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Abstract
Objective: To compare the risk of developing Alzheimers disease (AD) dementia in late mild cognitive impairment (LMCI), early MCI (EMCI), and subjective memory impairment (SMI) with
normal test performance.
Methods: The baseline sample (n 5 2892) of the prospective cohort study in nondemented individuals (German Study on Aging, Cognition and Dementia in Primary Care Patients) was divided into
LMCI, EMCI, SMI, and control subjects by delayed recall performance. These groups were subdivided by the presence of self-reported concerns associated with experienced memory impairment.
AD dementia risk was assessed over 6 years.
Results: Across all groups, risk of AD dementia was greatest in LMCI. In those with self-reported
concerns regarding their memory impairment, SMI and EMCI were associated with a similarly
increased risk of AD dementia. In those subgroups without concerns, SMI was not associated with
increased risk of AD dementia, but EMCI remained an at-risk condition.
Conclusions: SMI and EMCI with self-reported concerns were associated with the same risk of AD
dementia, suggesting that pre-LMCI risk conditions should be extended to SMI with concerns.
2014 The Alzheimers Association. All rights reserved.
Keywords:
Mild cognitive impairment; Subjective memory impairment; Alzheimers disease dementia; Prospective cohort
study; Risk
1. Introduction
Defining at-risk stages of dementia resulting from
Alzheimers disease (AD) is crucial for biomarker-based
predementia AD detection, which in turn is the requirement
Equal contribution.
*Corresponding author. Tel.: 149-228-287-11109; Fax: 149-228-28719732.
E-mail address: frank.jessen@ukb.uni-bonn.de
1552-5260/$ - see front matter 2014 The Alzheimers Association. All rights reserved.
http://dx.doi.org/10.1016/j.jalz.2012.09.017
2. Methods
2.1. Participants
The AgeCoDe study is a general practice (GP) registrybased longitudinal study in elderly individuals designed to
identify predictors of cognitive decline and dementia
[11,12]. The study recruitment was undertaken in six
German cities (Bonn, Dusseldorf, Hamburg, Leipzig,
Mannheim, and Munich) with a total of 138 GPs
connected to the study sites. The inclusion criteria for this
study were an age of 75 years and older, absence of
dementia according to GP judgment, and at least one
contact with the GP within the past 12 months. Exclusion
criteria were GP consultations by home visits only, living
in a nursing home, severe illness with an anticipated fatal
outcome within 3 months, language barrier, deafness or
blindness, and lack of ability to provide informed consent.
Baseline recruitment was performed in 2002 and 2003.
The study was approved by the local ethical committees
of the Universities of Bonn, Hamburg, Dusseldorf, Heidelberg/Mannheim, and Leipzig, and the Technical University
of Munich.
A total of 3327 subjects provided informed consent for
participation after being provided with a complete
description of the study protocol. The study assessments
were performed by trained interviewers at the subjects
home. Seventy individuals were excluded after baseline interview because of the presence of dementia according to
77
78
79
Table 1
Sample description for all groupsCO, SMI, EMCI, LMCIwith and without concerns
Sample
Characteristics
CO
SMI
EMCI
LMCI
All
Total sample
n
Age, years (mean, SD)
Female, n (%)
Level of education
Low, n (%)
Middle, n (%)
High, n (%)
Depressive symptoms,{ n (%)
APOE 41, n (%)
n
Age, years (mean, SD)
Female, n (%)
Level of education
Low, n (%)
Middle, n (%)
High, n (%)
Depressive symptoms,{ n (%)
APOE 41, n (%)
n
Age, years (mean, SD)
Female, n (%)
Level of education
Low, n (%)
Middle, n (%)
High, n (%)
Depressive symptoms,{ n (%)
APOE 41, n (%)
863
79.7 (3.47)
584 (67.7)
1061
79.8 (3.48)
618 (58.3)
251
79.4 (3.79)
162 (64.5)
358
79.9 (3.93)
277 (77.4)
2533
79.7 (3.58)
1641 (64.8)
530 (61.4)
249 (28.9)
84 (9.7)
41 (4.8)
163 (18.9)
863
79.7 (3.47)
584 (67.7)
604 (56.9)
308 (29)
149 (14)
98 (9.2)
210 (19.8)
261
79.6 (3.42)
180 (69.0)
167 (66.5)
60 (23.9)
24 (9.6)
24 (9.6)
44 (17.5)
70
78.7 (3.05)
46 (65.7)
229 (64)
96 (26.8)
33 (9.2)
58 (16.2)
100 (27.9)
133
79.7 (4.22)
110 (82.7)
1530 (60.4)
713 (28.1)
290 (11.4)
221 (8.7)
517 (20.4)
1327
79.6 (3.52)
920 (69.3)
530 (61.4)
249 (28.9)
84 (9.7)
41 (4.8)
163 (18.9)
863
79.7 (3.47)
584 (67.7)
162 (62.1)
61 (23.4)
38 (14.6)
49 (18.8)
54 (20.7)
800
79.8 (3.5)
438 (54.8)
50 (71.4)
15 (21.4)
5 (7.1)
13 (18.6)
10 (14.3)
181
79.7 (4.02)
116 (64.1)
86 (64.7)
33 (24.8)
14 (10.5)
30 (22.6)
40 (30.1)
225
80.0 (3.76)
167 (74.2)
828 (62.4)
358 (27.0)
141 (10.6)
133 (10.0)
267 (20.1)
2069
79.8 (3.56)
1305 (63.1)
530 (61.4)
249 (28.9)
84 (9.7)
41 (4.8)
163 (18.9)
442 (55.3)
247 (30.9)
111 (13.9)
49 (6.1)
156 (19.5)
117 (64.6)
45 (24.9)
19 (10.5)
11 (6.1)
34 (18.8)
143 (63.6)
63 (28.0)
19 (8.4)
28 (12.4)
60 (26.7)
1232 (59.5)
604 (29.2)
233 (11.3)
129 (6.2)
413 (20.0)
Subjects with
concerns only
Subjects without
concerns only
Group
differences
* y z x
* jj
* y z x **
y z x
z x
*y
* y **
y z x
* z x jj
* z
y z x
y z
Abbreviations: CO, control group; SMI, subjective memory impairment; EMCI, early mild cognitive impairment; LMCI, late mild cognitive impairment; SD,
standard deviation; APOE 4, apolipoprotein E4.
*Group differences (P , .05, adjusted for multiple comparisons): CO vs SMI.
y
Group differences (P , .05, adjusted for multiple comparisons): CO vs LMCI.
z
Group differences (P , .05, adjusted for multiple comparisons): SMI vs LMCI.
x
Group differences (P , .05, adjusted for multiple comparisons): EMCI vs LMCI.
jj
Group differences (P , .05, adjusted for multiple comparisons): SMI vs EMCI.
{
Depressive symptoms were defined as a score of 6 points on the Geriatric Depression Scale.
**Group differences (P , .05, adjusted for multiple comparisons): CO vs EMCI.
ratio (HR) for each group throughout the course of the study
are listed in Table 2. For the entire sample, the AD dementia
risk in subjects with LMCI was increased (HR, 7.27;
P , .001). The risk was increased also in subjects with
EMCI (HR, 3.10; P , .001) and with SMI (HR, 1.55;
P 5 .04) in comparison with the control subjects. Figure
1A shows the survival curves. In addition, age (HR, 1.13;
P , .001) and positive APOE 4 carrier status (HR, 1.88;
P , .001) were associated with an increased risk of AD dementia. With the SMI group as the reference group, both
LMCI (HR, 4.69; P , .001) and EMCI (HR, 2.0; P 5
.003) were associated with a significantly greater risk of
AD dementia.
In the second analysis, all three categories were restricted
to those participants reporting concerns regarding their memory impairment. In this analysis, the risk of AD dementia was
increased in the LMCI group (HR, 11.13; P , .001). The
EMCI group (HR, 2.46; P 5 .06) and the SMI group (HR,
2.44; P 5 .001) showed a very similar increase in risk. The
increase in risk in the EMCI group did not reach significance,
most likely because of the limited size of the group (Fig. 1B).
In this analysis there was also an increased risk of AD dementia associated with greater age (HR, 1.15; P , .001) and with
positive APOE 4 carrier status (HR, 2.2; P , .001). Compared with the SMI group, there was a difference in risk of incident AD dementia in the LMCI group (HR, 4.56; P ,.001),
but not in the EMCI group (HR, 1.01; P 5 .99).
In the third analysis, all three categories were restricted to
subjects who reported no concerns regarding their memory impairment. Here, the risk of incident AD was increased in LMCI
(HR, 5.64; P , .001) and EMCI (HR, 3.35; P , .001), but not
significantly in the SMI group (HR, 1.25; P 5 .343) (Fig. 1C).
Age (HR, 1.14; P , .001) and positive APOE 4 carrier status
(HR, 1.72; P 5.004) were also associated with a greater risk of
incident AD dementia. In addition, depressive symptoms (HR,
1.81; P 5.025) were associated with increased risk of incident
AD dementia in this analysis. When the SMI group was treated
as the reference group, both LMCI (HR, 4.51; P , .001) and
EMCI (HR, 2.67; P \, .001) were associated with a greater
risk of incident AD dementia.
80
Table 2
Conversion to Alzheimers disease for different risk groups
Sample
Incident AD dementia
CO
SMI
EMCI
LMCI
All
863
32 (3.7)
1.0
863
32 (3.7)
1.0
863
32 (3.7)
1.0
1061
66 (6.2)
1.55 (1.022.37)
261
25 (9.6)
2.44 (1.444.14)
800
41 (5.1)
1.25 (0.792.0)
251
27 (10.8)
3.1 (1.865.18)
70
5 (7.1)
2.46 (0.956.36)
181
22 (12.2)
3.35 (1.945.77)
358
89 (24.9)
7.27 (4.8210.97)
133
45 (33.8)
11.13 (6.9217.89)
225
44 (19.6)
5.64 (3.558.97)
2533
214 (8.4)
1327
107 (8.1)
2069
139 (6.7)
Abbreviations: CO, control subjects group; SMI, subjective memory impairment; EMCI, early mild cognitive impairment; LMCI, late mild cognitive impairment; AD, Alzheimers disease; CI, confidence interval.
*Risk in comparison with CO. Covariates: age, sex, education (low, medium, high), depressive symptoms (Geriatric Depression Scale scores ,6 points or 6
points), and apolipoprotein E4 status.
81
82
Fig. 1. (AC) Survival curve across all subjects (A), across all subjects with concerns regarding their experienced memory impairment (B), and across all subjects without concerns regarding their experienced memory impairment (C). AD, Alzheimers disease; SMI, subjective memory impairment; EMCI, early mild
cognitive impairment; LMCI, late mild cognitive impairment.
DSM-IV criteria for AD dementia rather than recently proposed criteria that involve biomarkers [33]. Also, our definition of MCI was restricted to amnestic MCI. It is uncertain
how subjective report and performance impairment in other
cognitive domains are related to dementia prediction. In
a number of cases, only informant-based information could
be obtained, mostly because of death or morbidity-related
reasons. In an exploratory analysis, we recalculated the
models after exclusion of those with informant-based information only. The prediction results were similar across the
entire sample (data not shown). Thus, we think that the results
are not biased by this approach.
Residual confounding of the data is unlikely because we
used well-defined categories for level of education and
APOE 4 status. Depressive symptoms were dichotomized
according to an established cutoff [34]. In addition, we
have also repeated our analyses with the Geriatric Depression Scale as a continuous predictor with similar results
(data not shown). Last, the subjective report was based on interview with the participants only. Reports from informants
were not considered for classification of SMI.
Overall, our data provide evidence that stages of very
mild impairment may not be well captured by standard neuropsychological testing and also highlight the relevance of
subjective reports as an indicator of individual change over
time and predictor of AD dementia.
Acknowledgments
This study/article is part of the German Research Network
on Dementia (KND) and the German Research Network
on Degenerative Dementia (KNDD) and was funded by
the German Federal Ministry of Education and Research
(grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423,
01GI0429, 01GI0431, 01GI0433, and 01GI0434; grants
KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713,
01GI0714, 01GI0715, 01GI0716, and 01ET1006B). Other
members of the AgeCoDe Study group include HeinzHarald Abholz, Cadja Bachmann, Wolfgang Blank, Sandra
Eifflaender-Gorfer, Marion Eisele, Annette Ernst, Kathrin
Heser, Teresa Kaufeler, Mirjam Kohler, Hans-Helmut
Konig, Alexander Koppara, Carolin Lange, Hanna Leicht,
Melanie Luppa, Manfred Mayer, Julia Olbrich, Jana Prokein, Anna Schumacher, Janine Stein, Susanne Steinmann,
Franziska Tebarth, Klaus Weckbecker, Dagmar Weeg,
Thomas Zimmermann. We thank Dr Deirdre Mahkorn for
reviewing the manuscript.
RESEARCH IN CONTEXT
1. Systematic review: We reviewed the literature on
prediction of Alzheimers dementia (AD) by early
and late mild cognitive impairment (MCI) and subjective memory impairment (SMI). We included
population-based studies and studies on AD biomarkers in clinical samples.
2. Interpretation: Our study shows that SMI without impairment on a standard cognitive test (SMI) but associated with self-reported concerns is as predictive of
AD dementia as early MCI defined by SMI plus
impairment on a cognitive task of 1.0 to 1.5 standard
deviations below the normal range. We conclude that
the requirement of very mild impairment on tests is
insensitive and that the definition of very early at-risk
populations of AD dementia should be extended to
SMI.
3. Future directions: The role of SMI as an indicator of
early AD and a predictor of AD dementia needs to be
evaluated by biomarker studies with long follow-up
as it is currently done in early MCI.
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