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This is the accepted version of a paper published in Neurobiology of Aging. This paper has been peerreviewed but does not include the final publisher proof-corrections or journal pagination.
Citation for the original published paper (version of record):
Enache, D., Solomon, A., Cavallin, L., Kåreholt, I., Kramberger, M G. et al. (2016)
CAIDE Dementia Risk Score and biomarkers of neurodegeneration in memory clinic patients
without dementia.
Neurobiology of Aging, 42: 124-131
https://doi.org/10.1016/j.neurobiolaging.2016.03.007
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CAIDE Dementia Risk Score and biomarkers of neurodegeneration in memory clinic
patients without dementia
Daniela Enachea1,b, Alina Solomona1,c,d, Lena Cavallin e,f, Ingemar Kåreholt d,g, Milica
Gregoric Krambergera1,h, Dag Aarslanda1,i,j, Miia Kivipeltoa1,c,d,i, Maria Eriksdottera2,i,
Bengt Winblada1,i, Vesna Jelica2,i
a
Department of Neurobiology, Care Sciences and Society, a1Division of Neurogeriatrics,
a2
Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; bPsychiatry
Southwest, Karolinska University Hospital Huddinge; cInstitute of Clinical
Medicine/Neurology, University of Eastern Finland, Kuopio, Finland; d Aging Research
Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden; eDepartment
of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm,
Sweden; fDepartment of Radiology, Karolinska University Hospital, Stockholm, Sweden;
g
Institute of Gerontology, School of Health and Welfare , Jönköping University,
Jönköping, Sweden; hDepartment of Neurology, University Medical Centre, Ljubljana,
Slovenia; iDepartment of Geriatric Medicine, Memory Clinic, Karolinska University
Hospital-Huddinge, Stockholm, Sweden; j Center for Age-Related Diseases, Psychiatric
Clinic, Stavanger University Hospital, Stavanger, Norway
*Corresponding author:
Daniela Enache, Department of Neurobiology, Care Sciences and Society; Division of
Neurogeriatrics,
Karolinska
Institutet,
Novum,
141
86
Stockholm,
Sweden;
daniela.enache@ki.se
Key words: mild cognitive impairment, subjective cognitive impairment, CAIDE Dementia
Risk Score, neurodegeneration, amyloid beta, tau
1
Abstract
The aim of this study was to explore cross-sectional associations between CAIDE Dementia
Risk Score and dementia-related CSF and neuroimaging biomarkers in 724 memory clinic
patients without dementia from the Memory Clinic at Karolinska University Hospital
Huddinge, Sweden. We additionally evaluated the score’s capacity to predict dementia. Two
risk score versions were calculated: one including age, gender, obesity, hyperlipidaemia, and
hypertension; and one additionally including APOE ε4 carrier status. CSF was analysed for
amyloid β (Aβ), total tau (t-tau), and phosphorylated tau (p-tau). Visual assessments of
medial temporal lobe atrophy (MTA), global cortical atrophy-frontal subscale (GCA-F) and
Fazekas scale for white matter changes (WMC) were performed. Higher CAIDE Dementia
Risk Score (version without APOE) was significantly associated with higher t-tau, more
severe MTA, WMC and GCA-F. Higher CAIDE Dementia Risk Score (version with APOE)
was associated with reduced Aβ, more severe MTA and WMC. CAIDE Dementia Risk
Score version with APOE seemed to predict dementia better in this memory clinic
population with short follow-up than the version without APOE.
2
1. Introduction
Prevention of dementia and Alzheimer’s disease (AD) is a major global public health
priority (http//www.who.int, 2015). Modifiable vascular and lifestyle-related risk factors
have been shown to increase the risk of dementia (Solomon et al., 2014). Dementia risk
scores have been developed in general populations (Kivipelto et al., 2006) (Barnes et al.,
2009) (Jefferson et al., 2015), primary care (Barnes et al., 2014) or specialized units (Buratti
et al., 2015) for the purpose of identifying at-risk individuals who could benefit from
preventive interventions (Ngandu et al., 2015).
The CAIDE Dementia Risk Score was developed in a Finnish population for predicting the
risk of dementia 20 years later in middle-aged individuals (Kivipelto et al., 2006). It includes
easily measurable factors like age, gender, education, BMI, systolic blood pressure, total
cholesterol and physical activity. A second version of the risk score additionally included
APOE genotype, but without significantly improved predictive performance compared to
the original score. The CAIDE Dementia Risk Score was validated in a large multi-ethnic
population from USA followed for 40 years (Exalto et al., 2014). Adding several other
factors to the risk score (e.g. central obesity, diabetes mellitus, head trauma, lung function,
depressed mood, and smoking) did not improve the prediction capacity of the original score
(Exalto et al., 2014).
A higher CAIDE Dementia Risk Score in midlife was shown to relate to more severe white
matter changes (WMC) and medial temporal atrophy (MTA) on brain MRI up to 30 years
later in a population-based study (Vuorinen et al., 2015). However, the risk score has not
been tested in memory clinic patients in relation to markers of neurodegeneration and
amyloid beta (Aβ) deposition, or dementia development. AD, the most common form of
dementia, is histopathologically characterized by Aβ plaques and neurofibrillary tangles
(NFT), and changes can be detected years before dementia diagnosis (Jack et al., 2010). AD3
related biomarkers have been divided into two main categories: markers of brain Aβ
deposition (e.g. cerebrospinal fluid (CSF) Aβ42), and markers of neurodegeneration (e.g.
CSF t-tau or p-tau, atrophy on structural MRI) (Jack et al., 2013). WMC have been related
to small vessel disease, and are known to have effects on cognitive functioning (Prins and
Scheltens, 2015). Memory clinic patients with Subjective Cognitive Impairment (SCI) or
Mild Cognitive Impairment (MCI) are very heterogeneous groups. SCI patients report
subjective changes in cognitive performance without objective measurable impairment
(Sperling et al., 2011) (Jessen et al., 2014a). MCI has been defined as both subjective and
objective cognitive impairment in patients without dementia (Petersen et al., 2014). The risk
for converting to dementia from SCI or MCI has been estimated to 10% and 25-40%
respectively, depending on study design, duration of the follow up, and population type
(clinic-based or general population) (Maioli et al., 2007) (Jessen et al., 2014b) (Mitchell et
al., 2014).
Risk scores including easily available and modifiable risk factors could help identify patients
who are most at risk for dementia development, and who may benefit most from preventive
interventions. The aim of this study was to explore cross-sectional associations between
CAIDE Dementia Risk Score and dementia-related CSF and MRI markers in memory clinic
patients without dementia, as well the predictive value of the score for the development of
dementia.
2. Methods
2.1. Study population
The study included 724 patients (412 with SCI and 312 with MCI) referred to the Memory
clinic at the Department of Geriatrics, Karolinska University Hospital Huddinge,
4
Stockholm, Sweden during 2007-2012. The study was approved by the Regional Ethical
Review Board in Stockholm. Written informed consent was obtained from all participants.
Inclusion criteria were: age 40 years or older; available data for CAIDE Dementia Risk
Score version without APOE genotype; available measurements of CSF biomarkers (total
tau – t-tau, tau phosphorylated at threonine 181 – p-tau, and Aβ 1-42); diagnosis of MCI or
SCI. Exclusion criteria were: dementia diagnosis at baseline or within one year from
baseline; and neurological conditions affecting CSF or MRI assessments (e.g.
hydrocephalus, brain tumours, large strokes or multiple sclerosis). Out of 1209 patients
without dementia evaluated at the Memory Clinic, 724 fulfilled inclusion criteria (Figure 1).
The standard evaluation protocol at the Memory Clinic (described in detail in e.g. Enache,
2015) included interviews with patients and informants, general physical and neurological
examination, standardised neuropsychological test-battery assessment of depressive and
other psychiatric symptoms, routine blood chemistry, CSF analyses including conventional
biomarkers of neurodegeneration (t-tau, p-tau and Aβ 1-42), and brain imaging (MRI or CT
scans). Diagnoses were established after consensus meetings using all available information.
Dementia diagnoses were made according to International Classification of Diseases 10
revision (ICD 10). MCI was diagnosed according to the Winblad et al 2004 (Winblad et al.,
2004) clinical criteria, which require subjective cognitive complaints, impairment on
objective cognitive tests, normal global cognitive function, no significant impairment of
activities of daily living and no dementia. The diagnosis of SCI was made if the assessments
did not show evidence of objective cognitive impairment, i.e. neither dementia nor MCI
criteria were fulfilled, although patients and/or informants reported changes in cognitive
performance.
According to the standard protocol at the Memory clinic, regular annual follow-up visits for
patients with MCI or SCI were planned after the initial assessments and diagnosis only if
5
clinically indicated (i.e. high risk of cognitive decline as judged by the physician). Followup data until March 2015 were collected from patient files. Altogether 324 (44.8%) patients
were followed for at least one year (mean 2.9, SD 1.6, range 1-7.8 years). 110 of the 324
patients had SCI at baseline, and 14 (12.7%) developed dementia. 214 of the 324 patients
had MCI at baseline, and 86 (40.2%) developed dementia.
2.2. Assessment of CAIDE Dementia Risk Score
The CAIDE Dementia Risk Score was calculated for each patient using data from the
baseline visit (first referral to the Memory Clinic). Points were given for elevated total
cholesterol or systolic blood pressure if the patient had a diagnosis and received treatment
for hyperlipidaemia or hypertension. No systematically collected data were available for
leisure time physical activity, and this variable was not included in the risk score (Exalto et
al., 2014). A second version of the risk score was calculated adding points for the presence
of the APOE ε4 allele. APOE genotype was analysed from blood leucocytes using
polymerase chain reaction and HhaI digestion (Tsukamoto et al., 1993) (Garcia-Ptacek et
al., 2014). The maximum number of points for the CAIDE Dementia Risk Score in the
present study was 14 (version without APOE) or 17 (version with APOE), one point less
than in the original publication (Kivipelto et al., 2006).
2.3. CSF and MRI measurements
CSF samples were obtained in connection to the baseline visit (first referral) at the Memory
Clinic. Lumbar puncture was done in the L3/L4 or L4/L5 intervertebral space, using a 25gauge needle, and collected in 12-ml polypropylene tubes. Samples were centrifuged within
two hours. CSF was aliquoted in polypropylene tubes of 0.5 or 1 ml, and stored at −80˚C
until further analysis. CSF Aβ1-42, t-tau and p-tau (phosphorylated tau at threonine 181) were
6
measured by commercially available sandwich enzyme linked immunoabsorbent assays
(ELISAs) (Innogenetics, Ghent, Belgium) as previously reported
(Kramberger et al., 2012). Memory Clinic physicians have access to CSF measurements,
which may be used as supportive information for differential diagnosis in dementia cases.
However, clinical diagnostic criteria always have priority due to lack of established CSFbased criteria for regular clinical practice. In the present study, patients were not selected
based on CSF biomarker levels, and a researcher without clinical ties to the Memory Clinic
(DE) collected data on primary clinical diagnoses (SCI, MCI, dementia). Medical record
comments on CSF markers, and specific diagnostic codes for dementia types (e.g. AD
dementia) were not considered. This approach also matches the original design of the
CAIDE Risk Score for predicting dementia in general, without focus on specific causes of
dementia.
MRI scans were performed either shortly before the referral to the Memory Clinic at
different radiology departments in Stockholm region as part of the routine dementia
assessment by the general practitioner or at the Department of Radiology, Karolinska
University Hospital during the assessment procedure at our Memory clinic. All images were
routinely collected in a common electronic database at the Department of Radiology,
Karolinska University Hospital-Huddinge. Images related to the baseline visit (first referral)
at the Memory Clinic were used in the present study. Because scanners and protocols were
not identical in all image sources, only visual assessments were considered.
MRI visual assessments were performed by an experienced rater (LC) who was blinded to
all other data. For visual assessment of medial temporal lobe atrophy (MTA), T1-weighted
MRI images were oriented to oblique coronal sections. MTA was rated using the 5-point
Scheltens scale ranging from 0 (no atrophy) to 4 (severe atrophy) (Scheltens et al., 1992).
The MTA visual assessment included hippocampus proper, dentate gyrus, subiculum,
7
parahippocampal gyrus, entorhinal cortex and surrounding CSF spaces such as the temporal
horns and choroid fissure. White matter changes WMC were assessed on transverse FLAIR
images according to the modified 4-point Fazekas scale ranging from 0 (no WMC) to 3
(large confluent WMC) (Fazekas et al., 1987). Frontal lobe atrophy was assessed on a
FLAIR sequence according to the 4-point scale for global cortical atrophy–frontal subscale
(GCA-F) ranging from 0 (no atrophy) to 3 (severe ‘knife blade’ atrophy) (Pasquier et al.,
1996). Parietal atrophy (PA) was visually assessed by combining T1 weighted sagittal, T1
weighted coronal and axial FLAIR sequences, using Koedam score (Koedam et al., 2011),
a 4 points scale ranging from 0 (no atrophy) to 3 (severe atrophy).
2.4. Statistical analysis
Between-group comparisons were made using parametric (Student’s t-tests) or nonparametric tests (chi-square tests, Mann- Whitney) as appropriate. CAIDE Dementia Risk
Score was categorized into three groups of relatively similar size: 0-5 points (lower risk,
n=301 patients), 6-7 points (intermediate risk, n=214) and 8-14 points (higher risk, n=209)
for the version without APOE; and 0-6 points (lower risk, n=81 patients), 7-8 points
(intermediate risk, n=98) and 9-17 points (higher risk, n=131) for the version with APOE.
The lower risk category was used as reference in all analyses.
Based on recent studies suggesting that combinations of CSF biomarkers may be more
accurate indicators of Alzheimer’s disease(Duits et al., 2014)(Leuzy et al., 2015), the Aβ142/t-tau
and Aβ1-42/p-tau181 ratios were calculated. Zero-skewness log-transformation was
applied to Aβ1-42, t-tau, p-tau181, and Aβ1-42/t-tau and Aβ1-42/p-tau181 ratios. Linear regression
models with CSF markers as dependent variables were used to investigate associations with
CAIDE Dementia Risk Score. Results are shown as standardized beta-coefficients (p-
8
values). Ordinal regression was used to explore associations between visual assessment
scales on MRI and CAIDE Dementia Risk Score. MTA was visually assessed for right and
left hemisphere separately, and the mean MTA score was used in analyses (Pereira et al.,
2014). Due to the smaller number of patients with higher MTA ratings, patients with mean
MTA scores 2.5, 3 and 4 were grouped together. Results are shown as OR (95% CI).
Stratified analyses were conducted according to diagnosis (SCI or MCI).
The performance of the CAIDE Dementia Risk Score (versions without and with APOE) in
predicting dementia was assessed in patients with available follow-up data (n=324). Results
are reported as area under the receiver operating characteristics curve (AUC) and 95%
confidence interval (95% CI). Sensitivity, specificity, likelihood ratios for positive and
negative tests and their 95% confidence intervals were also calculated. To account for
missing follow-up data, additional analyses were conducted: 1) assuming that patients
without planned follow-up did not develop dementia; and 2) assuming that MCI patients
without planned follow-up developed dementia.
The level of statistical significance was set to p<0.05 in all analyses. Statistical analyses
were performed with SPSS software version 22.0. Analyses of the performance of the
CAIDE Dementia Risk Score in predicting dementia were conducted using the diagt and
roctab commands in Stata software version 13, and rocgold was used to compare the risk
score versions with and without APOE.
3. Results
Formation of the study population is shown in Figure 1. The study included 724 patients
with MCI and SCI, of which 310 had available data on APOE genotype, and 529 had
available MRI scans. Characteristics of the study population are shown in Table 2. Median
(range) for the CAIDE risk score version without APOE was 6 (0-14), and 301 (41.6%)
9
patients had lower dementia risk (0-5 points), 214 (29.6%) intermediate risk (6-7 points) and
209 (28.9%) higher dementia risk (8-14 points). Median (range) for the CAIDE risk score
version with APOE was 8 (0-17), and 81 (26.1%) patients had lower dementia risk (0-6
points), 98 (31.6%) intermediate risk (7-8 points) and 131 (42.3%) higher dementia risk (917 points).
Table 3 shows the characteristics of the study population compared to patients who did not
fulfil inclusion criteria. Excluded patients had significantly lower MMSE scores, were less
likely to be APOEε4 carriers, less likely to be diagnosed with SCI and more likely to be
diagnosed with MCI.
Associations between CAIDE Dementia Risk Score and CSF markers are shown in Table 4.
Compared to patients with lower risk (0-5 points) on CAIDE Dementia Risk Score version
without APOE, patients with intermediate risk (6-7 points) and higher risk (8-14 points) had
higher CSF t-tau and lower Aβ1-42/t-tau and Aβ1-42/p-tau181 ratios. For the CAIDE Dementia
Risk Score including APOE genotype, both intermediate (7-8 points) and higher (9-17
points) risk groups had significantly lower CSF Aβ1-42 and lower Aβ1-42/t-tau and Aβ1-42/ptau181 ratios. The association with higher CSF t-tau was significant for the intermediate but
not the higher risk group (Table 4). No significant associations were found with CSF p-tau
levels.
Table 4 shows associations between CAIDE Dementia Risk Score and MRI visual ratings.
Compared to patients with lower dementia risk (0-5 points) on CAIDE Dementia Risk Score
version without APOE, patients with intermediate risk (6-7 points) and higher risk (8-14
points) had significantly more severe WMC. For the CAIDE Dementia Risk Score including
APOE genotype, the association with more severe WMC was significant in the higher risk
group (9-17 points). More severe MTA was found in the higher risk group compared to the
lower risk group for both CAIDE Dementia Risk Score versions (without and with APOE).
10
Patients in the higher risk group (both risk score versions) were also more likely to have
higher GCA-F ratings. No significant associations were found with parietal atrophy ratings.
Additional analyses were conducted stratifying for diagnosis group (SCI and MCI
separately) (data not shown). In SCI patients, no significant associations were found between
CAIDE Dementia Risk Score versions and CSF markers. However, the higher risk group
(both risk score versions) had significantly more severe WMC. In MCI patients, the
intermediate and higher risk groups according to both CAIDE Dementia Risk Score versions
had more severe Aβ and tau pathology (CSF markers). Patients with MCI and higher
dementia risk according to both risk score versions had significantly more severe WMC on
MRI.
The performance of CAIDE Dementia Risk Score versions in predicting dementia in patients
with planned follow-up after at least one year is shown in Table 5. AUCs (95% CIs) were
0.64 (0.56-0.73) for the version with APOE, 0.58 (0.56-0.73) for the version without APOE,
and 0.61 (0.53-0.68) for APOE alone. Comparison of ROC areas was conducted in 168
patients with verified follow-up and available data on both APOE and CAIDE score: CAIDE
Dementia Risk Score version with APOE seemed to be significantly better than the version
without APOE (p=0.049); neither version was significantly different than APOE alone
(p>0.4). The version with APOE had good sensitivity in predicting dementia, but poor
specificity. Results from additional analyses accounting for missing follow-up data are
shown in supplementary tables S1 and S2.
4. Discussion
This is the first study assessing associations of CAIDE Dementia Risk Score with CSF and
MRI markers for neurodegeneration and amyloid deposition, as well as the performance of
the risk score in predicting dementia in memory clinic patients with SCI and MCI. A higher
11
risk level according to the CAIDE Dementia Risk Score (version with APOE) was
associated with lower Aβ1-42, higher t-tau, lower Aβ1-42/t-tau and Aβ1-42/p-tau181 ratios, and
more severe MTA and WMC at baseline. The CAIDE Dementia Risk Score version without
APOE showed a similar pattern of associations, although these were somewhat weaker, and
the relation to Aβ1-42 was not significant. In addition, an association with frontal lobe atrophy
was found only for the risk score version without APOE. Neither risk score version had any
relation to p-tau levels and parietal atrophy. These results are in line with recent findings
from a population-based study where higher CAIDE Dementia Risk Score in midlife was
associated with more severe WMC and MTA up to 30 years later
(Vuorinen et al., 2015).
Aβ deposition and NFT are the histopathological hallmarks of AD. According to Braak &
Baak stages, extracellular Aβ deposition begins in the frontal lobe, while NFT appear first
subcortically in the entorhinal cortex and medial temporal lobe (Braak and Braak, 1991).
The hypothetical model of dynamic biomarkers in AD suggests that Aβ and tau pathologies
can begin independently from each other, and both are necessary but not sufficient to
produce clinical symptoms of AD (Jack et al., 2013). Other pathologies (e.g. small vessel
disease, Lewy body accumulation) (Nelson et al., 2010), genetic factors, and brain resilience
or cognitive reserve are also important. CSF t-tau and p-tau, and MTA on MRI are
considered markers of neurodegeneration, and they have been associated with NFT burden
(Jack et al., 2013). Atrophy of the medial temporal lobe is a common finding in sporadic
AD, while more pronounced frontal or parietal lobe atrophy tend to be present primarily in
atypical forms of AD, or early onset AD (Lam et al., 2013). Importantly, Aβ and tau often
coexists with cerebrovascular pathology, particularly small vessel disease (Prins and
Scheltens, 2015), and interactions between the two pathology types have been described
(Kester et al., 2014). WMC are common at older ages, are often found in AD (Prins and
12
Scheltens, 2015), and may potentiate the effects of cortical atrophy on cognitive impairment
(Zi et al., 2014).
Because CAIDE Dementia Risk Score is mainly based on vascular risk factors, the
association with WMC is not surprising. In addition, midlife hypertension and
hypercholesterolemia have been associated with increased risk of AD neuropathology in
previous population-based autopsy studies (Petrovitch et al.) (Toledo et al., 2013), while
obesity has been related to lower brain volumes on MRI (Willette and Kapogiannis, 2015).
Cardiovascular risk factors, confluent white matter lesions, MTA and central atrophy have
been shown to increase the AD-likelihood of SCI subjects (Garcia-Ptacek et al., 2014). The
association of lower Aβ1-42 with higher CAIDE Dementia Risk Score including APOE (but
not the risk score version without APOE) could be explained by the well-known contribution
of the APOE ε4 allele to Aβ deposition and neurodegeneration (Liu et al., 2013). APOE ε4
seems to be related to increased Aβ deposition independently of cognitive performance (e.g.
normal cognition or MCI) (Risacher et al., 2013).
Although the APOE ε4 allele is the strongest known genetic risk factor for dementia, adding
APOE genotype to the midlife CAIDE Dementia Risk Score did not improve the ability to
predict dementia 20 years later in the general population (Kivipelto et al., 2006). However,
in the present study the CAIDE Dementia Risk Score version with APOE seemed to perform
better than the version without APOE in predicting dementia in memory clinic patients with
SCI and MCI. The ability of the CAIDE Dementia Risk Score to predict dementia shortterm (up to seven years) in memory clinic patients was nevertheless lower than the ability
to predict dementia long-term (20-40 years) in a middle-aged general population where AUC
(95%CI) was 0.77 (0.71–0.83) (Kivipelto et al., 2006) (Exalto et al., 2014). Although
performance of CAIDE Risk Score versions did not seem to be different from APOE alone
13
in the present study, the CAIDE Risk Score version including APOE has the advantage of
additionally including modifiable risk factors that can be targeted with preventive
interventions (e.g. lifestyle and vascular risk monitoring).
In the present study cut-offs were 1 point lower than in the original publication (Kivipelto
et al., 2006), but they were chosen to be higher than for points given for age alone. Sensitivity
remained high in the memory clinic population (above 80% for the version including
APOE), but specificity was lower. The risk score may thus be useful for identifying
individuals with higher dementia risk who could benefit more from preventive lifestyle
interventions and vascular and metabolic risk management, similarly to the selection of
participants in the successful FINGER prevention trial (Ngandu et al., 2015).
Risk profiles for dementia have been shown to differ between midlife and older ages
(Kivipelto et al., 2006) (Barnes et al., 2009). Blood pressure, BMI and cholesterol tend to
decline after midlife in individuals who develop dementia later on (Solomon et al., 2014).
The CAIDE Dementia Risk Score was formulated based on a midlife risk profile (mean
population age around 50 years) (Kivipelto et al., 2006). The Memory clinic at Karolinska
University Hospital Huddinge is known to have a relatively young population of patients
(Andersson, 2007), with a mean age of 61 years in the present study. However, patients in
most memory clinics tend to be older, and a late-life risk score for shorter-term dementia
prediction may work better in this type of population (e.g. modifying the list of vascular and
lifestyle factors included in the score, and the number of points given to each factor).
The present study has a number of methodological limitations. First, associations between
CAIDE Dementia Risk Score, CSF and MRI markers could only be evaluated crosssectionally at baseline because data on risk factors prior to the memory clinic referral were
not available. Second, physical activity was not routinely assessed, and could not be used
for calculating CAIDE Dementia Risk Score according to the original versions. Reduced
14
physical activity has been associated with Aβ deposition and neurodegeneration (Brown et
al., 2013). However, the CAIDE Dementia Risk Score version used in the present study is
the same as in a previous validation study which did not include physical activity (Exalto et
al., 2014). Third, the study population consisted of memory clinic patients, who have a more
advanced stage of Aβ pathology, neuronal injuries, or small vessel pathology, and an
increased prevalence of the APOE ε4 allele compared to the general population (GarciaPtacek et al., 2014). Associations with CSF markers of Aβ deposition and neurodegeneration
cannot thus be extrapolated to the general population based on the present study. However,
the associations with MTA and WMC on MRI found in memory clinic patients are in line
with a previous population-based longitudinal study (Vuorinen et al., 2015). Fourth, followup data on dementia development after more than one year was available only for patients
considered to have a high risk of cognitive and functional decline after the initial
comprehensive assessments. According to the routine Memory clinic protocol, if follow-up
beyond one year is not considered necessary in a patient with SCI or MCI, the general
practitioner (or referring physician) is instructed to send a new referral if there are signs of
cognitive decline. We have tried to account for missing data by conducting additional
analyses of dementia prediction performance based on this protocol (assuming that patients
without follow-up did not develop dementia), and also considering the progression of MCI
to dementia (assuming that all MCI patients without planned follow-up developed
dementia). CAIDE Dementia Risk Score is not used for risk assessment at the Memory
clinic, thus circularity was avoided.
5. Conclusions
A higher CAIDE Dementia Risk Score, particularly the version including APOE genotype,
tends to identify patients who are more likely to have brain pathology (e.g.
15
neurodegeneration, Aβ deposition, and/or cerebrovascular changes). This suggests that the
previously shown ability of the CAIDE Dementia Risk Score to predict dementia may be
explained by its links to AD/neurodegenerative and/or cerebrovascular pathological
processes. The CAIDE Dementia Risk Score version including APOE seems to be better at
predicting dementia up to 7 years later in memory clinic patients compared to the version
without APOE. The risk score does not perform as well in a memory clinic setting as it does
in the general population, particularly due to lower specificity. However, high sensitivity
could make the risk score useful for identifying patients with higher risk who may benefit
most from preventive lifestyle interventions. This is particularly important in a memory
clinic setting because no therapeutic measures are currently available for patients with SCI
or MCI. However, the risk score should not be used as a diagnostic tool (it was not designed
to predict or diagnose specific types of dementia), or for excluding dementia development
within short-term. An adjusted prediction model for use in older memory clinic patients with
SCI and MCI should be formulated in future studies to test whether the dementia prediction
performance of the CAIDE Risk Score can be improved.
Acknowledgements
The authors thank all participants in this study. The study was supported by Demensfonden
Forskningsstipendier, Stiftelsen Dementia, Gun och Bertil Stohnes stiftelse, Sheikha Salama
bint Hamdan Al Nahyan Foundation, Academy of Finland (grants 287490 and 294061),
CIMED and EiT Health.
Conflicts of interest: The authors report no conflicts of interest
16
Figure 1: Study population (flowchart)
17
Table 1. CAIDE Dementia Risk Score versions used in the study
CAIDE Dementia Risk Score
Age, years
Education, years
Sex
Hypertension
BMI, kg/m2
<47
47-53
>53
≥10
7-9
0-6
Women
Men
No
Yes
Without APOE
0
3
4
0
2
3
0
1
0
2
With APOE
0
3
5
0
3
4
0
1
0
2
≤30
>30
No
Yes
Non-carrier
Carrier
0
0
2
2
0
0
Hyperlipidaemia
2
1
0
APOE ε4
2
Total points
Max 14 p
Max 17 p
CAIDE: Cardiovascular Risk Factors, Aging and Dementia Study, BMI: body mass index,
APOE: apolipoprotein E genotype
18
Table 2. Baseline characteristics of the study population
Age, years*
Women, n (%)
Education, years*
CAIDE Dementia Risk Score
Hyperlipidaemia, n(%)
Hypertension, n(%)
BMI, kg/m2*
MMSE*
APOE ε4 carrier, n(%)
SCI, n (%)
MCI, n(%)
Cornell Depression Scale
Antidepressant treatment, n (%)
History of depression, n (%)
All (n=724)
60.8 (8.5)
417 (57.6)
12.5 (3.7)
6 (0-14)
201 (27.8)
246 (34.0)
26.2 (4.1)
27.7 (2.6)
412 (56.9)
312 (43.1)
6 (0-26)
192 (26.5)
261 (36.0)
APOE genotype available (n=310)
61.2 (7.7)
193 (62.3)
12.5 (3.7)
8 (0-17)
97 (31.3)
108 (34.8)
26.3 (4.2)
27.6 (2.6)
156 (50.3)
163 (52.6)
147 (47.4)
6 (0-24)
79 (25.5)
109 (35.2)
CSF markers
Aβ1-42, ng/L
t-tau, ng/L
p-tau, ng/L
Aβ1-42/t-tau *
Aβ1-42/p-tau181
855 (56-1920)
240.5 (41-1030)
51 (16-183)
3.91 (2.3)
18.22 (8.9)
821.5 (56-1680)
254 (41-1030)
53 (16-183)
3.70 (2.5)
16.90 (8.8)
MRI visual ratings
MTA
GCA-F
Parietal atrophy
WMC
n=529
1 (0-4)
0 (0-1)
0 (0-2)
1 (0-3)
n=235
1 (0-4)
0 (0-1)
0 (0-2)
1 (0-3)
Follow-up
Planned follow-up, n (%)
324(44.8)
168 (54.2)
Follow up years mean (SD)
2.90 (1.6)
3.00 (1.6)
Conversion to dementia n (%)
100 (13.8)
55 (17.7)
Values are medians (range) unless otherwise specified. *Values are means (SD). CAIDE:
Cardiovascular Risk Factors, Aging and Dementia Study, BMI: body mass index, SCI:
subjective cognitive impairment, MCI: mild cognitive impairment, MMSE: Mini-mental
State Examination, APOE: apolipoprotein E genotype, Aβ1-42: amyloid β1-42, t-tau: total tau,
p-tau181: phosphorylated tau at threonine 181, MTA: medial temporal lobe atrophy (mean
MTA scores of both hemispheres) , GCA-F : global cortical atrophy frontal subscale, parietal
atrophy: Koedam score for parietal atrophy, WMC: white matter changes measured with
Fazekas scale for white matter changes
19
Table 3. Included versus excluded patients
Included (n=724)
Excluded (n=485)
Age, years
60.8 (8.5)
60.7 (11.6)
Women, n(%)
417 (57.6)
294 (60.6)
#
Education, years
12.6 (3.7)
12.2 (3.9)
MMSE#
27.7 (2.6) *
26.9(3.2)
Cornell Depression Scale
6 (0-26)
7 (0-25)
Use of antidepressants, n(%)
192 (26.6)
149 (30.7)
History of depression, n(%)
262 (36.2)
200 (41.2)
APOEε4 carrier, n(%)/total number
156 (50.3)/310*
65 (42.0)/155
CAIDE Dementia Risk Score
6 (0-14)
SCI, n(%)
412 (56.9) *
233 (48.0)
MCI, n(%)
312 (43.1) *
252 (52.0)
Values are medians (range) unless otherwise specified. #Values are means (SD). *p<0.05;
#
P-values for the comparisons between excluded and included patients were based on t-test,
Mann-Whitney, Chi Squared tests as appropriate. SCI: subjective cognitive impairment,
MCI: mild cognitive impairment, MMSE: Mini-mental State Examination, APOE:
apolipoprotein E genotype, CAIDE: Cardiovascular Risk Factors, Aging and Dementia
Study
20
Table 4. Associations of CAIDE Dementia Risk Score with CSF and MRI markers at
baseline
CAIDE risk score (without APOE)
CAIDE risk score (with APOE)
CSF markers
(dependent variable)
Standardized beta-coefficients (p-values)
0-5 points (n=301)
Ref
0-6 points (n=81)
Ref
Aβ1-42 , pg/l
6-7 points (n=214)
-0.04 (0.37)
7-8 points (n=98)
-0.22 (0.002)
8-14 points (n=209) -0.07 (0.10)
9-17 points (n=131) -0.27 (<0.001)
0-5 points (n=301)
Ref
0-6 points (n=81)
Ref
t-tau, pg/l
6-7 points (n=214)
0.08 (0.06)
7-8 points (n=98)
0.14 (0.04)
8-14 points (n=209) 0.09 (0.04)
9-17 points (n=131) 0.10 (0.17)
0-5 points (n=301)
Ref
0-6 points (n=81)
Ref
p-tau, pg/l
6-7 points (n=214)
0.06 (0.17)
7-8 points (n=98)
0.05 (0.49)
8-14 points (n=209) 0.05 (0.22)
9-17 points (n=131) 0.05 (0.43)
0-5 points (n=301)
ref
0-6 points (n=81)
Ref
Aβ1-42/t-tau
6-7 points (n=214)
7-8 points (n=98)
-0.08 (0.04)
-0.21 (0.002)
8-14 points (n=209) -0.12 (0.004)
9-17 points (n=131) -0.23 (0.001)
0-5 points (n=301)
Ref
0-6 points (n=81)
Ref
Aβ1-42/p-tau
6-7 points (n=214)
-0.07 (0.09)
7-8 points (n=98)
-0.16 (0.02)
8-14 points (n=209) -0.10 (0.02)
9-17 points (n=131) -0.23 (0.001)
MRI visual ratings
(dependent variable)
OR (95%CI)
0-5 points (n=226)
Ref
0-6 points (n=57)
ref
MTA
6-7 points (n= 150) 1.11 (0.76-1.62)
7-8 points (n=78)
1.50 (0.80-2.78)
8-14 points (n=153) 1.47 (1.01-2.15)
9-17 points (n=100) 2.71 (1.48-5.95)
0-5 points (n=226)
Ref
0-6 points (n=57)
Ref
WMC
6-7 points (n= 150) 1.80 (1.16-2.77)
7-8 points (n=78)
1.78 (0.87-3.65)
8-14 points (n=153) 3.41 (2.20-5.27)
9-17 points (n=100) 3.91 (1.93-7.92)
0-5 points (n=226)
Ref
0-6 points (n=57)
Ref
GCA-F
6-7 points (n= 150) 1.14 (0.47-2.73)
7-8 points (n=78)
1.48 (0.26-8.40)
8-14 points (n=153) 2.40 (1.11-5.10)
9-17 points (n=100) 4.47 (0.99-20.47)
0-5 points (n=226)
Ref
0-6 points (n=57)
Ref
Parietal atrophy
6-7 points (n= 150) 0.88 (0.52-1.49)
7-8 points (n=78)
0.81 (0.36-1.84)
8-14 points (n=153) 1.36 (0.84-2.20)
9-17 points (n=100) 1.46 (0.70-3.05)
*p<0.05, Standardized beta-coefficients (p-values) are from linear regression with Aβ1-42, ttau and p- tau as dependent variable. Odds Ratios and 95% Confidence interval (OR and
95% CI) are from ordinal logistic regression with MTA, WMC, CGA-F and parietal atrophy
as dependent variable. CAIDE: Cardiovascular Risk Factors, Aging and Dementia Study,
Aβ1-42: amyloid β1-42, t-tau: total tau, p-tau181: phosphorylated tau at threonine 181 MTA:
medial temporal lobe atrophy (mean MTA scores of both hemispheres), GCA-F global
cortical atrophy frontal subscale, parietal atrophy – Koedam score for parietal atrophy,
WMC: white matter changes measured with Fazekas scale for white matter changes, APOE:
apolipoprotein E genotype
21
Table 5. Performance of the CAIDE Dementia Risk Score in predicting dementia
Cut-off
Sensitivity (95%CI)
Specificity (95%CI)
LR + (95%CI)
LR- (95%CI)
AUC (95%CI)
1.11 (0.99-1.26)
1.20 (1.01-1.42)
1.28 (1.00-1.65)
1.43 (1.03-1.98)
0.68 (0.43-1.10)
0.72 (0.52-1.01)
0.81 (0.65-1.02)
0.84 (0.70-1.00)
0.58 (0.51-0.65)
15.0 (9.0-23.0)
27.4 (19.5-36.6)
42.5 (33.2-51.2)
61.1 (51.4-70.1)
1.13 (1.03-1.24)
1.28 (1.12-1.46)
1.45 (1.19-1.77)
1.54 (1.12-2.11)
0.24 (0.06-1.01)
0.27 (0.10-0.71)
0.39 (0.20-0.73)
0.66 (0.46-0.93)
0.64 (0.56-0.73)
52.2 (42.6-61.7)
1.45 (1.11-1.88)
0.59 (0.38-0.91)
0.61 (0.53-0.68)
CAIDE Dementia Risk Score (version without APOE)
4/5
5/6
6/7
7/8
82.0 (73.1-89.0)
70.0 (60.0-78.8)
51.0 (40.8-61.1)
39.0 (29.4-49.3)
26.3 (20.7-32.6)
41.5 (35.0-48.3)
60.3 (53.5-66.7)
72.8 (66.4-78.5)
CAIDE Dementia Risk Score (version with APOE)
5/6
6/7
7/8
8/9
96.4 (87.5-99.6)
92.7 (82.4-98.0)
83.6 (71.2-92.2)
60.0 (45.9-73.0)
APOE alone
0/1
69.1 (55.2-80.9)
CAIDE: Cardiovascular Risk Factors, Aging and Dementia Study, LR+: likelihood ratio for
positive test, LR-: likelihood ratio for negative test, APOE: apolipoprotein E genotype
22
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