:10.1136/jnnp-2014-309033 963
Cognitive neurology
group.bmj.com on August 17, 2015 - Published by http://jnnp.bmj.com/Downloaded from
13 Harvey RJ, Skelton-Robinson M, Rossor MN. The prevalence and causes of dementia
in people under the age of 65 years. J Neurol Neurosurg Psychiatry 2003;74:1206–9.
14 Ott A, Breteler MM, van Harskamp F, et al. Prevalence of Alzheimer’s disease and
vascular dementia: association with education. The Rotterdam study. BMJ
1995;310:970–3.
15 Kokmen E, Beard CM, Offord KP, et al. Prevalence of medically diagnosed dementia
in a defined United States population: Rochester, Minnesota, January 1, 1975.
Neurology 1989;39:773–6.
16 Barnett K, Mercer SW, Norbury M, et al. Epidemiology of multimorbidity and
implications for health care, research, and medical education: a cross-sectional
study. Lancet 2012;380:37–43.
17 Ikejima C, Yasuno F, Mizukami K, et al. Prevalence and causes of early-onset
dementia in Japan: a population-based study. Stroke 2009;40:2709–1.
18 Newens AJ, Forster DP, Kay DW, et al. Clinically diagnosed presenile dementia of
the Alzheimer type in the Northern Health Region: ascertainment, prevalence,
incidence and survival. Psychol Med 1993;23:631–44.
19 Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors associated with
pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet
Neurol 2009;8:1006–18.
20 Inzitari D, Pracucci G, Poggesi A, et al. Changes in white matter as determinant of
global functional decline in older independent outpatients: three year follow-up of
LADIS (leukoaraiosis and disability) study cohort. BMJ 2009;6:339–57.
21 Cheng G, Huang C, Deng H, et al. Diabetes as a risk factor for dementia and mild
cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J
2012;42:484–91.
22 Kerti L, Witte A, Winkler A, et al. Higher glucose levels associated with
lower memory and reduced hippocampal microstructure. Neurology
2013;13:25–9.
23 Rouch I, Roche F, Dauphinot V, et al. Diabetes, impaired fasting glucose, and
cognitive decline in a population of elderly community residents. Aging Clin Exp Res
2012;24:377–83.
24 Xu WL, Qiu CX, Wahlin A, et al. Diabetes mellitus and risk of dementia
in the Kungsholmen project: a 6-year follow-up study. Neurology
2004;63:1181–6.
25 Launer LJ, Ross GW, Petrovitch H, et al. Midlife blood pressure and dementia: the
Honolulu-Asia Aging Study. Neurobiol Aging 2000;21:49–55.
26 Feinkohl I, Keller M, Robertson CM, et al. Clinical and subclinical macrovascular
disease as predictors of cognitive decline in older patients with type 2 diabetes: the
Edinburgh type 2 diabetes study. Diabetes Care 2013;36:2779–86.
27 Alzheimer’s Society, Alzheimer Scotland, Action on Dementia. Mapping the
Dementia Gap 2011: progress on improving diagnosis of dementia 2010–2011.
2012.
28 Poirier J, Davignon J, Bouthillier D, et al. Apolipoprotein E polymorphism and
Alzheimer’s disease. Lancet 1993;342:697–9.
29 Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type
4 allele and the risk of Alzheimer’s disease in late onset families. Science
1993;261:921–3.
30 Kurz A, Corder EH, Saunders AM, et al. Apolipoprotein E type 4 allele and
Alzheimer’s disease: effect on age at onset and relative risk in different age groups.
J Neurol 1996;243:452–6.
964 Heath CA, et al.J Neurol Neurosurg Psychiatry 2015;86:959–964. doi:10.1136/jnnp-2014-309033
Cognitive neurology
group.bmj.com on August 17, 2015 - Published by http://jnnp.bmj.com/Downloaded from
middle-aged people in Scotland
245 population-based study of 616
with dementia: a cross-sectional
Vascular comorbidities in younger people
C A Heath, S W Mercer and B Guthrie
doi: 10.1136/jnnp-2014-309033
online November 18, 2014 2015 86: 959-964 originally publishedJ Neurol Neurosurg Psychiatry
http://jnnp.bmj.com/content/86/9/959
Updated information and services can be found at:
These include:
Material
Supplementary
html
http://jnnp.bmj.com/content/suppl/2014/11/19/jnnp-2014-309033.DC1.
Supplementary material can be found at:
References #BIBLhttp://jnnp.bmj.com/content/86/9/959
This article cites 29 articles, 7 of which you can access for free at:
service
Email alerting box at the top right corner of the online article.
Receive free email alerts when new articles cite this article. Sign up in the
Collections
Topic Articles on similar topics can be found in the following collections
(60)Ischaemic heart disease
(353)Hypertension
(1371)Stroke (1290)Memory disorders (psychiatry)
(943)Dementia (104)JNNP Patients' choice
Notes
http://group.bmj.com/group/rights-licensing/permissions
To request permissions go to:
http://journals.bmj.com/cgi/reprintform
To order reprints go to:
http://group.bmj.com/subscribe/
To subscribe to BMJ go to:
group.bmj.com on August 17, 2015 - Published by http://jnnp.bmj.com/Downloaded from
