The aim of the present study was to elucidate a mechanism of weight loss in AD patients.
Contrary to what was expected, AD patients in our population did not lose, but gained
weight during the 3.5Â years of follow-up. Recent studies have reported similar results
43],44]. Secher et al. showed that community-dwelling patients with moderate AD did not lose weight during
4Â years of follow-up 43], Gu et al. showed that after the clinical onset of AD, BMI increased 44]. How can the increase in body weight be explained?
The number of community-dwelling AD patients with weight loss described in the literature,
varies between 20% and 45% 5]-10]. The highest numbers are reported in studies from the pre-ChEI era 5],6],9], and recent studies showed a decreased risk of weight loss in AD patients treated
with a ChEI compared to untreated patients 7],8],45],46]. In these studies, ChEIs appeared to protect against weight loss. Therefore, the
weight gain in our cohort might be explained by the use of a ChEI.
It could be that weight loss in AD patients is currently less frequently observed
due to the increased quality of care of home-dwelling AD patients. In the past decade,
it is not just the pharmacological treatment that has changed the management of AD.
Drugs are given in addition to multiple non-pharmacological interventions, including
dietary advice and provision of meals at home services 31],47]. Gu et al. showed that the BMI of AD patients declined up to the clinical onset of AD. After
clinical onset, there was no decrease of BMI, which even increased, possibly because
care was arranged after the diagnosis of AD 44]. We postulate that weight loss in AD patients could be regarded as a marker for the
quality of care for AD patients, rather than a marker for the severity of AD. This
is underpinned by our finding that the severity of AD, measured by the severity of
MTA, was not related to the trajectory of weight.
Contrary to what was expected, there was no difference in body weight between patients
with moderate, severe or very severe MTA, neither at the time of diagnosis, nor during
the course of the disease. Moreover, during follow-up, a time period in which the
severity of MTA is expected to increase, patients did not lose but gained weight.
Therefore, we reject the hypothesis that weight loss is associated with MTA. As far
we know, four other studies investigated the relation of brain pathology with nutritional
status in AD patients 22],26]-28]. Contrary to our finding, Grundman et al. showed that MTA was associated with low body weight in AD patients 22]. In addition, Burns et al. showed that a higher BMI was associated with less brain atrophy 27]. This association, however, was modest 27]. Hu et al. found no association between a low BMI and the medial temporal lobe 26], which is in line with our finding that there was no difference in body weight between
patients with moderate, severe or very severe MTA. Ho et al. reported that more severe hippocampal atrophy was associated with a higher BMI in
patients with mild AD 28], which confirms our result that patients with moderate, severe or very severe MTA
weighed more than patients with no or mild MTA. These results also underline the findings
of Gustafson et al. 48] and Ward et al. 49]. Gustafson et al. investigated the longitudinal relationship between BMI and MTA in a cohort of middle-aged
women during 24Â years of follow-up 48]. The average BMI of women who developed MTA was higher at all examinations than women
who did not develop MTA 48]. In the same cohort, a higher BMI was associated with a higher incidence of dementia,
particularly AD 2]. It is suggested that this latter relationship could be explained by the fact that
being overweight is a risk factor for hypertension, type 2 diabetes, and cardiovascular
diseases, all of which have been shown to increase the risk of AD 50]. Though, it is also possible that being overweight increases the risk of AD by directly
affecting the neurodegenerative process in the brain 50]. Ward et al. performed a cross-sectional study to investigate the relationship between BMI and
brain atrophy in middle-aged (40 to 66Â years) adults 49]. A higher BMI was associated with more severe brain atrophy, though BMI was not associated
with cognitive function 49].
It must be taken into consideration that comparison of our study with the aforementioned
studies has to be performed cautiously, because of differences in patient characteristics
and study methodology. For example, patients in the study of Grundman et al. and Burns et al. were not treated with a ChEI. In addition, the severity of AD varied with mean MMSE
score in the study of Grundman et al. of 19 18], in the study of Burns et al. 26 23], versus a median MMSE of 23 in our cohort. Not all patients in the study of Gustafson
et al. and Ward et al. were diagnosed with AD at baseline 48],49]. Moreover, the way in which brain pathology was measured differed. In the present
study, brain atrophy was measured with MRI, Hu et al. investigated brain glucose metabolism by positron emission tomography (PET) and
[18F]fluordeoxyglucose (FDG) 26], Ho et al. applied an automated hippocampal mapping method to measure hippocampal volume 28] and Grundman et al. performed morphometric analysis to assess the severity of MTA 22], while we used a visual rating scale to assess MTA. These differences may have contributed
to the conflicting results. The conflicting results might also reflect variation in
sample sizes, ranging from 27 26] to 162Â AD patients 28], versus 214Â AD patients in the present study. In addition, nutritional status was
measured cross-sectional in the mentioned studies 22],26]-28], while we measured weight longitudinally.
Our surprising finding that patients with more severe MTA weighed more than patients
with no or mild MTA, has to be interpreted carefully since less than 10% of the patients
from our cohort had a MTA score of 0 or 1. The representativeness of patients with
no or mild MTA in our cohort is unclear. As expected, patients with no or mild MTA
had a higher baseline MMSE score and were less dependent than patients with moderate,
severe or very severe MTA 25]. Though, despite the fact that these patients had no or only mild MTA, they were
referred to the memory clinic. There are no data on the weight of patients with a
MTA score of 0 or 1 who were not referred to a memory clinic. It cannot be ruled out
that these patients have a higher body weight than the patients with a MTA score of
0 or 1 who presented at our memory clinic.
Some limitations of the present study must be considered when interpreting the findings.
Since we only investigated the relationship between MTA and body weight, it cannot
be ruled out that pathology of other brain regions or other forms of brain pathology
are associated with the trajectory of body weight in AD patients. In addition, our
study was performed in a selected group of patients (that is they had an indication
for a MRI scan and were all treated with a ChEI), which may have contributed to some
degree of selection bias. ChEIs appear to slow the progression of hippocampal atrophy
by 1.2% a year 51]. It cannot be ruled out that the ChEIs slowed the progression of hippocampal atrophy,
thereby preventing weight loss mediated by MTA. Whether a delay of 1.2% a year is
enough to prevent weight loss and even result in weight gain, is unclear. In addition,
it could be that patients that lost weight were more frequently ‘lost to follow-up’
inducing a bias. However, all subjects were patients receiving care in accordance
with the standardized treatment protocol, which included regular visits to our clinic.
Although bias cannot fully be excluded, we think that the extent of this kind of bias
is negligible since the main reason for the reduced number of subjects in our longitudinal
analysis is the timing of entering the care program. In this, patients differ in the
duration of participation in the care program, rather than patients leave the program
due to disease-related causes. Another limitation is the absence of data regarding
the trajectory of weight before the diagnosis AD was made. Weight loss may be a preclinical
feature of AD 44],52]. Perhaps, weight loss in patients from our cohort may have occurred before they were
referred to the memory clinic. In addition, the association between MTA and the trajectory
of weight change could depend on disease severity at baseline as measured with the
MMSE. Unfortunately, we did not have enough patients to stratify by MMSE or to do
a sensitivity analysis. Moreover, MTA was measured cross-sectionally, instead of longitudinally.
Therefore, it was not possible to investigate whether percent change in MTA over time
predicts weight change, nor to elucidate whether weight loss causes disease progression
by aggravating MTA. In addition, it was not possible to elucidate patterns of MTA
atrophy. These patterns are, unfortunately, not fully elucidated by other studies
25]. Because of the retrospective nature of the study, we were dependent on data collected
in the past. As a consequence, some data was not available, for instance information
on appetite measured with a valid scale and information on dietary intake. In addition,
we could not adjust for all known factors associated with weight loss, such as caregiver
burden 53].
To the best of our knowledge, this is the largest study examining the relationship
between MTA and the trajectory of weight change in AD patients, and the only study
in which body weight was measured longitudinally. Another strength of the study is
the use of the GLMM. Statistical analysis of longitudinal data is complicated because
of interdependency of measurements and, particular in older AD patients, drop out
of patients 54]. The GLMM is specifically developed for the analysis of longitudinal-dependent data.
All data contribute to the longitudinal analysis and even data from patients who dropped
out can be used. This way we could include a large number of patients with a long
length of follow-up. Moreover, the severity of MTA was scored independently by two
raters. The agreement between the raters was fair to good, and better than the interobserver
agreement of Scheltens et al., which was fair 37].