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ORIGINAL COMMUNICATION
Predictors of progression of cognitive decline in Alzheimer’s
disease: the role of vascular and sociodemographic factors
Massimo Musicco ÆKatie Palmer ÆGiovanna Salamone ÆFederica Lupo Æ
Roberta Perri ÆSerena Mosti ÆGianfranco Spalletta ÆFulvia di Iulio Æ
Carla Pettenati ÆLuca Cravello ÆCarlo Caltagirone
Received: 17 December 2008 / Revised: 19 February 2009 / Accepted: 18 March 2009 / Published online: 8 April 2009
ÓThe Author(s) 2009. This article is published with open access at Springerlink.com
Abstract Rates of disease progression differ among
patients with Alzheimer’s disease, but little is known about
prognostic predictors. The aim of the study was to assess
whether sociodemographic factors, disease severity and
duration, and vascular factors are prognostic predictors of
cognitive decline in Alzheimer’s disease progression. We
conducted a longitudinal clinical study in a specialized
clinical unit for the diagnosis and treatment of dementia in
Rome, Italy. A total of 154 persons with mild to moderate
Alzheimer’s disease consecutively admitted to the dementia
unit were included. All patients underwent extensive clinical
examination by a physician at admittance and all follow-ups.
We evaluated the time-dependent probability of a worsening
in cognitive performance corresponding to a 5-point
decrease in Mini-Mental State Examination (MMSE) score.
Survival analysis was used to analyze risk of faster disease
progression in relation to age, education, severity and dura-
tion of the disease, family history of dementia, hypertension,
hypercholesterolemia, and type 2 diabetes. Younger and
more educated persons were more likely to have faster
Alzheimer’s disease progression. Vascular factors such as
hypertension and hypercholesterolemia were not found to be
significantly associated with disease progression. However,
patients with diabetes had a 65% reduced risk of fast
cognitive decline compared to Alzheimer patients without
diabetes. Sociodemographic factors and diabetes predict
disease progression in Alzheimer’s disease. Our findings
suggest a slower disease progression in Alzheimer’s patients
with diabetes. If confirmed, this result will contribute new
insights into Alzheimer’s disease pathogenesis and lead to
relevant suggestions for disease treatment.
Keywords Disease progression Cognitive decline
Dementia Diabetes Education
Introduction
Persons with Alzheimer’s disease (AD) show memory
decline that progressively worsens and is accompanied by a
parallel decline in other cognitive domains. Patients
become completely dependent in activities of daily living
and die after 8–10 years from the first diagnosis [15,16,42].
The disease is marked by key events such as severe
cognitive impairment, the inability to dress, eat, and wash,
institutionalization, and death. The time of occurrence of
these events is highly variable from patient to patient, and
thus it is difficult for clinicians to make prognostic pre-
dictions about individual patients. It is important to identify
prognostic markers to improve patient care and long-term
planning.
A number of sociodemographic factors and vascular risk
factors have been found to increase the risk of elderly
individuals developing AD [24]. However, little is known
M. Musicco (&)
Institute of Biomedical Technologies-National Research Council
(ITB-CNR), Via F.lli Cervi 93, 20099 Segrate, Milan, Italy
e-mail: m.musicco@hsantalucia.it
M. Musicco K. Palmer G. Salamone F. Lupo R. Perri
S. Mosti G. Spalletta F. di Iulio L. Cravello
C. Caltagirone
IRCCS Foundation ‘‘Santa Lucia’’, Rome, Italy
K. Palmer
e-mail: k.palmer@hsantalucia.it
C. Pettenati
Alzheimer Center Hospital of Passirana di Rho, Milan, Italy
C. Caltagirone
University ‘‘Tor Vergata’’, Rome, Italy
123
J Neurol (2009) 256:1288–1295
DOI 10.1007/s00415-009-5116-4
about whether such factors also play a role in the pro-
gression of the disease itself. Some vascular risk factors
and disorders have been found to be associated with a
faster progression rate [5,19,27], including cerebrovas-
cular accidents [27] and systolic hypertension [19].
In the current study, we aimed to examine whether
sociodemographic and vascular factors predict faster
cognitive decline in patients with AD, using a clinical
sample of AD patients from a specialized dementia clinic
in Italy, who were followed for an average of 2 years.
Identifying predictors of disease progression in AD might
provide new insights into the pathogenic mechanisms of
AD and suggest new therapeutic interventions.
Materials and methods
Patients
The cohort of AD patients was enrolled at the Center for
Dementia Diagnosis and Treatment, IRCCS Foundation
Santa Lucia Hospital in Rome, Italy. The dementia center
was set up as part of a country-wide project promoted by
the Italian health authorities called ‘‘Progetto Cronos’’ [26],
which aims to offer patients with AD and other dementias a
multi-disciplinary approach and a prospective treatment
plan. Patients are referred to the center, mostly by GPs, for
evaluation. After diagnosis, some patients continued their
care at the center, but since the Foundation Santa Lucia
Hospital is not a primary center for AD, some patients were
referred elsewhere depending on, for example, demo-
graphic factors. A total of 1,096 patients were
consecutively admitted to the clinic between 2000 and
2006. All patients were examined by a neurologist and
neuropsychologist. At the first visit to the center, 109
(9.5%) patients were normal, 167 (15.2%) had MCI [10],
377 (34.9%) patients had ‘‘pure’’ AD diagnosed according
to the NINCDS-ARDRA criteria [18], 226 (20.6%) had
other types of dementia, and 217 (19.8%) had other diag-
noses, including Parkinson’s disease, depression, etc. Only
the 377 patients with pure AD were eligible for this study.
At the center a neurologist followed up the patients and
carried out all activities concerned with diagnosis, drug
prescription, and treatment monitoring. When necessary, a
geriatrician and/or a psychiatrist were consulted. At the
first visit a brain MRI examination was performed. Patients
whose brain imaging results confirmed cerebrovascular
damage that could justify all or part of their cognitive
disorders were diagnosed as possible AD. We excluded
220 patients with severe cranial trauma, focal neurological
signs, and possible AD, as well as patients who attended
the clinic only once. A further four patients were excluded
from the analysis due to suspended acetyl-cholinesterase
inhibitor treatment because of adverse drug reactions or
perceived inefficacy. Thus, the study population consisted
of 154 patients with probable AD.
Ethics
Ethical permission was provided by the Ethical Committee
of Foundation Santa Lucia, and the study was performed in
accordance with the ethical standards of the 1964 Helsinki
declaration. Patients and their next-of-kin gave their con-
sent to be included in the study.
Evaluation
Patients underwent extensive examination by a neurologist,
and a complete health history was collected from all
patients and their relatives. Patients with mildly or
moderately severe AD started treatment with an acetyl-
cholinesterase inhibitor and were invited to periodic
follow-up visits. At the time of enrollment and follow-up
examinations, cognitive performance was evaluated with
the Mini-Mental State Examination (MMSE) [11] accord-
ing to age- and education-adjusted scores [10].
The clinical examination included information con-
cerning the maximum number of years of formal education
of the patients, age, sex, and family history of dementia.
Hypertension, type 2 diabetes, and hypercholesterolemia
were defined as (1) a diagnosis and subsequent treatment
by a physician at the clinic or (2) a relative’s report of
previous and ongoing treatment for the respective condi-
tion. Disease duration of AD was defined in months by the
examining neurologist based on the clinical exam and
anamnesis. Disease duration of AD was categorized into
three groups: \1 year, 1–2 years, and [2 years.
Outcome: disease progression
A decrease of 5 points or more on the MMSE since
enrollment was considered an indicator of disease pro-
gression based on previous research [30]. A 5-point
decrease was considered a clinically relevant worsening
and too large of a change to be due to the intrinsic limits of
test reliability [7]. The date of the visit when the 5-point
reduction was recorded marked the time of occurrence of
the progression.
Statistical analyses
The occurrence rates of the time-dependent event ‘‘disease
progression’’ were evaluated by survival analysis, and
survival curves were derived with the Kaplan-Meier’s
method [14]. The following variables were considered as
possible predictors of disease progression: age, sex,
J Neurol (2009) 256:1288–1295 1289
123
education, MMSE score at enrollment, family history of
dementia, disease duration and severity, hypertension, type
2 diabetes, and hypercholesterolemia. The continuous
variables (age, education, and MMSE) were categorized
according to the tertile distribution. The age categories
included: B70 years, 71–77 years, and C77 years. Educa-
tion was categorized as follows: B5 years, 6–8 years, and
C8 years. Age- and education-adjusted MMSE scores were
divided into three groups corresponding to the following
categories: B17, 17.1–20.2, and C20.3.
As previous research on the topic [19] suggested that
various vascular factors may have different roles on the
progression of AD, we examined vascular factors sepa-
rately. First, analyses of survival were carried out with
Cox’s proportional hazard models [8] in which variables
were entered separately into the model. Second, the anal-
ysis of survival was repeated with adjustment for all
sociodemographic and vascular factors.
Results
The 154 AD patients fulfilling the inclusion criteria
underwent at least one follow-up visit after initial exami-
nation. The mean follow-up time was 23 months (SD 15.6),
and on average patients had 3.3 (SD 1.6) follow-up visits.
The demographic and clinical characteristics of the patients
are presented in Table 1. There were twice as many women
as men. Mean age was 73 years and mean education
8 years. Severity of AD was mild to moderate with mean
disease duration of about 2 years. More than a third of the
patients reported having a relative with dementia. Hyper-
tension and hypercholesterolemia were common. The 36
hypertensive patients were all treated; the most common
drugs used were ACE inhibitors as monotherapy or with
diuretics. None of the women were treated with estrogen
replacement therapy. Diabetes was present in the same
proportion of men and women. All but one of the diabetic
patients had type 2 diabetes and were treated with oral
drugs. Of the 20 patients treated with oral drugs 12 were
prescribed metformin, 6 sulphonylureas, and the remaining
2 were treated with both sulphonylureas and metformin.
The average follow-up duration was about 2 years. During
this period, 40% (n=61) had a fast disease progression,
defined as a 5-point decrease in the MMSE.
Table 2shows AD progression rates as well as the crude
(predictors entered separately) and multivariable hazard
ratios (adjustment for all predictors) of progression
according to baseline sociodemographic and vascular fac-
tors. More advanced age was associated with reduced risk
of progression, i.e., the progression of patients over
70 years of age was almost half that of younger patients.
The risk of progression of patients with 6?years of edu-
cation was twice that of patients with \5 years of
education. Severity of cognitive impairment, as measured
by the MMSE, did not influence disease progression.
Patients with a 2 year disease duration had reduced risk of
progression compared both to patients with shorter or
longer disease duration, but this difference was not statis-
tically significant in the crude analysis. Hypertension,
hypercholesterolemia, and family history of dementia were
not associated with disease progression. On the contrary,
disease progression in AD patients with diabetes was about
60% less than that of non-diabetic AD patients.
The cumulative time-dependent probabilities of disease
progression for the entire cohort and by categories of age,
education, and diabetes are presented in Fig. 1. Disease
progression was generally similar for the different cate-
gories of patients for the first year and then tended to
diverge. No clear trend for slower progression with
increasing age was apparent, and the main difference was
between patients aged B70 years and all older patients.
The same was true for education where patients with
B5 years of education had less disease progression than
Table 1 Demographic and
clinical characteristics of
Alzheimer disease patients
Women (n=101) Men (n=53) Total (n=154)
Mean (SD) Mean (SD) Mean (SD)
Age (years) 74 (8.4) 72 (7.6) 73 (8.2)
Disease duration (months) 26 (13.7) 27 (17.0) 26 (14.7)
MMSE 17 (4.3) 19 (4.4) 18 (4.8)
Follow-up (months) 23 (14.5) 25 (17.7) 23 (15.6)
Education (years) 7 (3.7) 11 (4.3) 8 (4.4)
n(%) n(%) n(%)
Hypertension 34 (33.7) 18 (34.6) 52 (34.0)
Hypercholesterolemia 19 (18.9) 9 (17.3) 28 (18.3)
Diabetes 15 (14.9) 7 (13.5) 22 (14.4)
Family history for AD 29 (24.8) 21 (40.4) 50 (32.7)
MMSE score decrease at follow-up
greater than or equal to 5
38 (38.6) 23 (44.2) 61 (39.9)
1290 J Neurol (2009) 256:1288–1295
123
other patients. We conducted a supplemental analysis to
investigate whether the association between younger age
and disease progression was due to early onset AD cases.
Twenty-four patients had AD onset before the age of 65. In
early onset AD patients, fast disease progression was
observed in 18 (75.0%) subjects, as opposed to 43 (33.1%)
of the 130 patients with onset after the age of 65 years. The
hazard ratio of fast progression in early compared to late
onset AD patients was 2.2 (95% CI: 1.3–3.9, P=0.007).
The multivariable analysis (Table 2) did not introduce
any relevant modification of the size or direction of the
crude hazard ratio estimates. The reduction in the proba-
bility of progression observed in association with disease
durations of 2 years became more evident and statistically
significant. The hazard of disease progression in diabetic
AD patients was slightly lower than the univariate esti-
mates and maintained the statistical significance.
Discussion
In the current study, we followed a clinical cohort of AD
patients to examine factors related to disease progression
and found that older age, lower education, and type 2
diabetes are associated with slower disease progression in
AD patients.
The finding of a worse prognosis in younger AD patients
is not unique to the current study, as others have found
trends for faster cognitive decline in younger AD patients
[6,21]. Considering that AD is an aging-related disorder,
which is present well before symptoms appear, it is reasonable
to expect that when the disease is manifest at younger ages it
might be also more aggressive and progress more quickly. In
our patients, there were 24 people with early onset AD,
defined as an onset before age 65. These patients accounted
for half of the cases in the age group\71. The higher risk of
progression observed in association with younger age was
completely explained by these early onset patients. This
observation suggests that early onset AD, where hereditary
forms of the disease are more frequent, might have a worse
prognosis in comparison to sporadic cases.
Lower education has also been found to be associated
with slower progression rates in previous studies [22,33,36].
It is likely that persons with low education have a
reduced cognitive reserve and thus are more vulnerable to
the effects of the pathological process of AD, leading to an
earlier manifestation of the distinctive signs and symptoms
of dementia. If the progression rate of AD pathology is not
Table 2 Progression rates and
crude and multivariable hazard
ratios of progression according
to baseline sociodemographic
and vascular factors
a
Crude hazard ratios: Cox
proportional hazard models
using single predictors, with
95% confidence intervals
(95% CI)
b
Multivariate hazard ratios:
Cox proportional hazard models
with multiple adjustment for all
variables in the table, with 95%
confidence intervals (95% CI)
Total Patients with disease progression of [5 MMSE
n(%) n(%) Crude
a
Multivariate
b
HR (95% CI) HR (95% CI)
Age (years)
B70 49 (31.8) 28 (57.1) 1 1
71–77 52 (33.8) 18 (34.6) 0.48 (0.3–0.9) 0.54 (0.3–1.1)
[77 53 (34.4) 15 (28.3) 0.48 (0.3–0.9) 0.50 (0.3–1.0)
Sex
Women 101 (65.6) 38 (37.6) 1 1
Men 53 (34.4) 23 (43.4) 1.1 (0.7–1.9) 0.79 (0.4–1.5)
Education (years)
B5 71 (46.1) 18 (25.4) 1 1
6–8 31 (20.1) 17 (54.8) 2.2 (1.1–4.2) 2.5 (1.2–5.2)
C9 52 (33.8) 26 (50.0) 2.5 (1.3–4.5) 2.8 (1.4–5.5)
Disease duration (years)
B1 53 (34.4) 23 (43.4) 1 1
1–2 49 (31.8) 18 (36.7) 0.67 (0.4–1.3) 0.46 (0.2–0.9)
[2 yrs 52 (33.8) 20 (38.5) 1.2 (0.7–2.2) 1.0 (0.5–2.0)
MMSE at enrollment
B17 51 (33.1) 16 (31.4) 1 1
17.0–20.2 51 (33.1) 25 (49.0) 1.2 (0.6–2.2) 1.6 (0.8–3.3)
C20.30 52 (33.8) 20 (38.5) 1.3 (0.7–2.5) 1.5 (0.7–3.2)
Hypertension 52 (33.8) 19 (36.5) 1.0 (0.6–1.7) 1.2 (0.7–2.2)
Diabetes 22 (14.3) 5 (22.7) 0.38 (0.2–0.9) 0.36 (0.1–0.9)
Hyper-cholesterolemia 28 (18.2) 8 (28.6) 0.73 (0.3–1.5) 0.58 (0.3–1.3)
Family history of dementia 50 (32.5) 19 (38.1) 0.90 (0.6–1.7) 1.0 (0.6–1.9)
J Neurol (2009) 256:1288–1295 1291
123
influenced by cognitive reserve, it is possible that more
educated persons experience clinically evident AD for a
shorter period of time, and thus their cognitive decline will
appear to be faster than less educated patients. In the
current study, we were unable to determine whether edu-
cation levels per se were responsible for the reduced risk of
AD progression, or whether education was a proxy for
another associated factor, such as sociodemographic status.
We found an association between diabetes and an
approximately 65% reduction in risk of fast progression in
AD. This association was independent from all the other
variables considered as potential prognostic predictors. This
finding replicates results reported in another study [19],
which found some vascular risk factors and disorders were
associated with higher progression rates of the cognitive
disturbance in AD patients, yet diabetic AD patients had
reduced progression rates. As their study included a very
elderly sample of people aged 85?, our findings demon-
strate that this pattern of cognitive decline in AD also occurs
in younger AD patients. Furthermore, two studies reported
less severe AD neuropathology [2] and reduced cognitive
decline [41] in association with diabetes medication.
Epidemiological studies have indicated that diabetes
increases the risk of dementia both of vascular and
neurodegenerative origin [4]. The reasons for this associa-
tion are unknown, although it has been hypothesized that
some characterizing features and complications of diabetes
such as micro-vascular damage [17], impaired glucose metab-
olism [13], and insulin imbalance [9,32] might play a role.
One potential explanation of the association between
diabetes and AD progression is that it is not diabetes per se
but the vascular complications of diabetes that lead to
neurodegeneration. The association between better AD
prognosis and diabetes might be due to the existence of
brain vascular damage in these patients that is associated
with the cognitive impairment. Indeed, unlike neurode-
generative dementia, where the disturbance is progressive,
in dementia of vascular origin cognitive decay tends to
occur concomitantly with new cerebrovascular events. It is
possible that the better prognosis of diabetic AD patients
might be linked to the fact that by treating diabetes the
vascular complications of the disease are prevented.
However, it is not easy to prevent vascular events with
antidiabetic therapy [37], because the vascular damage
Fig. 1 Cumulative time-
dependent probability of AD
progression (reduction of 5
points on MMSE) for the whole
cohort and by age, education,
and presence of diabetes
1292 J Neurol (2009) 256:1288–1295
123
seems independent of glycemic control. Therefore, we
cannot explain the lower AD progression rates of the
diabetic patients observed in this study as the result of
having prevented cerebrovascular events with antidiabetic
drugs. Furthermore, this explanation is contradicted by the
fact that the hypertensive patients observed in this, and
other studies, did not show any prognostic advantage
[24,27], and with adequate, early control, the risk of
cerebrovascular events in the elderly is reduced in hyper-
tensive individuals [35].
Much evidence links type 2 diabetes to neurodegenera-
tive disorders and AD. Pancreatic islet cells producing
insulin might evolve from an ancestral insulin-producing
neuron [31]. Insulin crosses the blood–brain barrier in ani-
mals [1] and, probably, in humans [40]. In the whole brain,
neurons and astrocytes express insulin receptors at synapses
but insulin binding is prevalent in the olfactory bulb, cere-
bral cortex, and hippocampus [34] which are among the
principal brain areas involved in the pathological process of
AD. Indeed, insulin administration has been shown to
improve cognitive functioning [3,20,28]. Contrary to these
observations, chronic hyperinsulinemia and diabetes are
associated with higher occurrence of AD and with reduced
learning and memory [38,39]. In diabetic patients, this
association does not seem to be mediated by chronic
hyperglycemia because cognitive impairment was also
evident in subjects with normal levels of glycosylated
hemoglobin [38]. These apparently contradictory findings
suggest a potentially different role of acute and chronic
exposure to insulin [38] on the brain and brain functions.
Insulin might promote the intraneuronal release of b-amy-
loid (Ab)[12] and insulin, and Abpeptides are degraded by
the insulin degrading enzyme (IDE) which is also able to
reduce amyloid plaque formation [25]. Thus, chronic nor-
moglycemic hyperinsulinemia, which characterizes the
early phases of type 2 diabetes, might increase the pro-
duction of Abcreating a competition for the IDE between
Abpeptides and insulin itself. On the other hand, when
diabetes is clinically manifest the insulin levels are reduced
due to failure of pancreatic islet cells, and the degradation of
Abpeptides becomes more efficient even in comparison
with non-diabetic individuals. This two-phase mechanism,
which postulates more efficient degradation of b-amyloid
peptides in patients with type 2 diabetes, might explain why
reduced AD progression rates are observed in these patients.
Other more complex mechanisms may play a role. For
example, insulin presents some analogies with the neuronal
growth factor, insulin-like growth factor 1 (IGF 1). Insulin
and IGF 1 have specific receptors on neurons, and at high
concentrations insulin can cross-react with IGF 1 receptor
[23]. Thus, a possible role of insulin on neuronal trophy
and on resistance to neurodegenerative processes cannot be
excluded.
Another explanation of the better prognosis for diabetic
patients with AD might be related to antidiabetic treatment.
It has been hypothesized that some drugs that enhance the
sensitivity of insulin receptors may be effective in AD. One
of these drugs (rosiglitazone) is being studied, but the first
results are controversial [29]. All but one patient in our
study was treated with antidiabetic oral drugs that increase
both the sensitivity of the insulin receptor and the produc-
tion of insulin by the pancreatic islet cells. Thus, it is
possible that the higher levels of insulin induced by these
treatments might have a role in explaining our observation
of a slower progression rate of AD in diabetic patients. As in
other studies [19], it was not possible to determine whether
the slower cognitive decline in diabetic AD patients was
associated with treatment, as all patients underwent therapy.
There are a few limitations of our study that deserve
mention. First, our sample was relatively small, which
affected statistical power. However, we were able to follow
patients closely. Second, our results may not be generalizable
to all populations, particularly as all our patients were treated
with acetyl-cholinesterase inhibitors. The strengths of our
study include the extensive clinical examination and follow-
ups, as well as the inclusion of a wide age range of patients,
which verified previous findings in older patients [19].
Identifying factors that will predict progression of AD,
will help clinicians estimate disease prognosis, which may
help to improve patient care as well as long-term planning
for caregivers. Furthermore, identifying factors associated
with faster disease progression may help better understand
AD disease mechanisms, which will have relevant impli-
cations for AD comprehension and treatment. Further
studies are needed to replicate the observation of better
prognosis of AD patients with type 2 diabetes and to
determine the mechanisms behind the association.
Acknowledgment Dr Palmer was supported by a Marie Curie
Fellowship from the European Union.
Conflict of interest statement The authors report no conflict of
interest.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
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