Alzheimer’s & Dementia 12 (2016) 144-153

Featured Article

Trajectories of decline in cognition and daily functioning

in preclinical dementia
Vincentius J. A. Verlindena,b, Jos N. van der Geestc, Renee F. A. G. de Bruijna,d, Albert Hofmana,
Peter J. Koudstaald, M. Arfan Ikrama,b,d,*
a
Department of Epidemiology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands
b
Department of Radiology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands
c
Department of Neuroscience, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands
d
Department of Neurology, Erasmus MC University Medical Centre Rotterdam, Rotterdam, The Netherlands

Abstract Introduction: Although preclinical dementia is characterized by decline in cognition and daily func-
tioning, little is known on their temporal sequence. We investigated trajectories of cognition and daily
functioning in preclinical dementia, during 18 years of follow-up.
Methods: In 856 dementia cases and 1712 controls, we repetitively assessed cognition and daily
functioning with memory complaints, mini-mental state examination (MMSE), instrumental activ-
ities of daily living (IADL), and basic activities of daily living (BADL).
Results: Dementia cases first reported memory complaints 16 years before diagnosis, followed by
decline in MMSE, IADL, and finally BADL. Vascular dementia related to earlier decline in daily
functioning but later in cognition, compared with Alzheimer’s disease. Higher education related to
larger preclinical cognitive decline, whereas apolipoprotein E (APOE) ε4 carriers declined less in
daily functioning.
Discussion: These results emphasize the long hierarchical preclinical trajectory of functional decline
in dementia. Furthermore, they show that various pathologic, environmental, and genetic factors may
influence these trajectories of decline.
Ó 2016 The Alzheimer’s Association. Published by Elsevier Inc. All rights reserved.

Keywords: Activities of daily living; Alzheimer’s disease; Apolipoproteins E; Cognition; Dementia; Preclinical; Vascular
dementia

1. Introduction deterioration in cognitive and physical functioning and

Dementia is a common disease in the elderly, character-
ized by both cognitive impairment and impairment in daily
functioning [1,2]. Typically, people with dementia have a
long preclinical phase, during which first biomarkers such
as amyloid b and tau increase, followed by deterioration in
magnetic resonance imaging markers, leading to
M.A.I. reports receiving research grants from Internationaal Parkinson
Fonds, Internationale Stichting Alzheimer Onderzoek, Netherlands Heart
Foundation, and the Netherlands Organization for Health Research and
Development (ZonMw). The other authors report no conflicts of interest.
*Corresponding author. Tel.: 131-107043930; Fax: 131-107044657.
E-mail address: m.a.ikram@erasmusmc.nl
http://dx.doi.org/10.1016/j.jalz.2015.08.001
1552-5260/Ó 2016 The Alzheimer’s Association. Published by Elsevier Inc. All rights reserved.
ultimately clinical symptoms [3]. However, the temporal
pattern of deterioration in clinical functioning during this
preclinical phase is largely unknown. Insight in the long-
term trajectories of cognition and daily functioning before
dementia is important because it may aid physicians in early
identification of people likely to become demented. Further-
more, it may aid clinical studies in identifying people who
may benefit most from interventions and are thus suitable
for trials on prevention or intervention for dementia.
Only few studies have investigated the pattern of deterio-
ration during preclinical dementia, focusing on Alzheimer’s
disease (AD) [4–7]. Two reports suggested cognition to
decline as early as 15 years before AD diagnosis [4,5].
Additionally, they found functioning on instrumental
 V.J.A. Verlinden et al. / Alzheimer’s & Dementia 12 (2016) 144-153
activities of daily living (IADL), which are cognitively more
challenging, to start declining around 7 years before AD.
Interestingly, one of these reports also suggested
differences in trajectories of cognition for level of
education, suggesting a role for cognitive reserve [4].
However, much remains unknown on the pattern of dete-
rioration in preclinical dementia. For example, surprisingly
little is known on preclinical trajectories of more physical
basic activities of daily living (BADL), even though these
are part of the diagnostic criteria for dementia [8]. Similarly,
although apolipoprotein E (APOE) ε4 carrier status is
considered one of the most important risk factors of demen-
tia, it is unknown whether preclinical trajectories in cogni-
tion and daily functioning differ for APOE ε4 status [9].
Finally, little is known on trajectories of decline for demen-
tias other than AD, such as vascular dementia [7].
We aimed to investigate trajectories of decline in cogni-
tion and daily functioning before dementia diagnosis.
Importantly, we also investigated differences in trajectories
for APOE ε4 carrier status, education, and dementia
subtypes.
2. Methods
2.1. Setting
The study is embedded in the Rotterdam Study, a
population-based cohort study based in Ommoord, suburb
of Rotterdam, in the Netherlands [10]. The study was initi-
ated in 1990, inviting all inhabitants of Ommoord aged
55 years. A total of 7983 participants (78%) agreed to
participate. Until 2011, the study has had a total of five
visits, including four follow-up visits: between 1993–
1995, 1997–1999, 2002–2004, and 2009–2011. At all
visits, participants undergo home interviews and medical
examinations at the research centre. Educational level
was assessed at baseline and categorized into primary edu-
cation or less versus higher education. APOE genotyping
was performed as previously described [11]. The Rotter-
dam Study has been approved by the medical ethics com-
mittee according to the Population Study Act Rotterdam
Study, executed by the Ministry of Health, Welfare, and
Sports of the Netherlands. Written informed consent was
obtained from all participants.
2.2. Assessment of memory complaints and cognition
Memory complaints were assessed using three questions,
which could be answered by yes or no. These questions were
“Do you have more trouble remembering things than
before?”; “Does it happen more often that you are on your
way to do something and forget what you wanted to do?”;
and “Do you more often have trouble finding words during
a conversation?”
Cognition was objectively assessed using the mini-
mental state examination (MMSE) [12].
145
2.3. Assessment of BADL
BADL was assessed using the disability index of the
Stanford Health Assessment Questionnaire [13]. The
questionnaire consists of 20 items constituting eight com-
ponents: activities, arising, dressing and grooming, eating,
hygiene, grip, reach, and walking. In our study, two of
three items of eating (ability to cut meat and drink a glass
of milk) were combined into one. Items could be scored
from 0 to 3, with higher scores reflecting worse ability:
0 5 no difficulty, 1 5 some difficulty, 2 5 much diffi-
culty, and 3 5 unable to. Component scores were calcu-
lated as the highest scored item belonging to the
respective component. Subsequently, BADL was calcu-
lated as the sum of the eight components.
2.4. Assessment of IADL
IADL was assessed using the IADL scale [14]. The
IADL-scale consists of eight items as follows: shopping,
washing, traveling on your own, finance management,
phoning, medication use, housekeeping, and meal prepara-
tion. Similar to BADL, items were coded 0–3, with higher
scores reflecting worse ability. For IADL, items scored as
nonapplicable were imputed using means of five imputa-
tions, based on age, sex, scores on BADL-items, and scores
on other IADL-items. Imputation of nonapplicable values
has been suggested and implemented by previous studies
to prevent loss of data [15,16]. Imputations were
performed separately for each study visit, with 5.3% of
variables imputed per visit. Subsequently, IADL was
calculated by summing the eight items.
2.5. Dementia diagnosis
Participants were followed up for incident dementia using
a three-step protocol [17]. Participants were screened for
dementia at baseline and follow-up visits using the MMSE
and geriatric mental state schedule (GMS) [12,18].
Participants with a score 25 on the MMSE or .0 on the
GMS underwent further assessment using the Cambridge
Mental Disorders of the Elderly Examination diagnostic
interview [19]. Participants suspected of having dementia
based on this assessment underwent further extensive neuro-
psychological testing. In addition to the screening, partici-
pants were continuously monitored for diagnosis of
dementia through medical records of the general practi-
tioner’s office and the Regional Institute for Outpatient
Mental Health Care. Diagnoses of dementia were made
according to the Diagnostic and Statistical Manual of
Mental Disorders, Third Edition, Revised (DSM-III-R)
criteria for all-cause dementia, National Institute of
Neurological and Communicative Disorders and Stroke
and Alzheimer’s Disease and Related Disorders
Association (NINCDS-ADRDA)-criteria for Alzheimer’s
disease, and National Institute of Neurological Disorders
and Stroke and the Association Internationale pour la
146 V.J.A. Verlinden et al. / Alzheimer’s & Dementia 12 (2016) 144-153
Recherche et l’Enseignement en Neurosciences (NINDS-
AIREN)-criteria for vascular dementia [8,20,21]. All
participants with AD were included as AD cases,
including AD cases with cardiovascular disease. Dementia
follow-up was complete until January 1st of 2011.
2.6. Study population
The study consists of a matched nested case-control
sample from the Rotterdam Study. All participants
diagnosed with dementia during follow-up were included
as cases, if they met the following criteria: they were non-
demented at the baseline visit and participated at the visit
before dementia diagnosis, to ensure they were dementia-
free at that visit. Participants used as controls had to
have the following characteristics: they participated at the
visit before diagnosis of the matched dementia case, to
ensure they were dementia-free until that visit; they were
assessed as dementia-free until the visit after the diagnosis
of the matched dementia case; and they were matched to a
dementia case by age (63 years), sex, and education. We
matched two controls for every dementia case at follow-
up, resulting in inclusion of 856 dementia cases and 1712
controls. Because of missing data on some measures,
numbers of participants slightly vary across analyses.
2.7. Statistical analysis
We used the “lcmm” function from the “lcmm” package
in R to investigate differences in trajectories of decline in
memory complaints, MMSE, IADL, and BADL with
incident dementia. A link function with quadratic splines
was used to capture the distribution and account for ceiling
effects of the dependent variables (memory complaints,
MMSE, IADL, and BADL). This link function is used to
transform the distribution of the dependent variables to
enable the formation of a linear equation to estimate param-
eter coefficients. To best adhere to the distribution of the
dependent variables but not needlessly complicate the
model, we used the Bayesian information criterion (BIC)
to estimate the optimal number and position of splines, in
a basic model including age, sex, education, their interac-
tions with time, age ! time2, time itself, time2, and time3.
We included random intercepts and random slopes over
time. Time was calculated from diagnosis of dementia for
dementia cases, ensuring that time 5 0 corresponds to
time of dementia diagnosis. For controls, the conversion
time for dementia was calculated as the conversion time
for dementia of the matched case. To obtain time to demen-
tia, as used in the figures, conversion time for dementia was
subtracted from the follow-up of the control. Hence, at
time 5 0, corresponding to time of dementia diagnosis,
follow-up time for controls equals that of their matched case.
We investigated up to cubic associations of incident
dementia with memory complaints, MMSE, IADL, and
BADL over time (i.e. interactions with time, time2, and
time3), adjusting for any non–time-dependent effect of
incident dementia. These analyses were repeated for inci-
dent AD and vascular dementia, in which participants
with other or undefined dementia subtypes were excluded.
For visualization of trajectories in memory complaints,
MMSE, IADL, and BADL, models including all interac-
tions of dementia up to time3 were used.
To investigate interactions of education with incident
dementia, we included interaction-terms of education with
dementia and up to time2 in the models.
To investigate interactions with APOE ε4, we included
APOE ε4 carrier status, its interaction with up to time2,
and their interactions with incident dementia in the analyses.
All analyses were adjusted for the basic model of age,
sex, education, their interactions with time, age ! time2,
time itself, time2, and time3.
For both categories of education and APOE ε4 carrier sta-
tus, we additionally investigated differences in rank ordering
of decline in trajectories of memory complaints, MMSE,
IADL, and BADL for incident demented participants. To
do this, we rescaled trajectories of memory complaints and
MMSE to the range of IADL and BADL. Subsequently,
we subtracted trajectories of nondemented participants
from those of incident-demented participants, for the respec-
tive category of education or APOE ε4 carrier status. Finally,
we plotted trajectories of memory complaints, MMSE,
IADL, and BADL in graphs for each respective category.
To investigate influence of APOE ε2/ε4 carriers on our as-
sociations for APOE ε4, we repeated analyses on APOE ε4
while excluding APOE ε2/ε4 carriers as a sensitivity analysis.
To investigate differences at each separate study visit in
memory complaints, MMSE, IADL, and BADL, the
“lcmm” method was used as a cross-sectional analysis
adjusted for age at visit, time, sex, and education.
Because spline link-function estimates vary across
analyses, the exact transformation of the dependent variables
also varies. Therefore, effect sizes cannot be readily inter-
preted and compared across analyses. Hence, we only report
significance of associations. Effect sizes may be compared
using the figures. Because the splines are only used in the
transformation of the dependent variables, they only have
subtle influence on the figures not specific to a certain
location.
We used nominal thresholds of statistical significance
(P , .05). All analyses were performed using R version 3.1.0.
3. Results
The average age at (matched) dementia diagnosis was
82.4 years (standard deviation, 6.7) and 67.8% were women.
A total of 1203 participants (46.8%) had attained only
primary education or less. Of 856 dementia cases, 685
(80.0%) were identified as AD and 83 (9.7%) as vascular
dementia. APOE genotyped data were available in 2391
participants, of which 711 (29.7%) were APOE ε4 carriers,
including 41.3% of dementia cases and 23.9% of controls.
 V.J.A. Verlinden et al. / Alzheimer’s & Dementia 12 (2016) 144-153 147

Table 1 pants, reflected by a slow decline in MMSE from 14 years

Number of incident dementia cases and controls across visits before dementia diagnosis onward, which accelerated
Visit* Time to dementia, years (SD) Cases, n Controls, n around 7 years before diagnosis (Fig. 1). Furthermore,
24 215.5 (2.2) 266 532 MMSE differed significantly at each visit from third visit
23 211.5 (2.7) 526 1057 before dementia (the study visit w11.5 years before diag-
22 27.2 (2.6) 694 1375 nosis) onward (all P , .008).
21 23.0 (2.0) 856 1712 Similar to MMSE, we found a significantly larger decline
1 1.4 (1.8) 416 1018
in IADL for incident-demented participants, reflected by
Abbreviation: SD, standard deviation. increased decline from around 6 years before diagnosis
*Negative visits represent visits before dementia diagnosis, whereas pos- (Fig. 1). A trend of difference in IADL was already present
itive visits represent visits after diagnosis.
at the second visit before dementia diagnosis (the study visit
w7.2 years before, P 5 .05), which became significant from
Numbers of participants included per visit before dementia the first visit before diagnosis (the study visit w3.0 years
diagnosis are listed in Table 1. before) onward (all P , .004).
BIC for analyses used in figure creation are reported in We found a significantly larger decline in BADL for
Supplementary Table 1. incident-demented participants compared with dementia-
free participants, reflected by a differentiation in BADL at
around 5 years before dementia diagnosis (Fig. 1). The
3.1. Trajectories before all-cause dementia
difference in BADL was significant only at the first visit after
Incident-demented participants already had more mem- diagnosis (the study visit w1.4 years after, P , .001).
ory complaints at 16 years before diagnosis, and this differ-
ence gradually and significantly increased over time (Fig. 1).
3.2. Trajectories before dementia subtypes
The severity of memory complaints differed significantly at
all visits, from fourth visit before diagnosis (the study visit Similar to all-cause dementia, participants with incident
w15.5 years before diagnosis) onward (all P , .04). AD already had more memory complaints at w16 years
We found significantly larger decline in MMSE for before dementia, whereas those with vascular dementia
incident demented compared with nondemented partici- started to accumulate memory complaints at w12 years

Fig. 1. Trajectories of decline in cognition and daily functioning before dementia diagnosis. (A) Trajectories for memory complaints. (B) Trajectories for
MMSE. (C) Trajectories for IADL. (D) Trajectories for BADL. The trajectories are derived from the lcmm analyses and plotted for the mean age, sex, and
education. The vertical dark green dotted lines reflect the mean time to dementia at which the participants participated in the five separate study visits. The
red lines represent the incident dementia cases and the blue lines the controls. The dotted lines around the red and blue lines reflect the 95% confidence intervals.
Abbreviations: MMSE, mini-mental state examination; IADL, instrumental activities of daily living; BADL, basic activities of daily living.
148 V.J.A. Verlinden et al. / Alzheimer’s & Dementia 12 (2016) 144-153

before diagnosis. Participants with incident AD deteriorated
earlier in MMSE compared with those with incident vascular
dementia (w12 years before diagnosis compared with
w4 years, Fig. 2). Although participants with incident AD
and vascular dementia started declining in IADL at the
same time (w5–6 years before diagnosis), those with
vascular dementia declined more strongly. Participants
with incident AD declined much later in BADL compared
with incident vascular dementia (w1 year before diagnosis
compared with w7 years). We found significantly increased
decline in MMSE, IADL, memory complaints, and BADL
for both incident AD and vascular dementia.
3.3. Influence of education
We found a significant interaction for education on the
trajectory of MMSE before dementia (pinteraction 5 .005).
Incident-demented participants with higher education
started with higher MMSE but declined faster compared
with lower educated participants toward dementia diagnosis,
resulting in similar MMSE 2 years after diagnosis (Fig. 3).
Although similar patterns were seen for memory complaints
and BADL, no significant interactions were found. The inter-
action with education for MMSE was also found for AD but
not for vascular dementia.
Lower educated people with incident dementia showed a
clear hierarchical decline with earliest deterioration in
memory complaints, followed by MMSE, then IADL, and
deterioration in BADL only starting the last year before
diagnosis. In contrast, higher educated people with dementia
were earlier to deteriorate in IADL and BADL, with the
decline in IADL coinciding with the acceleration in decline
of MMSE.
3.4. Influence of APOE ε4 carrier status
We found no differences for APOE ε4 carrier status in
trajectories of memory complaints and MMSE before inci-
dent dementia (Fig. 4). Decline in IADL before dementia
started later for APOE ε4 carriers, which was supported by
a significant interaction term (pinteraction 5 .008). For
BADL, we found increased decline in non–APOE ε4
carriers with incident dementia, whereas APOE ε4 carriers
with incident dementia showed no increased decline at all.
This difference was supported by an interaction with less
decline in BADL before dementia for APOE ε4 carriers
(pinteraction 5 .002).
Excluding APOE ε2/ε4 carriers from the analyses only
marginally changed results, with the interaction terms
remaining significant.
Similar interactions of APOE ε4 in IADL and BADL
were found for incident AD. For vascular dementia, an inter-
action was only found for APOE ε4 carrier status with
BADL.
APOE ε4 carriers showed a clear hierarchical decline,
starting with decline in memory complaints, followed by

Fig. 2. Trajectories of decline in cognition and daily functioning before Alzheimer’s disease and vascular dementia. (A) Trajectories for memory complaints.
(B) Trajectories for MMSE. (C) Trajectories for IADL. (D) Trajectories for BADL. The trajectories are derived from the lcmm analyses and plotted for the mean
age, sex, and education. The vertical dark green dotted lines reflect the mean time to dementia at which the participants participated in the five separate study
visits. The red lines represent the incident Alzheimer cases, the pink lines the incident vascular dementia cases, and the blue lines the controls. Abbreviations:
MMSE, mini-mental state examination; IADL, instrumental activities of daily living; BADL, basic activities of daily living.
 V.J.A. Verlinden et al. / Alzheimer’s & Dementia 12 (2016) 144-153 149

Fig. 3. Trajectories of decline in cognition and daily functioning before dementia diagnosis, stratified by education. (A) Trajectories for memory complaints in
incident dementia cases and controls, stratified by education. (B) Trajectories for MMSE in incident dementia cases and controls, stratified by education. (C)
Trajectories for IADL in incident dementia cases and controls, stratified by education. (D) Trajectories for BADL in incident dementia cases and controls, strat-
ified by education. (E) Rescaled trajectories for memory complaints, MMSE, IADL, and BADL of incident dementia cases compared with controls, in partic-
ipants with low education. (F) Rescaled trajectories for memory complaints, MMSE, IADL, and BADL of incident dementia cases compared with controls, in
participants with high education. The trajectories are derived from the lcmm analyses and plotted for the mean, age, and sex. The vertical dark green dotted lines
reflect the mean time to dementia at which the participants participated in the five separate study visits. Abbreviations: MMSE, mini-mental state examination;
IADL, instrumental activities of daily living; BADL, basic activities of daily living.

MMSE, IADL, and finally BADL. In contrast, non–APOE
ε4 carriers deteriorated earlier and more strongly in IADL
and BADL, with decline in IADL even surpassing decline
in MMSE.
4. Discussion
In this population-based study, we found that during the
preclinical phase of dementia, people decline more quickly
in memory complaints, MMSE, IADL, and BADL
compared with nondemented participants. Earliest decline
was found for memory complaints at 16 years before diag-
nosis. Next, MMSE declined, followed by IADL, and finally
BADL. Trajectories were similar for AD, whereas partici-
pants with vascular dementia declined later in cognition
but earlier in BADL. Higher educated persons started with
better MMSE but declined faster before diagnosis.
APOE ε4 carriers had similar trajectories in MMSE and
memory complaints before dementia compared with noncar-
riers, but declined less quickly in IADL and BADL.
Study strengths are the large number of dementia cases
included, investigation of trajectories in all of memory
complaints, MMSE, IADL, and BADL, separate investiga-
tion of all-cause dementia, AD, and vascular dementia,
and investigation of interactions with education and
APOE ε4 carrier status.
150 V.J.A. Verlinden et al. / Alzheimer’s & Dementia 12 (2016) 144-153

Fig. 4. Trajectories of decline in cognition and daily functioning before dementia diagnosis, stratified by APOE ε4 carrier status. (A) Trajectories for memory
complaints in incident dementia cases and controls, stratified by APOE ε4 carrier status. (B) Trajectories for MMSE in incident dementia cases and controls,
stratified by APOE ε4 carrier status. (C) Trajectories for IADL in incident dementia cases and controls, stratified by APOE ε4 carrier status. (D) Trajectories for
BADL in incident dementia cases and controls, stratified by APOE ε4 carrier status. (E) Rescaled trajectories for memory complaints, MMSE, IADL, and BADL
of incident dementia cases compared with controls, in non–APOE ε4 carriers. (F) Rescaled trajectories for memory complaints, MMSE, IADL, and BADL of
incident dementia cases compared with controls, in APOE ε4 carriers. The trajectories are derived from the lcmm analyses and plotted for the mean age, sex, and
education. The vertical dark green dotted lines reflect the mean time to dementia at which the participants participated in the five separate study visits. Abbre-
viations: MMSE, mini-mental state examination; IADL, instrumental activities of daily living; BADL, basic activities of daily living.

Study limitations include ceiling effects in our measures
of cognition and daily functioning. Possibly, earlier decline
would have been found with continuous measures. Although
MMSE is a well-known objective measurement of cognition,
objective assessment of memory using dedicated memory
tests may be even more sensitive to detect early deterioration
in incident-demented participants [4]. Furthermore, we used
questionnaires to assess daily functioning and memory
complaints, which are reliant on self-report. People who
become demented may not accurately report problems in
daily functioning and memory. However, this applies partic-
ularly to the last years before dementia, and not the early
phase of disease.
Our study illustrates the long trajectories of decline in
cognition and daily functioning during the preclinical phase
of dementia. We found a clear hierarchical decline starting
with memory complaints, then decline in global cognition
(MMSE), followed by decline in more cognitive daily func-
tioning (IADL), and finally simpler basic daily functioning
(BADL). Comparison of our results for all-cause dementia
with previous studies is limited, because those mainly inves-
tigated incident AD [4,5]. Nonetheless, results were similar,
with earliest deterioration in cognition from 16 years before
dementia diagnosis, which increased dramatically from 7
years before dementia, closely followed by decline in
IADL [4,5]. Interestingly, we found earliest symptoms of
 V.J.A. Verlinden et al. / Alzheimer’s & Dementia 12 (2016) 144-153
incident dementia to be memory complaints, at 16 years
before diagnosis. Importantly, as follow-up started at
16 years before diagnosis, memory complaints may have
been present even earlier in the disease process. This finding
is in line with studies suggesting that people may notice
memory deterioration before cognitive tests are able to
detect it [22,23]. Yet, because we did not have objective
measurements of memory available, we cannot ascertain
whether these would have been able to detect similar
differences, as have previously been identified for higher
educated people [4]. Participants with incident dementia
deteriorated finally in BADL, from around 4 to 5 years
before diagnosis onward.
The shape of trajectories of decline in MMSE, IADL, and
BADL, in which decline keeps increasing until dementia
diagnosis, corresponds closely to those suggested in previ-
ous studies [3]. Similarly, we found a slowing of decline in
memory around dementia diagnosis, corresponding to the
sigmoid shaped trajectories suggested previously.
Because most dementia cases in our sample had AD,
trajectories of cognition and daily functioning before AD
closely resembled those for all-cause dementia. Yet, clear
differences were appreciated for vascular dementia. Similar
to a previous study, we found that participants with incident
AD deteriorated earlier in cognition, as reflected by memory
complaints and MMSE [7]. We are first to show that partic-
ipants with incident vascular dementia deteriorate earlier
and faster in daily functioning, especially the more physical
BADL. These differences between AD and vascular
dementia may be driven by differences in (localization of)
pathology. AD pathology is thought to first affect the hippo-
campus and temporal lobe, which are foremost involved in
cognition and memory [24–26]. In contrast, people with
vascular dementia are more prone to accumulate both
global and focal brain changes, which are known to also
affect daily functioning [16,24,26].
We found higher educated people to start with better
cognition compared with lower educated people, but to
decline earlier before incident dementia. Although a previ-
ous study could not statistically verify this difference, we
found a significant interaction with higher educated people
declining more quickly in cognition, as reflected by
MMSE [4]. A similar interaction was found for AD, but
not for vascular dementia, probably due to lack of power.
Additionally, we found differences in rank ordering of
decline before dementia, with higher educated people
declining relatively earlier in IADL and BADL. These find-
ings support the cognitive reserve hypothesis, suggesting
that higher educated people can withstand more brain
pathology, through a larger brain or greater redundancy in
neural circuits, before deteriorating in cognition [4,27].
Once brain pathology reaches a certain critical threshold,
higher educated people may decline quickly in cognition
and concurrently start declining in daily functioning. This
cognitive reserve hypothesis is further supported by
previous findings that higher amounts of brain pathology,
151
such as neuritic plaques and amyloid load, have less effect
on cognition in higher educated people [28,29].
Although APOE ε4 is the strongest genetic risk factor for
late-onset AD, its relationship with cognition and daily func-
tioning is less clear [9,30–32]. We found no differences for
APOE ε4 carriers in trajectories of cognition before
dementia, similar to a previous study in demented
participants [33]. However, we did find APOE ε4 carriers
with incident dementia to decline less in daily functioning
compared with noncarriers. Similar associations were found
for AD and vascular dementia. A previous study found
similar protective effects of APOE ε4 on decline in daily
functioning after AD diagnosis [32]. Additionally, we found
a difference in rank ordering of decline, with non–APOE ε4
carriers declining earlier in IADL and BADL, and decline in
IADL even surpassing decline in MMSE. Possibly, these
findings may be explained by differences in brain
morphology or patterns of brain aging between APOE ε4
carriers and noncarriers [34]. Future studies should investi-
gate the relationship between APOE ε4, the brain, and
dementia.
5. Conclusions
Incident dementia has a long preclinical trajectory of
decline in cognition and daily functioning which already
starts at 16 years before clinical diagnosis. People first report
memory complaints, followed by decline in global
cognition, cognitive IADL, and finally physical BADL.
These trajectories differ by dementia subtype, education,
and APOE ε4 carrier status.
Acknowledgments
The Rotterdam Study is sponsored by the Erasmus MC and
Erasmus University Rotterdam, the Netherlands Organiza-
tion for Scientific Research (NWO), the Netherlands
Organization for Health Research and Development
(ZonMW), the Research Institute for Diseases in the Elderly
(RIDE), the Netherlands Genomics Initiative, the Ministry
of Education, Culture and Science, the Ministry of Health,
Welfare and Sports, the European Commission (DG XII),
and the Municipality of Rotterdam. None of the study
sponsors had any role in the study design; in the collection,
analysis, and interpretation of data; in the writing of the
report; in the decision to submit the article for publication;
or any other aspect of the study. M.A.I. confirms that he
had full access to all the data in the study and had final
responsibility for the decision to submit for publication.
Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.jalz.2015.08.001.
152 V.J.A. Verlinden et al. / Alzheimer’s & Dementia 12 (2016) 144-153
RESEARCH IN CONTEXT
1. Systematic review: We searched Medline until
January 2015 for reports on trajectories of cognition
and daily functioning in preclinical dementia. Only
few studies investigated long-term preclinical
trajectories in dementia, mainly focusing on
Alzheimer’s disease and cognitive decline.
2. Interpretation: We found earliest symptoms 16 years
before dementia diagnosis, initiating with memory
complaints, followed by decline in mini-mental
state examination, then instrumental activities of
daily living, and finally basic activities of daily
living. Higher educated people declined more
quickly in cognition before disease. Vascular de-
mentia related to later decline in cognition but earlier
in daily functioning compared with Alzheimer’s
disease. Finally, APOE ε4 carriers declined less in
daily functioning compared with noncarriers in pre-
clinical dementia.
3. Future directions: Future studies should investigate
whether decline initiates even earlier than 16 years
before dementia diagnosis. Additionally, future
studies should investigate whether underlying brain
pathology or morphology explains the differences
in preclinical trajectories of decline between demen-
tia subtypes and APOE ε4 carrier status.
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