Вы находитесь на странице: 1из 10

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


ultimately clinical symptoms [3]. However, the temporal
Dementia is a common disease in the elderly, character-
pattern of deterioration in clinical functioning during this
ized by both cognitive impairment and impairment in daily
preclinical phase is largely unknown. Insight in the long-
functioning [1,2]. Typically, people with dementia have a
term trajectories of cognition and daily functioning before
long preclinical phase, during which first biomarkers such
dementia is important because it may aid physicians in early
as amyloid b and tau increase, followed by deterioration in identification of people likely to become demented. Further-
magnetic resonance imaging markers, leading to
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.
M.A.I. reports receiving research grants from Internationaal Parkinson Only few studies have investigated the pattern of deterio-
Fonds, Internationale Stichting Alzheimer Onderzoek, Netherlands Heart ration during preclinical dementia, focusing on Alzheimer’s
Foundation, and the Netherlands Organization for Health Research and
Development (ZonMw). The other authors report no conflicts of interest.
disease (AD) [4–7]. Two reports suggested cognition to
*Corresponding author. Tel.: 131-107043930; Fax: 131-107044657. decline as early as 15 years before AD diagnosis [4,5].
E-mail address: m.a.ikram@erasmusmc.nl Additionally, they found functioning on instrumental
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.
V.J.A. Verlinden et al. / Alzheimer’s & Dementia 12 (2016) 144-153 145

activities of daily living (IADL), which are cognitively more 2.3. Assessment of BADL
challenging, to start declining around 7 years before AD.
Interestingly, one of these reports also suggested BADL was assessed using the disability index of the
differences in trajectories of cognition for level of Stanford Health Assessment Questionnaire [13]. The
education, suggesting a role for cognitive reserve [4]. questionnaire consists of 20 items constituting eight com-
However, much remains unknown on the pattern of dete- ponents: activities, arising, dressing and grooming, eating,
rioration in preclinical dementia. For example, surprisingly hygiene, grip, reach, and walking. In our study, two of
little is known on preclinical trajectories of more physical three items of eating (ability to cut meat and drink a glass
basic activities of daily living (BADL), even though these of milk) were combined into one. Items could be scored
are part of the diagnostic criteria for dementia [8]. Similarly, from 0 to 3, with higher scores reflecting worse ability:
although apolipoprotein E (APOE) ε4 carrier status is 0 5 no difficulty, 1 5 some difficulty, 2 5 much diffi-
considered one of the most important risk factors of demen- culty, and 3 5 unable to. Component scores were calcu-
tia, it is unknown whether preclinical trajectories in cogni- lated as the highest scored item belonging to the
tion and daily functioning differ for APOE ε4 status [9]. respective component. Subsequently, BADL was calcu-
Finally, little is known on trajectories of decline for demen- lated as the sum of the eight components.
tias other than AD, such as vascular dementia [7].
We aimed to investigate trajectories of decline in cogni- 2.4. Assessment of IADL
tion and daily functioning before dementia diagnosis. IADL was assessed using the IADL scale [14]. The
Importantly, we also investigated differences in trajectories IADL-scale consists of eight items as follows: shopping,
for APOE ε4 carrier status, education, and dementia washing, traveling on your own, finance management,
subtypes. phoning, medication use, housekeeping, and meal prepara-
tion. Similar to BADL, items were coded 0–3, with higher
2. Methods scores reflecting worse ability. For IADL, items scored as
nonapplicable were imputed using means of five imputa-
2.1. Setting tions, based on age, sex, scores on BADL-items, and scores
on other IADL-items. Imputation of nonapplicable values
The study is embedded in the Rotterdam Study, a
has been suggested and implemented by previous studies
population-based cohort study based in Ommoord, suburb
to prevent loss of data [15,16]. Imputations were
of Rotterdam, in the Netherlands [10]. The study was initi-
performed separately for each study visit, with 5.3% of
ated in 1990, inviting all inhabitants of Ommoord aged
variables imputed per visit. Subsequently, IADL was
55 years. A total of 7983 participants (78%) agreed to
calculated by summing the eight items.
participate. Until 2011, the study has had a total of five
visits, including four follow-up visits: between 1993–
2.5. Dementia diagnosis
1995, 1997–1999, 2002–2004, and 2009–2011. At all
visits, participants undergo home interviews and medical Participants were followed up for incident dementia using
examinations at the research centre. Educational level a three-step protocol [17]. Participants were screened for
was assessed at baseline and categorized into primary edu- dementia at baseline and follow-up visits using the MMSE
cation or less versus higher education. APOE genotyping and geriatric mental state schedule (GMS) [12,18].
was performed as previously described [11]. The Rotter- Participants with a score 25 on the MMSE or .0 on the
dam Study has been approved by the medical ethics com- GMS underwent further assessment using the Cambridge
mittee according to the Population Study Act Rotterdam Mental Disorders of the Elderly Examination diagnostic
Study, executed by the Ministry of Health, Welfare, and interview [19]. Participants suspected of having dementia
Sports of the Netherlands. Written informed consent was based on this assessment underwent further extensive neuro-
obtained from all participants. psychological testing. In addition to the screening, partici-
pants were continuously monitored for diagnosis of
dementia through medical records of the general practi-
2.2. Assessment of memory complaints and cognition
tioner’s office and the Regional Institute for Outpatient
Memory complaints were assessed using three questions, Mental Health Care. Diagnoses of dementia were made
which could be answered by yes or no. These questions were according to the Diagnostic and Statistical Manual of
“Do you have more trouble remembering things than Mental Disorders, Third Edition, Revised (DSM-III-R)
before?”; “Does it happen more often that you are on your criteria for all-cause dementia, National Institute of
way to do something and forget what you wanted to do?”; Neurological and Communicative Disorders and Stroke
and “Do you more often have trouble finding words during and Alzheimer’s Disease and Related Disorders
a conversation?” Association (NINCDS-ADRDA)-criteria for Alzheimer’s
Cognition was objectively assessed using the mini- disease, and National Institute of Neurological Disorders
mental state examination (MMSE) [12]. 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- time3), adjusting for any non–time-dependent effect of
AIREN)-criteria for vascular dementia [8,20,21]. All incident dementia. These analyses were repeated for inci-
participants with AD were included as AD cases, dent AD and vascular dementia, in which participants
including AD cases with cardiovascular disease. Dementia with other or undefined dementia subtypes were excluded.
follow-up was complete until January 1st of 2011. For visualization of trajectories in memory complaints,
MMSE, IADL, and BADL, models including all interac-
tions of dementia up to time3 were used.
2.6. Study population
To investigate interactions of education with incident
The study consists of a matched nested case-control dementia, we included interaction-terms of education with
sample from the Rotterdam Study. All participants dementia and up to time2 in the models.
diagnosed with dementia during follow-up were included To investigate interactions with APOE ε4, we included
as cases, if they met the following criteria: they were non- APOE ε4 carrier status, its interaction with up to time2,
demented at the baseline visit and participated at the visit and their interactions with incident dementia in the analyses.
before dementia diagnosis, to ensure they were dementia- All analyses were adjusted for the basic model of age,
free at that visit. Participants used as controls had to sex, education, their interactions with time, age ! time2,
have the following characteristics: they participated at the time itself, time2, and time3.
visit before diagnosis of the matched dementia case, to For both categories of education and APOE ε4 carrier sta-
ensure they were dementia-free until that visit; they were tus, we additionally investigated differences in rank ordering
assessed as dementia-free until the visit after the diagnosis of decline in trajectories of memory complaints, MMSE,
of the matched dementia case; and they were matched to a IADL, and BADL for incident demented participants. To
dementia case by age (63 years), sex, and education. We do this, we rescaled trajectories of memory complaints and
matched two controls for every dementia case at follow- MMSE to the range of IADL and BADL. Subsequently,
up, resulting in inclusion of 856 dementia cases and 1712 we subtracted trajectories of nondemented participants
controls. Because of missing data on some measures, from those of incident-demented participants, for the respec-
numbers of participants slightly vary across analyses. 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.
2.7. Statistical analysis
To investigate influence of APOE ε2/ε4 carriers on our as-
We used the “lcmm” function from the “lcmm” package sociations for APOE ε4, we repeated analyses on APOE ε4
in R to investigate differences in trajectories of decline in while excluding APOE ε2/ε4 carriers as a sensitivity analysis.
memory complaints, MMSE, IADL, and BADL with To investigate differences at each separate study visit in
incident dementia. A link function with quadratic splines memory complaints, MMSE, IADL, and BADL, the
was used to capture the distribution and account for ceiling “lcmm” method was used as a cross-sectional analysis
effects of the dependent variables (memory complaints, adjusted for age at visit, time, sex, and education.
MMSE, IADL, and BADL). This link function is used to Because spline link-function estimates vary across
transform the distribution of the dependent variables to analyses, the exact transformation of the dependent variables
enable the formation of a linear equation to estimate param- also varies. Therefore, effect sizes cannot be readily inter-
eter coefficients. To best adhere to the distribution of the preted and compared across analyses. Hence, we only report
dependent variables but not needlessly complicate the significance of associations. Effect sizes may be compared
model, we used the Bayesian information criterion (BIC) using the figures. Because the splines are only used in the
to estimate the optimal number and position of splines, in transformation of the dependent variables, they only have
a basic model including age, sex, education, their interac- subtle influence on the figures not specific to a certain
tions with time, age ! time2, time itself, time2, and time3. location.
We included random intercepts and random slopes over We used nominal thresholds of statistical significance
time. Time was calculated from diagnosis of dementia for (P , .05). All analyses were performed using R version 3.1.0.
dementia cases, ensuring that time 5 0 corresponds to
time of dementia diagnosis. For controls, the conversion
3. Results
time for dementia was calculated as the conversion time
for dementia of the matched case. To obtain time to demen- The average age at (matched) dementia diagnosis was
tia, as used in the figures, conversion time for dementia was 82.4 years (standard deviation, 6.7) and 67.8% were women.
subtracted from the follow-up of the control. Hence, at A total of 1203 participants (46.8%) had attained only
time 5 0, corresponding to time of dementia diagnosis, primary education or less. Of 856 dementia cases, 685
follow-up time for controls equals that of their matched case. (80.0%) were identified as AD and 83 (9.7%) as vascular
We investigated up to cubic associations of incident dementia. APOE genotyped data were available in 2391
dementia with memory complaints, MMSE, IADL, and participants, of which 711 (29.7%) were APOE ε4 carriers,
BADL over time (i.e. interactions with time, time2, and 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 deterioration in BADL only starting the last year before
earlier in MMSE compared with those with incident vascular diagnosis. In contrast, higher educated people with dementia
dementia (w12 years before diagnosis compared with were earlier to deteriorate in IADL and BADL, with the
w4 years, Fig. 2). Although participants with incident AD decline in IADL coinciding with the acceleration in decline
and vascular dementia started declining in IADL at the of MMSE.
same time (w5–6 years before diagnosis), those with
vascular dementia declined more strongly. Participants 3.4. Influence of APOE ε4 carrier status
with incident AD declined much later in BADL compared
with incident vascular dementia (w1 year before diagnosis We found no differences for APOE ε4 carrier status in
compared with w7 years). We found significantly increased trajectories of memory complaints and MMSE before inci-
decline in MMSE, IADL, memory complaints, and BADL dent dementia (Fig. 4). Decline in IADL before dementia
for both incident AD and vascular 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
3.3. Influence of education
carriers with incident dementia, whereas APOE ε4 carriers
We found a significant interaction for education on the with incident dementia showed no increased decline at all.
trajectory of MMSE before dementia (pinteraction 5 .005). This difference was supported by an interaction with less
Incident-demented participants with higher education decline in BADL before dementia for APOE ε4 carriers
started with higher MMSE but declined faster compared (pinteraction 5 .002).
with lower educated participants toward dementia diagnosis, Excluding APOE ε2/ε4 carriers from the analyses only
resulting in similar MMSE 2 years after diagnosis (Fig. 3). marginally changed results, with the interaction terms
Although similar patterns were seen for memory complaints remaining significant.
and BADL, no significant interactions were found. The inter- Similar interactions of APOE ε4 in IADL and BADL
action with education for MMSE was also found for AD but were found for incident AD. For vascular dementia, an inter-
not for vascular dementia. action was only found for APOE ε4 carrier status with
Lower educated people with incident dementia showed a BADL.
clear hierarchical decline with earliest deterioration in APOE ε4 carriers showed a clear hierarchical decline,
memory complaints, followed by MMSE, then IADL, and 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 BADL. Trajectories were similar for AD, whereas partici-
ε4 carriers deteriorated earlier and more strongly in IADL pants with vascular dementia declined later in cognition
and BADL, with decline in IADL even surpassing decline but earlier in BADL. Higher educated persons started with
in MMSE. better MMSE but declined faster before diagnosis.
APOE ε4 carriers had similar trajectories in MMSE and
memory complaints before dementia compared with noncar-
4. Discussion
riers, but declined less quickly in IADL and BADL.
In this population-based study, we found that during the Study strengths are the large number of dementia cases
preclinical phase of dementia, people decline more quickly included, investigation of trajectories in all of memory
in memory complaints, MMSE, IADL, and BADL complaints, MMSE, IADL, and BADL, separate investiga-
compared with nondemented participants. Earliest decline tion of all-cause dementia, AD, and vascular dementia,
was found for memory complaints at 16 years before diag- and investigation of interactions with education and
nosis. Next, MMSE declined, followed by IADL, and finally 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 Our study illustrates the long trajectories of decline in
of cognition and daily functioning. Possibly, earlier decline cognition and daily functioning during the preclinical phase
would have been found with continuous measures. Although of dementia. We found a clear hierarchical decline starting
MMSE is a well-known objective measurement of cognition, with memory complaints, then decline in global cognition
objective assessment of memory using dedicated memory (MMSE), followed by decline in more cognitive daily func-
tests may be even more sensitive to detect early deterioration tioning (IADL), and finally simpler basic daily functioning
in incident-demented participants [4]. Furthermore, we used (BADL). Comparison of our results for all-cause dementia
questionnaires to assess daily functioning and memory with previous studies is limited, because those mainly inves-
complaints, which are reliant on self-report. People who tigated incident AD [4,5]. Nonetheless, results were similar,
become demented may not accurately report problems in with earliest deterioration in cognition from 16 years before
daily functioning and memory. However, this applies partic- dementia diagnosis, which increased dramatically from 7
ularly to the last years before dementia, and not the early years before dementia, closely followed by decline in
phase of disease. IADL [4,5]. Interestingly, we found earliest symptoms of
V.J.A. Verlinden et al. / Alzheimer’s & Dementia 12 (2016) 144-153 151

incident dementia to be memory complaints, at 16 years such as neuritic plaques and amyloid load, have less effect
before diagnosis. Importantly, as follow-up started at on cognition in higher educated people [28,29].
16 years before diagnosis, memory complaints may have Although APOE ε4 is the strongest genetic risk factor for
been present even earlier in the disease process. This finding late-onset AD, its relationship with cognition and daily func-
is in line with studies suggesting that people may notice tioning is less clear [9,30–32]. We found no differences for
memory deterioration before cognitive tests are able to APOE ε4 carriers in trajectories of cognition before
detect it [22,23]. Yet, because we did not have objective dementia, similar to a previous study in demented
measurements of memory available, we cannot ascertain participants [33]. However, we did find APOE ε4 carriers
whether these would have been able to detect similar with incident dementia to decline less in daily functioning
differences, as have previously been identified for higher compared with noncarriers. Similar associations were found
educated people [4]. Participants with incident dementia for AD and vascular dementia. A previous study found
deteriorated finally in BADL, from around 4 to 5 years similar protective effects of APOE ε4 on decline in daily
before diagnosis onward. functioning after AD diagnosis [32]. Additionally, we found
The shape of trajectories of decline in MMSE, IADL, and a difference in rank ordering of decline, with non–APOE ε4
BADL, in which decline keeps increasing until dementia carriers declining earlier in IADL and BADL, and decline in
diagnosis, corresponds closely to those suggested in previ- IADL even surpassing decline in MMSE. Possibly, these
ous studies [3]. Similarly, we found a slowing of decline in findings may be explained by differences in brain
memory around dementia diagnosis, corresponding to the morphology or patterns of brain aging between APOE ε4
sigmoid shaped trajectories suggested previously. carriers and noncarriers [34]. Future studies should investi-
Because most dementia cases in our sample had AD, gate the relationship between APOE ε4, the brain, and
trajectories of cognition and daily functioning before AD dementia.
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 5. Conclusions
AD deteriorated earlier in cognition, as reflected by memory
complaints and MMSE [7]. We are first to show that partic- Incident dementia has a long preclinical trajectory of
ipants with incident vascular dementia deteriorate earlier decline in cognition and daily functioning which already
and faster in daily functioning, especially the more physical starts at 16 years before clinical diagnosis. People first report
BADL. These differences between AD and vascular memory complaints, followed by decline in global
dementia may be driven by differences in (localization of) cognition, cognitive IADL, and finally physical BADL.
pathology. AD pathology is thought to first affect the hippo- These trajectories differ by dementia subtype, education,
campus and temporal lobe, which are foremost involved in and APOE ε4 carrier status.
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 Acknowledgments
affect daily functioning [16,24,26]. The Rotterdam Study is sponsored by the Erasmus MC and
We found higher educated people to start with better Erasmus University Rotterdam, the Netherlands Organiza-
cognition compared with lower educated people, but to tion for Scientific Research (NWO), the Netherlands
decline earlier before incident dementia. Although a previ- Organization for Health Research and Development
ous study could not statistically verify this difference, we (ZonMW), the Research Institute for Diseases in the Elderly
found a significant interaction with higher educated people (RIDE), the Netherlands Genomics Initiative, the Ministry
declining more quickly in cognition, as reflected by of Education, Culture and Science, the Ministry of Health,
MMSE [4]. A similar interaction was found for AD, but Welfare and Sports, the European Commission (DG XII),
not for vascular dementia, probably due to lack of power. and the Municipality of Rotterdam. None of the study
Additionally, we found differences in rank ordering of sponsors had any role in the study design; in the collection,
decline before dementia, with higher educated people analysis, and interpretation of data; in the writing of the
declining relatively earlier in IADL and BADL. These find- report; in the decision to submit the article for publication;
ings support the cognitive reserve hypothesis, suggesting or any other aspect of the study. M.A.I. confirms that he
that higher educated people can withstand more brain had full access to all the data in the study and had final
pathology, through a larger brain or greater redundancy in responsibility for the decision to submit for publication.
neural circuits, before deteriorating in cognition [4,27].
Once brain pathology reaches a certain critical threshold,
higher educated people may decline quickly in cognition
Supplementary data
and concurrently start declining in daily functioning. This
cognitive reserve hypothesis is further supported by Supplementary data related to this article can be found at
previous findings that higher amounts of brain pathology, 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

NINCDS-ADRDA Work Group under the auspices of Department of


RESEARCH IN CONTEXT Health and Human Services Task Force on Alzheimer’s Disease.
Neurology 1984;34:939–44.
[9] Ridge PG, Ebbert MT, Kauwe JS. Genetics of Alzheimer’s disease.
1. Systematic review: We searched Medline until Biomed Res Int 2013;2013:1–13.
January 2015 for reports on trajectories of cognition [10] Verlinden VJ, van der Geest JN, Hoogendam YY, Hofman A,
Breteler MM, Ikram MA. Gait patterns in a community-
and daily functioning in preclinical dementia. Only dwelling population aged 50 years and older. Gait Posture 2013;
few studies investigated long-term preclinical 37:500–5.
trajectories in dementia, mainly focusing on [11] Ikram MA, Liu F, Oostra BA, Hofman A, van Duijn CM, Breteler MM.
Alzheimer’s disease and cognitive decline. The GAB2 gene and the risk of Alzheimer’s disease: Replication and
2. Interpretation: We found earliest symptoms 16 years meta-analysis. Biol Psychiatry 2009;65:995–9.
[12] Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A
before dementia diagnosis, initiating with memory practical method for grading the cognitive state of patients for the
complaints, followed by decline in mini-mental clinician. J Psychiatr Res 1975;12:189–98.
state examination, then instrumental activities of [13] Fries JF, Spitz PW, Young DY. The dimensions of health outcomes:
daily living, and finally basic activities of daily The health assessment questionnaire, disability and pain scales. J
living. Higher educated people declined more Rheumatol 1982;9:789–93.
[14] Lawton MP, Brody EM. Assessment of older people: Self-maintaining
quickly in cognition before disease. Vascular de- and instrumental activities of daily living. Gerontologist 1969;
mentia related to later decline in cognition but earlier 9:179–86.
in daily functioning compared with Alzheimer’s [15] Gold DA. An examination of instrumental activities of daily living
disease. Finally, APOE ε4 carriers declined less in assessment in older adults and mild cognitive impairment. J Clin
daily functioning compared with noncarriers in pre- Exp Neuropsychol 2012;34:11–34.
[16] Verlinden VJ, van der Geest JN, de Groot M, Hofman A, Niessen WJ, van
clinical dementia.
der Lugt A, et al. Structural and microstructural brain changes predict
3. Future directions: Future studies should investigate impairment in daily functioning. Am J Med 2014;127:1089–10962.
whether decline initiates even earlier than 16 years [17] Schrijvers EM, Verhaaren BF, Koudstaal PJ, Hofman A, Ikram MA,
before dementia diagnosis. Additionally, future Breteler MM. Is dementia incidence declining? Trends in dementia
studies should investigate whether underlying brain incidence since 1990 in the Rotterdam Study. Neurology 2012;
78:1456–63.
pathology or morphology explains the differences [18] Copeland JR, Kelleher MJ, Kellett JM, Gourlay AJ, Gurland BJ,
in preclinical trajectories of decline between demen- Fleiss JL, et al. A semi-structured clinical interview for the assessment
tia subtypes and APOE ε4 carrier status. of diagnosis and mental state in the elderly: the Geriatric Mental State
Schedule. I. Development and reliability. Psychol Med 1976;
6:439–49.
[19] Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrie H, Verma S, et al.
CAMDEX. A standardised instrument for the diagnosis of mental
disorder in the elderly with special reference to the early detection
References of dementia. Br J Psychiatry 1986;149:698–709.
[20] A.P. Association. Diagnostic and Statistical Manual of Mental Disor-
[1] Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The ders: DSM-III-R. Washington, DC: American Psychiatric Association;
global prevalence of dementia: A systematic review and metaanalysis. 1987.
Alzheimers Dement 2013;9:63–752. [21] Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC,
[2] Luppa M, Luck T, Weyerer S, Konig HH, Brahler E, Riedel-Heller SG. Garcia JH, et al. Vascular dementia: diagnostic criteria for research
Prediction of institutionalization in the elderly. A systematic review. studies. Report of the NINDS-AIREN International Workshop.
Age Ageing 2010;39:31–8. Neurology 1993;43:250–60.
[3] Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, [22] Geerlings MI, Jonker C, Bouter LM, Ader HJ, Schmand B. Associa-
Aisen PS, et al. Tracking pathophysiological processes in Alzheimer’s tion between memory complaints and incident Alzheimer’s disease
disease: An updated hypothetical model of dynamic biomarkers. in elderly people with normal baseline cognition. Am J Psychiatry
Lancet Neurol 2013;12:207–16. 1999;156:531–7.
[4] Amieva H, Mokri H, Le Goff M, Meillon C, Jacqmin-Gadda H, Fou- [23] van Oijen M, de Jong FJ, Hofman A, Koudstaal PJ, Breteler MM. Sub-
bert-Samier A, et al. Compensatory mechanisms in higher-educated jective memory complaints, education, and risk of Alzheimer’s dis-
subjects with Alzheimer’s disease: A study of 20 years of cognitive ease. Alzheimers Dement 2007;3:92–7.
decline. Brain 2014;137:1167–75. [24] Risacher SL, Saykin AJ. Neuroimaging biomarkers of neurodegener-
[5] Amieva H, Le Goff M, Millet X, Orgogozo JM, Peres K, Barberger- ative diseases and dementia. Semin Neurol 2013;33:386–416.
Gateau P, et al. Prodromal Alzheimer’s disease: Successive emergence [25] Ikram MA, Vrooman HA, Vernooij MW, den Heijer T, Hofman A,
of the clinical symptoms. Ann Neurol 2008;64:492–8. Niessen WJ, et al. Brain tissue volumes in relation to cognitive func-
[6] Hamel R, Kohler S, Sistermans N, Koene T, Pijnenburg Y, van der tion and risk of dementia. Neurobiol Aging 2010;31:378–86.
Flier W, et al. The trajectory of cognitive decline in the pre- [26] Korczyn AD, Vakhapova V, Grinberg LT. Vascular dementia. J Neurol
dementia phase in memory clinic visitors: findings from the 4C-MCI Sci 2012;322:2–10.
study. Psychol Med 2015;45:1509–19. [27] Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R.
[7] Laukka EJ, Macdonald SW, Fratiglioni L, Backman L. Preclinical Influence of education and occupation on the incidence of Alzheimer’s
cognitive trajectories differ for Alzheimer’s disease and vascular disease. JAMA 1994;271:1004–10.
dementia. J Int Neuropsychol Soc 2012;18:191–9. [28] Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE. Educa-
[8] McKhann G, Drachman D, Folstein M, Katzman R, Price D, tion modifies the association of amyloid but not tangles with cognitive
Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the function. Neurology 2005;65:953–5.
V.J.A. Verlinden et al. / Alzheimer’s & Dementia 12 (2016) 144-153 153

[29] Bennett DA, Wilson RS, Schneider JA, Evans DA, Mendes de [32] Hoyt BD, Massman PJ, Schatschneider C, Cooke N, Doody RS.
Leon CF, Arnold SE, et al. Education modifies the relation of AD pa- Individual growth curve analysis of APOE epsilon 4-associated
thology to level of cognitive function in older persons. Neurology cognitive decline in Alzheimer disease. Arch Neurol 2005;62:
2003;60:1909–15. 454–9.
[30] Packard CJ, Westendorp RG, Stott DJ, Caslake MJ, Murray HM, [33] Sherva R, Tripodis Y, Bennett DA, Chibnik LB, Crane PK, de
Shepherd J, et al. Association between apolipoprotein E4 and cogni- Jager PL, et al. Genome-wide association study of the rate of cogni-
tive decline in elderly adults. J Am Geriatr Soc 2007;55:1777–85. tive decline in Alzheimer’s disease. Alzheimers Dement 2014;
[31] Jonker C, Schmand B, Lindeboom J, Havekes LM, Launer LJ. Asso- 10:45–52.
ciation between apolipoprotein E epsilon4 and the rate of cognitive [34] Reinvang I, Espeseth T, Westlye LT. APOE-related biomarker profiles
decline in community-dwelling elderly individuals with and without in non-pathological aging and early phases of Alzheimer’s disease.
dementia. Arch Neurol 1998;55:1065–9. Neurosci Biobehav Rev 2013;37:1322–35.