BMJ No 7115 Volume 315
Papers Saturday 25 October 1997
Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study
Johanna Kuusisto, Keijo Koivisto, Leena Mykkänen, Eeva-Liisa Helkala, Matti Vanhanen, Tuomo Hänninen, Kari Kervinen,Y Antero Kesäniemi, Paavo J Riekkinen, Markku Laakso
Abstract
Objective: To determine the association between features of the insulin resistance syndrome and Alzheimer's disease.Design: Cross sectional population based study.
Subjects: 980 people aged 69 to 78 (349 men, 631 women).
Setting: Population of Kuopio, eastern Finland.
Main outcome measures: Presence of features of the insulin resistance syndrome and diagnosis of Alzheimer's disease by detailed neurological and neuropsychological evaluation.
Results: 46 (4.7%) subjects were classified as having probable or possible Alzheimer's disease. In univariate analyses, apolipoprotein E4 phenotype (odds ratio; 95% confidence interval 3.24: 1.77 to 5.92), age (1.16; 1.05 to 1.29), low level of education (0.82; 0.72 to 0.93), low total cholesterol concentration (0.77; 0.59 to 1.00), high systolic blood pressure (1.01; 1.00 to 1.03), high fasting and 2 hour plasma glucose concentrations (1.11; 1.01 to 1.23 and 1.08; 1.03 to 1.13, respectively), high fasting and 2 hour insulin concentrations (1.05; 1.02 to 1.08 and 1.003; 1.00 to 1.01, respectively), and abnormal glucose tolerance (1.86; 1.23 to 2.80) were significantly associated with Alzheimer's disease. In multivariate analysis including apolipoprotein E4 phenotype, age, education, systolic blood pressure, total cholesterol concentration, fasting glucose concentration, and insulin concentration, apolipoprotein E4 phenotype, age, education, total cholesterol, and insulin were significantly associated with Alzheimer's disease. In 532 non-diabetic subjects without the e4 allele hyperinsulinaemia was associated with an increased risk for Alzheimer's disease (prevalence of disease 7.5% v 1.4% in normoinsulinaemic subjects, P=0.0004). In contrast, in the 228 with the e4 allele hyperinsulinaemia had no effect on the risk of disease (7.0% v 7.1%, respectively).
Conclusion: Features of the insulin resistance syndrome are associated with Alzheimer's disease independently of apolipoprotein E4 phenotype.
Introduction
The importance of apolipoprotein E4 phenotype as a risk
factor for late onset Alzheimer's disease has recently been well
established.(1-2) Our previous study indicated that the
prevalence of Alzheimer's disease in an elderly Finnish cohort was
2.9% in subjects with no e4 alleles, 7.6% in subjects with one e4
allele, and 21.4% in subjects with two e4 alleles.(2) Yet,
apolipoprotein E4 phenotype is neither necessary nor sufficient for
the expression of Alzheimer's disease.(2-3) Evidently,
other genetic or environmental factors contribute to the a As Alzheimer's disease is common, its risk factors should also be
prevalent. Adverse changes in cardiovascular risk factors are common in
Western countries, particularly in elderly subjects. Information on the
relation of other cardiovascular risk factors apart from apolipoprotein
E4 phenotype with the risk for Alzheimer's disease, however, is
limited.(4-5) The insulin resistance
syndrome - characterised by insulin resistance and concomitant
hyperinsulinaemia, obesity, especially central obesity, high
triglyceride concentration, low high density lipoprotein cholesterol
concentration, hypertension, impaired glucose tolerance, and
diabetes - has not been thoroughly evaluated as a risk factor for
Alzheimer's disease. There are few previous reports on small numbers
of patients suggesting that high glucose, insulin,(6) and
triglyceride concentrations,(5) all features of the insulin
resistance syndrome, are associated with Alzheimer's disease, but
there are also studies contradicting these
associations.(7-8) Lately, two population based studies
have also shoiwn an association between Alzheimer's disease and
diabetes(9) and between Alzheimer's disease and
atherosclerosis.(10). In our study we investigated the
association of cardiovascular risk factors with Alzheimer's disease in
a large randomly selected elderly population from eastern
Finland. Subjects Laboratory tests Glucose tolerance - All subjects, except for those receiving
insulin, underwent a 75 g oral 2 hour glucose tolerance test after a
12 hour fast. World Health Organisation diagnostic criteria for normal
glucose tolerance, impaired glucose tolerance, and diabetes mellitus
were used in the classification of glucose tolerance
group.(12)
Determination of apolipoprotein E phenotypes - The
apolipoprotein E phenotype was determined from serum samples with
isoelectric focusing and immunoblotting techniques by using
commercial antibodies.(1-14)
Other laboratory methods - Plasma glucose concentration was
determined by the glucose oxidase method (Glucose Auto and Stat
HGA-1120 analyser, Daiichi, Kyoto, Japan). Plasma insulin was
determined from samples stored at -70°C by a double antibody solid
phase radioimmunoassay (Phadeseph Insulin RIA 100, Pharmacia
Diagnostica AB, Uppsala Sweden).(15) Concentrations of
glycated haemoglobin A1c, total and high density
lipoprotein cholesterol, and total triglyceride were determined as
previously described in detail.(16)
Diagnosis of coronary heart disease and stroke
events - Both at baseline and follow up a conventional 12 lead
resting electrocardiogram was recorded, and the classification of the
tracings was made according to the Minnesota code.(17) We
used WHO criteria modified by the Finnish MONICA (monitoring trends and
determinants in cardiovascular disease) Study Group for verified
definite and possible myocardial infarction based on symptoms of chest
pain, electrocardiographic changes, and enzyme determinations in
ascertaining previous myocardial infarction.(18-19) WHO
criteria for definite and possible stroke were used in the
ascertainment of previous stroke, which was defined as a clinical
syndrome consisting of neurological deficits persisting over 24 hours
and observed by a neurologist without other diseases explaining the
symptoms.(20) Thromboembolic and haemorrhagic strokes, but
not subarachnoidal haemorrhage, were included in the diagnosis of
stroke.
Diagnosis of dementia Phase 1 - All study subjects (n=980) were evaluated by
neuropsychological tests. Phase 1 involved a screening battery of five
neuropsychological tests aimed at identifying patients who were
potentially demented. The cognitive test battery included the
minimental state examination, Russell's adaptation of the visual
reproduction test, the trail making test, the verbal fluency test, and
the Buschke selective reminding test. A detailed description of these
screening tests has been recently published.(21)
Phase 2 - Subjects scoring 1 SD and under below the mean score in
the minimental status examinations adjusted for education or below the
cut off point score (1 SD and under below the mean score in normal healthy
elderly subjects of similar age), or both, in three of four other
screening tests were selected for an extensive neuropsychological and
neurological examination to confirm the possibility of dementia
(n=232). The detailed neuropsychological test battery included 12
tests.(22-23) The diagnosis of dementia was based on the
criteria of Diagnostic and Statistical Manual of Mental
Disorders, third edition, revised (DSM-III-R).(24)
Phase 3 - All subjects with possible dementia (n=66)
were admitted to the department of neurology, Kuopio University
Hospital, for further studies. The final diagnosis and classification
of dementia was set by the board of two neuropsychologists and two
neurologists. All those for whom the diagnosis was confirmed
u Statistical methods Approval of ethics committee Altogether 980 subjects completed the follow up examination and
neuropsychological screening for dementia (phase 1). Of these, 19 were
diagnosed with dementia of non-Alzheimer type (nine with vascular
dementia and 10 with secondary dementia) and excluded, leaving 961
subjects (762 non-diabetic and 199 diabetic subjects) in the study. Of
these, 46 were diagnosed with Alzheimer's disease. In 38 of these 46
patients the diagnosis was made in our study.
Table 1 shows the levels of cardiovascular risk factors measured 2-3
weeks before the screening for dementia in study subjects with and
without Alzheimer's disease. In addition to having increased
prevalence of apolipoprotein E4 phenotype, patients with Alzheimer's
disease were older and had fewer years of education, higher systolic
blood pressure, higher fasting and 2 hour glucose concentrations,
higher fasting and 2 hour insulin concentrations, and increased
prevalence of diabetes and impaired glucose tolerance. Of the 46
subjects with Alzheimer's disease, only 13 had normal glucose
tolerance. In non-diabetic subjects, the results of the aforementioned
analyses were the same except that diastolic blood pressure was
significantly higher and hypertension was more prevalent in subjects
with Alzheimer's disease compared with those without it (data not
shown).
Table 2 shows risk factors for Alzheimer's disease by univariate
logistic regression analysis in all study subjects. In addition to
apolipoprotein E4 phenotype, age, low level of education, the presence
of abnormal glucose tolerance (diabetes or impaired glucose tolerance),
high systolic blood pressure, low total cholesterol concentration, high
fasting and 2 hour glucose concentrations, and high fasting and 2 hour
insulin concentrations were associated with an increased risk for
Alzheimer's disease. In non-diabetic subjects, in addition to these
variables, hypertension and high diastolic blood pressure were also
associated with Alzheimer's disease (data not
shown). Table 3 shows the results of the multiple logistic regression analysis
on risk factors for Alzheimer's disease in all study subjects.
Variables associated with the risk for Alzheimer's disease in
univariate analyses were included in the model. Age, low level of
education, low total cholesterol concentration, apolipoprotein E4
phenotype, and high fasting insulin concentration were independently
associated with the risk for Alzheimer's disease. In non-diabetic
subjects, low level of education, high systolic blood pressure, low
total cholesterol concentration, apolipoprotein E4 phenotype, and high
fasting insulin concentration were independently associated with the
risk of Alzheimer's disease.
The association between Alzheimer's disease and baseline
cardiovascular risk factors measured 3.5 years before the screening for
dementia were also studied by logistic regression analyses. In
univariate analysis, the same variables which were associated with
Alzheimer's disease at follow up were also associated with
Alzheimer's disease when we used parameters measured at baseline (data
not shown). In multivariate analysis, age (1.15; 1.03 to 1.29;
P=0.013), low level of education (0.83; 0.73 to 0.95; P=0.005), low
cholesterol concentration (0.67; 0.50 to 0.87; P=0.004), apolipoprotein
E4 phenotype (3.53; 1.86 to 6.68; P=0.0001), and high insulin
concentration (1.03; 1.00 to 1.05; P=0.040) but not systolic blood
pressure (1.01; 0.73 to 1.02; P=0.25) or fasting plasma glucose (1.09;
0.74 to 1.23; P=0.46) were significantly associated with the risk for
Alzheimer's disease.
Finally, we investigated the risk of Alzheimer's disease in
hyperinsulinaemic subjects with and without the e4 allele. As insulin
concentration is a good marker for insulin resistance in non-diabetic
subjects but not in those with diabetes(26) we analysed the
association between Alzheimer's disease and hyperinsulinaemia in
non-diabetic subjects. Hyperinsulinaemia was defined as the highest
insulin quintile (>89.4 pmol/l) in this subgroup. In subjects without
the e4 allele (n=532) hyperinsulinaemia was associated with an
increased risk for Alzheimer's disease (the prevalence of Alzheimer's
disease in hyperinsulinaemic versus normoinsulinaemic subjects 7.5%
and 1.4%, respectively, P=0.0004). In contrast, in subjects with the
e4 allele (n=228) hyperinsulinaemia had no effect on the risk of
Alzheimer's disease (7.0% and 7.1%, respectively, P=0.65). The results of the present study indicate that cardiovascular risk
factors related to the insulin re Why have previous studies not been able to show an association between
cardiovascular risk factors related to insulin resistance and
Alzheimer's disease? Most studies have included patients with
established Alzheimer's disease. Advanced Alzheimer's disease is a
catabolic state with low blood pressure and low total cholesterol and
low blood glucose concentrations.(8) This catabolic state
may interfere with the insulin resistance syndrome characterised by
opposite features and bias risk factor analysis.
How might the insulin resistance syndrome increase the risk for
Alzheimer's disease? On the basis of the present results definitive
answers cannot be given, but other studies suggest interesting
connections between glucose and insulin metabolism and brain function.
Diabetes is associated with dementia,(9) and in our study
diabetes increased the risk for Alzheimer's disease. Consequently,
hyperglycaemia might be a risk factor for Alzheimer's disease. Indeed,
according to a recent report, advanced glycation end products, which
accumulate in tissues as a function of time and blood glucose
concentration(27) are found in amyloid plaques of
Alzheimer's disease.(28) Thus, hyperglycaemia associated
with an increased production of advanced glycation end products may
contribute to the formation of amyloid plaques in Alzheimer's disease.
Although hyperglycaemia might be one factor explaining the association
between the insulin resistance syndrome and Alzheimer's disease, it is
probably not the only one. In our study, fasting insulin, a key feature
of the insulin resistance syndrome and also an integral part of
impaired glucose tolerance, was significantly associated with
Alzheimer's disease. In non-diabetic subjects, hyperinsulinaemia
(fasting insulin >89.4 pmol/l) was, in fact, associated with as high
a risk of Alzheimer's disease as the presence of apolipoprotein E4
phenotype. In our previous study, hyperinsulinaemic hypertension was
also associated with poor cognitive function.(29) Insulin is
transported to cerebrospinal fluid and also synthesised in the
brain, where it acts as a neuromodulator regulating energy
balance.(30-31) Hyperinsulinaemia might interfere with
brain function making it more vulnerable to Alzheimer's disease or
contribute to amyloid plaque formation. It is also possible, however,
that other aspects of the insulin resistance syndrome, such as
accelerated atherosclerosis,(10)(32) are responsible for the
association between the insulin resistance syndrome and Alzheimer's
disease.
In patients with Alzheimer's disease, the question of validity of
informed consent is appropriate. In our study, 38 of the 46 patients
with Alzheimer's disease were diagnosed with dementia during our
study. The eight patients with previously known Alzheimer's disease
were relatively mildly affected and could participate in the study by
themselves.
In conclusion, features of the insulin resistance syndrome are
associated with Alzheimer's disease, independently of the
apolipoprotein E4 phenotype. Alzheimer's disease may resemble coronary
heart disease, in which several factors contribute to the risk for the
disease. Even more importantly, as the insulin resistance syndrome is
at least in part preventable by modification of life style,
Alzheimer's disease might also be preventable, at least in some cases,
thus opening new areas for researchers.
Department of Medicine, Department of Neurology, Department of
Internal Medicine,
Correspondence to: Professor Laakso
Funding: This study was supported by a grant from the Medical
Research Council of the Academy of Finland.
(Accepted 18 September 1997)
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Subjects and methods
The subjects for this study were selected from a po
The cardiovascular risk factors used in this study were measured
at the follow up examination of the study, about 2-3 weeks before the
screening for dementia. All cardiovascular risk factors, including
glucose tolerance and insulin concentrations, however, were also
measured at baseline, 3.5 years before screening for dementia, and the
association of these previously measured variables with Alzheimer's
disease was also evaluated.
The diagnosis of dementia was based on a three phase programme.
Data analyses were conducted with the SPSSX and
SPSS/PC+ programs. Data are given as mean (SE) or
percentages. Student's two tailed t test for
independent samples or chi2 test were used in the
assessment of the differences between the groups when appropriate.
Univariate and multiple logistic regression analyses based on the
maximum likelihood method were used to investigate the association of
cardiovascular risk factors with the prevalence of Alzheimer's
disease. Odds ratios (95% confidence intervals) were calculated by
logistic regression analysis.
This study was approved by the ethics committee of the Kuopio
University Hospital. All study subjects gave informed consent. Results
Table 1 - Characterics of study subjects with and
without Alzheimer's disease. Values are means (SE) unless stated
otherwise
Characteristic
No Alzheimer's disease
(n=915)Alzheimer's disease
(n=46) Sex
(M/F) 324/591 14/32
Age (years) 72.9
(0.1)74.1
(0.4)**
Education (years) 6.8
(0.1)5.1
(0.6)** No (%) of smokers 61
(6.7) 3
(6.7) No (%) of alcohol
users 163
(17.8) 8
(17.4) No
(%) with hypertension† 507
(55.4) 29
(63.8) No (%) with myocardial
infarction 129
(14.1) 8
(17.4)
No (%) with stroke 34
(3.7) 1
(2.2) No (%) with diabetes 182
(19.9) 15
(32.6)** No (%) with impaired
glucose tolerance 182
(19.9) 17
(37.0)*** Body mass index (kg/m2) 27.1
(0.1)27.4
(0.8) Waist:hip
ratio 0.94
(0.00)0.95
(0.01)
Systolic blood pressure (mm Hg)‡ 155
(1)162
(4)* Diastolic blood pressure (mm
Hg)‡ 82
(0)84
(2) Total
cholesterol (mmol/l) 6.5
(0.0)6.2
(0.2) High density lipoprotein cholesterol
(mmol/l)1.36
(0.01)1.30
(0.06)
Triglycerides (mmol/l) 1.68
(0.03)1.85
(0.14) No (%) with apolipoprotein E4
phenotype (%) 279
(30.5) 27
(58.7)*** Fasting plasma glucose (mmol/l) 6.2
(0.1)6.9
(0.4)* Two hour plasma glucose
(mmol/l) 8.3
(0.1)10.6
(0.9)**
Haemoglobin A1c 6.0
(0.0)6.3
(0.2) Fasting insulin
(pmol/l) 74.8
(1.5)99.3
(9.4)*** Two
hour insulin (pmol/l) 500.9
(14.8)682.3
(108.8)*
*P<0.05, **P<0.01, ***P<0.001.
†Systolic blood pressure 160 mm Hg and over, diastolic blood pressure
95 mm Hg and over, or drug treatment for hypertension.
‡ Measured twice on right arm in supine position after 5
minutes' rest. Second reading used in analyses.
Table 2 - Association of characteristics with
Alzheimer's disease in univariate logistic regression
analysis
Characteristic
Odds ratio
(95% CI) P
value Sex 1.25
(0.66 to
2.36)0.49 Age 1.16
(1.05 to
1.29)0.005 Education 0.82
(0.72 to
0.93)0.002 Smoking 0.88
(0.61 to
1.25)0.47 Alcohol use 0.97
(0.45
to 2.11)0.94 Hypertension 1.37
(0.75 to 2.52)0.31 Myocardial
infarction 1.28
(0.59 to 2.79)0.53
Stroke 0.58
(0.08 to 4.30)0.59
Abnormal glucose tolerance 1.86
(1.23 to
2.80)0.003 Body mass index 1.02
(0.95 to 1.09)0.67 Waist:hip
ratio 2.96
(0.08 to 108.08)0.56
Systolic blood pressure 1.01
(1.00 to
1.03)0.039 Diastolic blood
pressure 1.03
(1.00 to 1.050.09
Total cholesterol 0.77
(0.59 to
1.00)0.049 High density lipoprotein
cholesterol 0.60
(0.25 to 1.45)0.26
Triglycerides 1.13
(0.91 to
1.41)0.28 Apolipoprotein E4
phenotype 3.24
(1.77 to 5.92)0.0001
Fasting plasma glucose 1.11
(1.01 to
1.23)0.031 Two hour plasma
glucose 1.08
(1.03 to 1.13)0.002
Haemoglobin A1C 1.14
(0.95 to
1.36)0.16 Fasting insulin 1.05
(1.02 to 1.08)0.0005 Two hour
insulin 1.003
(1.00 to
1.01)0.013 Table 3 - Multiple logistic regression analysis on risk
factors for Alzheimer's disease
Character
Odds ratio
(95% CI) P value
Age 1.12
(1.01 to
1.25)0.039 Education 0.83
(0.73 to
0.95)0.006 Systolic blood
pressure 1.01
(1.00 to 1.02)0.129
Total cholesterol 0.69
(0.52 to
0.92)0.011 Apolipoprotein E4
phenotype 3.60
(1.91 to 6.79)0.0001
Fasting plasma glucose 1.10
(0.93 to
1.24)0.095 Fasting insulin 1.04
(1.01
to 1.08)0.018 Discussion
Key Messages
Apolipoprotein E4 phenotype is a risk factor for Alzheimer's
disease Other risk factors for Alzheimer's disease are not well
documented in previous studies In this study, hyperinsulinaemia and other features of the
insulin resistance syndrome were associated with Alzheimer's disease Insulin resistance is affected by modifications in lifestyle,
so the risk of Alzheimer's disease might be reducible by the same
measures
Kuopio University
Hospital,
PO Box 1777,
FIN-70211 Kuopio,
Finland
Johanna
Kuusisto, lecturer in medicine
Leena
Mykkänen, consultant physician
Markku
Laakso, professor
Kuopio University Hospital
Keijo
Koivisto, consultant
physician
Eeva-Liisa
Helkala, psychologist
Matti
Vanhanen, psychologist
Tuomo
Hänninen, psychologist
Paavo J
Riekkinen, professor
Oulu University Hospital and Biocenter Oulu,
University of Oulu,
Oulu,
Finland
Kari
Kervinen, consultant physician
Y Antero
Kesäniemi, professor
Conflict of interest: None.
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