Diabetes, hypertension, and cognitive decline

Age and Ageing 2004; 33: 355361 Age and Ageing Vol. 33 No. 4 British Geriatrics Society 2004; all rights reserved
DOI: 10.1093/ageing/afh100 Published electronically 10 May 2004

Comorbid type 2 diabetes mellitus

and hypertension exacerbates cognitive
decline: evidence from a longitudinal study
LINDA B. HASSING1, SCOTT M. HOFER2, SVEN E. NILSSON4, STIG BERG4, NANCY L. PEDERSEN5,6,
GERALD MCCLEARN3, BOO JOHANSSON1
1
Department of Psychology, Gteborg University, Gteborg, Sweden
2
Department of Human Development and Family Studies and 3Center for Developmental and Health Genetics, Pennsylvania
State University, University Park, PA, USA
4
Institute of Gerontology, School of Health Sciences, Jnkping, Sweden
5
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
6
Department of Psychology, University of Southern California, Los Angeles, CA, USA

Address correspondence to: Linda B. Hassing, Department of Psychology, Gteborg University, Box 500, SE-405 30 Gteborg,
Sweden. Fax: (+46) 31 773 4628. Email: Linda.Hassing@psy.gu.se

Abstract
Background: diabetes and hypertension are two highly prevalent diseases in the old population. They are highly related such
that comorbidity is common.
Objectives: to examine (i) the independent impact of the respective diseases on cognitive decline in very old age and (ii) the
interactive impact of the two diseases on cognitive decline.
Subjects: 258 individuals (mean age = 83 years), all non-demented at baseline. Of these, 128 individuals (non-cases) were
free from diabetes and hypertension, 92 individuals had a diagnosis of hypertension, 16 had a type 2 diabetes mellitus diagnosis
without hypertension, and 22 had comorbid diabetes and hypertension.
Method: a population-based longitudinal study of ageing (The OCTO-Twin Study), including four measurement occasions
2 years apart. The Mini-Mental State Examination was used to measure general cognitive function. Data were analysed using
SAS Proc Mixed multilevel modelling.
Results: longitudinal trajectories indicated a steeper decline in cognitive function related to diabetes but not related to hyper-
tension. However, the results indicated greatest cognitive decline among persons with comorbid diabetes and hypertension.
Conclusions: it is concluded that comorbidity of diabetes and hypertension produce a pronounced cognitive decline. This
finding emphasises the importance of prevention and treatment of those highly prevalent diseases in the old population.

Keywords: hypertension, type 2 diabetes mellitus, cognitive decline, older age, longitudinal study, vascular disease

Introduction Extensive research on the effects of diabetes on cognitive

Type 2 diabetes mellitus and hypertension are two highly
prevalent diseases among the old that are known to be risk
factors for vascular disease. The prevalence of type 2 diabe-
tes is estimated to range between 15% and 25% in the age
group of 65 years and older [1]. The corresponding num-
bers for hypertension range between 50% and 70% [13].
Diabetes and hypertension are furthermore highly related
such that comorbidity is common [1].
function in old age has provided mixed findings [4, 5].
Although the majority of the studies have found negative
effects on cognitive functioning related to diabetes [68],
several studies have reported no relationship [9, 10]. The
effects of hypertension on cognitive function have also been
a subject for extensive research [11]. Most studies indicate
that hypertension is negatively related to cognitive test per-
formance [1214], although some studies report no associa-
tion [15]. Variation in findings concerning the consequences

355
L. B. Hassing et al.

of hypertension may be partially explained by age; thus, high and hypertension performed worse on several cognitive
blood pressure in young and middle age predicts lower cog- tasks compared with normoinsulinaemic hypertensive people.
nitive performance whereas high blood pressure in old age The purpose of the present study was to examine the
has given mixed findings. comorbid effects of type 2 diabetes and hypertension on
A methodological issue that may be a source of these cognitive decline across a 6-year interval in old individuals
conflicting results is that comorbid diseases are often not using the Mini-Mental State Examination [18].
considered. The most important condition that has to be
screened for or controlled when examining older samples is Method
dementia. The significance of comorbid dementia was dem-
onstrated in a recent study where it was found that initially Participants
observed differences between people with diabetes and
people without diabetes in cognitive performance were no The participants were drawn from the ongoing population-
longer significant when dementia was accounted for [8]. It is based longitudinal study Origins of variance in the Old-Old
also important to control for dementia when examining the [19] which started in 1991. The full sample included 702
impact of hypertension on cognitive function in old age, individuals at inclusion, in 351 like-sexed pairs, aged 80
given that blood pressure decreases following the develop- years and older. The present study was based on the first four
ment of dementia. Thus, given the association between waves of the study and included a sample of individuals that
dementia and diabetes, respectively dementia and hyperten- survived the four waves, were not diagnosed with dementia
sion, it is possible that one reason for conflicting results as at the first occasion (following DSM-III-R criteria), and had
to whether hypertension and diabetes are related to lower a MMSE score >23 at the first occasion. One hundred and
cognitive functioning is that some studies control for twenty-eight individuals (non-cases) were free from diabetes
dementia whereas others do not. and hypertension, 92 individuals had a diagnosis of hyper-
Little is known about the comorbid effect of diabetes tension, 16 had a type 2 diabetes mellitus diagnosis without
and hypertension on cognitive function. For example, it is hypertension, and 22 had comorbid diabetes and hypertension
not known if it is more detrimental to have comorbid (see Table 1). The total sample size for analyses was 258.
hypertension and diabetes than having only diabetes.
Findings from the Framingham Heart Study indicated that Procedure
comorbid diabetes and hypertension were associated with The participants were investigated in their home. A complete
lower performance in tasks measuring visual organisation testing session, including rest periods, took about 3.5 to 4.0
and memory [16]. Furthermore, Kuusisto and colleagues hours. The participants were assessed four times at 2-year
[17] found that people with comorbid hyperinsulinaemia intervals beginning in 1991.

Table 1. Baseline participant characteristics and diseases across groups

Hypertension without Diabetes without Diabetes and
Non-cases diabetes hypertension hypertension
Characteristics (n = 128) (n = 92) (n = 16) (n = 22)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Years of age
M SD 82.5 2.3 82.5 2.2 84.0 3.9 83.1 2.6
Years of education
M SD 7.4 2.3 7.0 2.1 7.6 1.2 7.4 1.5
MMSE
M SD 28.2 1.6 28.0 1.7 28.0 1.4 28.3 1.6
Sex (women) % 67 78 50 68
Never smoked % 59 73 63 55
Myocardial infarction % 12 11 13 18
Angina pectoris % 14 19 25 23
Congestive heart failure % 13 17 13 18
Stroke % 9 12 0 18
TIA % 7 10 6 9
Body mass index (kg/m2)
M SD 24.2 3.4 25.2 3.4 24.0 3.6 25.5 3.7
sBP (mm Hg)
M SD 149.9 20.4 172.5 24.2 155.9 16.0 171.6 18.2
dBP (mm Hg)
M SD 80.2 11.5 87.3 13.6 80.0 9.5 84.8 7.9
Years with diabetes
M SD 5.6 4.6 7.1 6.3
Range 015 024

M = mean, SD = standard deviation, MMSE = Mini-Mental State Examination.

356

Medical information
During the interview the participants were asked for per-
mission to review their medical records. Medical records for
the period 19851998 were ordered from hospitals, outpatient
clinics, district physicians, and primary health care centers,
and multiple requests were made to secure the quality of
information and to make sure that the records covered the
entire time period and also contained a summary of diseases
earlier in life. A physician (co-author Sven E. Nilsson) made
a concurrent review of (i) medical records, including reported
medical history; (ii) medicine use; and (iii) self-reported
information about diseases. An independent 2nd opinion on
classification performed by another physician in a 20% sub-
sample produced only marginal amendment. Diagnoses
were classified according to the ICD-10 [20]. The conditions
of interest for subsequent analyses are hypertension (which
was diagnosed in cases where either the records contained
information of specific hypertension treatment, or in cases
with more than one diastolic value of at least 95 mm Hg or
systolic value higher than 160mmHg), type 2 diabetes mellitus
(diagnosed using the 1980 WHO criteria when diagnostic
level for venous whole blood glucose was 6.7 mmol/l [21]),
congestive heart failure, myocardial infarction, angina pectoris,
transient cerebral ischemic attack (TIA; that is defined as
lasting shorter than 24 hours), stroke, and dementia.
Cognitive assessment
The MMSE is a measure of global cognitive functioning.
The task reflects orientation, memory, attention, ability to
follow verbal and written commands, writing, and copying.
The maximum score is 30, indicating normal cognitive func-
tioning.
Data analyses
Group differences in demographic and health conditions
were analysed with one-way analyses of variance and Chi-square
tests.
Random coefficients modelling using SAS Proc Mixed
was used to estimate individual-level change and predictors
of change while accounting for the dependency associated
with twin pair status. The multilevel model was characterised
by a fixed part which contained average effects for the intercept
(initial status) and slope (rate of change) and a random part
which contained individual differences (variance) in the
intercept, slope, and the within person residual. A three-level
linear growth model was composed of a level-1 component
of individual outcomes over time, a level-2 component
which models individual fixed and random effects of initial
status and change over time (person-level covariates can be
added at this level), and the level-3 component which models
variance associated with twin-pair status. Thus, a three-level
structure was characterised by longitudinal measurements
nested within individuals which were nested within groups
(twin dyad). The syntax for these models is presented in
Appendix A.
The baseline model specifies a growth model with no
level-2 covariates and was used to evaluate the fit of the
growth model parameters. In this and subsequent models,
zygosity was not modelled as a fixed effect because the
Diabetes, hypertension, and cognitive decline
expectation was for no or random differences among MZ
and DZ twins in terms of average slope and rate of change.
Random effects were, however, estimated separately by
zygosity because we expected higher intraclass correlations
for MZs than for DZs. Finally, we permitted different esti-
mates of the residual (level-one) variance for the two zygos-
ity groups.
Four nested models were estimated for MMSE as the
outcome variable. A baseline model, without any covariates,
was run to assess initial status and rate of change for the
MMSE. Model A introduces the single covariate of hyper-
tension status (0 = no, 1 = yes) adjusted for age, education,
gender, smoking habit, angina, myocardial infarction, con-
gestive heart failure, stroke, and TIA. Model B introduces
the single covariate of diabetic status (0 = no, 1 = yes),
adjusted for the same factors as in Model A. Finally, Model
C introduces the interaction term of diabetes and hyperten-
sion, also adjusted for same factors as in Model A and B.
Results
Participant characteristics at baseline
Participant characteristics are presented in Table 1. No sig-
nificant differences between groups in participant character-
istics were observed except in systolic and diastolic blood
pressure (PS < 0.05) which were higher among the two groups
with hypertension as compared with the normotensive
groups. The two groups with hypertension did not differ in
systolic and diastolic blood pressure (PS > 0.05). Further,
the two groups with diabetes did not differ with respect to
how many years they had had the diagnosis of diabetes
(P > 0.05).
Change in MMSE Scores across a 6-year Interval
Results from the growth curve modelling are reported in
Table 2. The estimates of the average intercept (mean) and
rate of change across persons (slope) in the Baseline model
were significant. For example, the average person began
with a score of 28.36 and declined by 0.33 points per 2-year
interval.
Model A allows us to explore whether variation in inter-
cepts and slopes is related to hypertension status as a lone
covariate of interest after adjusting for age, education, gender,
smoking habit, angina, myocardial infarction, congestive
heart failure, stroke, and TIA. Neither estimates are signific-
ant, indicating that hypertension alone is not a significant
factor for change in the MMSE. Model B examines the
effect of diabetes. As seen in Table 2, diabetes is signifi-
cantly associated with rate of change in the MMSE such that
those with diabetes decline by an additional 0.29 points per
2-year interval as compared to those without diabetes.
However, diabetes was not a significant predictor of initial
status in the MMSE. Finally, Model C examines the effect
of having co-morbid diabetes and hypertension. This model
shows that there is a significant interaction between diabetes
and hypertension in rate of change in the MMSE such that
those with both diseases decline additionally by 0.42 points
per 2-year interval as compared to those free from both
357
L. B. Hassing et al.

Table 2. Parameter estimates (SE) of the fixed effects for cognitive change
Baseline model Model Aa Model Ba Model Ca
(No covariate) (Hypertension) (Diabetes) (Diabetes hypertension)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Level (SE) Slope (SE) Level (SE) Slope (SE) Level (SE) Slope (SE) Level (SE) Slope (SE)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Mean 28.36 (0.11)* 0.33 (0.05)* 31.52 (3.78)* 0.25 (0.07)* 32.14 (3.77)* 0.29 (0.06)* 31.75 (3.73)* 0.30 (0.05)*
Hypertension 0.03 (0.21) 0.18 (0.10)
Diabetes 0.61 (0.30) 0.29 (0.14)*
Diabetes hypertension 0.92 (0.37)* 0.42 (0.18)*
a
Adjusted for age, education, gender, smoking habit, angina, myocardial infarction, congestive heart failure, stroke, and TIA.
*P < 0.05.

30 hypertension and diabetes (23%), although the difference

between groups was not statistically significant.
28
Discussion
26 In the present study, we examined the effects of comorbid
hypertension and diabetes on change in MMSE score across
Mean

a 6-year interval. The participants were drawn from a longi-

24
22
20
T1
Non-cases
Diabetes
Figure 1. Observed mean performance on the MMSE across
groups and time.
hypertension and diabetes. The rate of decline in the MMSE
related to hypertension and diabetes is portrayed in Figure 1.
Survival, prevalent, and incident dementia
across groups
As shown in Table 3 the overall survival rate (based on the
initial sample of 702 individuals) between T1 and T4 was
52%. The lowest survival rate was observed in the diabetes
groups (44% and 46%), however, there was no statistically
significant difference between groups (P > 0.05). Prevalence
of dementia at baseline across groups is reported in Table 3
(note that demented persons at baseline were excluded from
the data analyses on MMSE). The highest prevalence of
dementia at baseline was seen among the people with hyper-
tension and diabetes (24%). Further, the highest incidence
rate of dementia at T4 was seen among the people with
tudinal population-based study and were measured on four
occasions. Individuals with dementia at baseline were excluded.
The main findings showed that all groups had declined after the
6-year follow-up period. Further, differential cognitive change
was observed between the groups reflecting the greatest decline
T2 T3 T4 among those with comorbid hypertension and diabetes.
Hypertension
Our results showed that people with diabetes demon-
Diabetes + hypertension strated greater cognitive change across the 6-year interval as
compared with people without diabetes. This finding is in
agreement with other longitudinal studies that report increased
cognitive decline related to diabetes [6, 7] and an increased
risk of dementia [22, 23]. On the other hand, the impact of
hypertension on cognitive function was not statistically
significant, although the hypertensives had a somewhat
greater decline than the non-cases. A greater decline among
the hypertensives would have been expected given the many
findings showing this result [1215, 2426]. These findings
may possibly be a result of the high age of our sample, as
several investigations suggest that the negative effects asso-
ciated with hypertension may vary with age such that greater
effects are found among young samples as compared to old
samples. For example, Waldstein [27] suggested that non-
significant association between hypertension and cognitive
function in old age might reflect selective attrition. Another
possibility would be that early-onset hypertension confers
greater risk for cognitive impairment [11].
Although hypertension alone was not related to signifi-
cantly greater cognitive decline our results suggest that
comorbid hypertension and diabetes is combined with

Table 3. Survival, prevalent, and incident dementia across groups

Non-cases Hypertension Diabetes Diabetes+hypertension Total
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Survival until T4 171/331 (52%) 135/251 (54%) 29/52 (44%) 31/68 (46%) 366/702 (52%)
Prevalent dementia at T1a 51/331 (15%) 30/251 (12%) 11/52 (21%) 16/68 (24%) 108/702 (15%)
Incident dementia between T1 and T4b 10/128 (8%) 12/92 (13%) 3/16 (19%) 5/22 (23%) 30/258 (12%)
a
These individuals were excluded from this study.
b
Based on the sample that met the criteria for inclusion in the data analyses (see Methods).

358

increased risk for cognitive impairment. These results are
consistent with prior research [1517]. When looking into
the underlying mechanisms through which diabetes and
hypertension interact it should be kept in mind that these
conditions may be a part of a larger metabolic syndrome,
including hyperglycaemia, hyperinsulinaemia and dyslipid-
aemia. Thus, several pathways for how these conditions
may interact and cause cognitive impairment have been
suggested [28]. For example, hyperglycaemia has been
shown to be related to loss of cortical neurons as well as a
decrease in acetylcholine synthesis and release in the brain
of rats [29]. Dyslipidemiea as well as hyperinsulinaemia are
related to arteriosclerosis, although it should be noted that
hyperinsulinaemia is not always apparent in type 2 diabetes.
Furthermore, hypertension is a known risk factor for cere-
brovascular disease, lacunar brain infarct, and white matter
lesion [30]. In our study we found that there was a higher
prevalence of stroke among those with comorbid diabetes
and hypertension as compared to people with diabetes
without hypertension. This reflects increased vulnerability
among those with both diabetes and hypertension. It is also
if interest to note that this group had had diabetes for a
longer period of time than those with diabetes only. Thus, it
may be the case that the longer the period with diabetes, the
greater the risk of hypertension and of cognitive impair-
ment. When comparing the incidence rates of dementia
across groups in our study we find the highest rate among
people with comorbid diabetes and hypertension, followed
by people with diabetes without hypertension. However,
these figures are based on very small numbers and should
therefore be treated cautiously.
The main strength of the present study is the longitudinal
design, which provides us with the opportunity to simulta-
neously explore the long-term effects of two risk factors of
cognitive impairment. There is also an advantage in using a
population-based sample, which minimises selection bias
and increases generalisability. However, we need to be cau-
tious when interpreting our results, as there are some limita-
tions to our study. The first limitation is the small sample
size. This is, however, a result of the high attrition rate,
common for longitudinal studies of very old samples. Fur-
thermore, the attrition rate is especially problematic when
studying diseases that are associated with a greater mortality
rate, such as diabetes. In our study the survival rate among
people with diabetes was somewhat lower as compared to
people without diabetes. Another limitation is that cognitive
performance was only measured by a global measure that
may be too insensitive to detect more subtle and differential
change in various cognitive domains.
To summarise, this study demonstrates that comorbid
diabetes and hypertension further increases the risk of
cognitive decline. Thus, it underlines the importance of
prevention and treatment of these two common diseases.
Key points
Hypertension in very old age is not independently related
to cognitive decline.
Diabetes, hypertension, and cognitive decline
People with diabetes and hypertension are at a greater
risk for cognitive decline than normotensive people with
diabetes.
Acknowledgements
The OCTO Twin Study is an ongoing longitudinal study
conducted at the Institute of Gerontology, School of Health
Sciences, Jnkping, Sweden, in collaboration with the
Center for Developmental and Health Genetics at the
Pennsylvania State University, USA and the Department of
Medical Epidemiology and Biostatistics at the Karolinska
Institute in Stockholm, Sweden. The authors want to thank
RNs Lene Ahlbck (19912001), Agneta Carlholt (19922002),
Gunilla Hjalmarsson (19911993), Eva Georgsson (19931995),
and Anna-Lena Wetterholm (19931994) who travelled
throughout the country and examined the participants.
There are no conflicts of interest in this study.
Funding
This study is supported by a grant from the National Insti-
tute on Aging (NIA: AG 08861) of the National Institutes
of Health, The Swedish Council for Working Life and Social
Research, The Wenner-Gren Foundations, Wilhelm and
Martina Lundgrens Foundation, Knut and Alice Wallenberg
Foundation, and The Adlerbertska Foundation.
References
1. Fillenbaum G, Pieper C, Cohen H, Cornoni-Huntley J, Guralnik J.
Comorbidity of five chronic health conditions in elderly com-
munity residents: determinants and impact on mortality.
J Gerontol A Biol Sci Med Sci 2000; 55: M8489.
2. Wolz M, Cutler J, Roccella EJ, Rohde F, Thom T, Burt V.
Statement from the National High Blood Pressure Education
Program: prevalence of hypertension. Am J Hypertens 2000;
13: 1034.
3. The sixth report of the Joint National Committee on prevention,
detection, evaluation, and treatment of high blood pressure.
Arch Intern Med 1997; 157: 241346.
4. Ryan CM, Geckle M. Why is learning and memory dysfunction
in Type 2 diabetes limited to older adults? Diabetes/Metabolism
Res Rev 2000; 16: 30815.
5. Stewart R, Liolitsa D. Type 2 diabetes mellitus, cognitive
impairment and dementia. Diabetic Med 1999; 16: 93112.
6. Fontbonne A, Berr C, Ducimetiere P, Alperovitch A. Changes
in cognitive abilities over a 4-year period are unfavorably
affected in elderly diabetic subjects: results of the Epidemiol-
ogy of Vascular Aging Study. Diabetes Care 2001; 24: 36670.
7. Gregg EW, Yaffe K, Cauley JA et al. Is diabetes associated
with cognitive impairment and cognitive decline among older
women? Study of Osteoporotic Fractures Research Group.
Arch Intern Med 2000; 160: 17480.
8. Hassing LB, Johansson B, Pedersen NL, Nilsson SE, Berg S,
McClearn G. Type 2 diabetes mellitus and cognitive perform-
ance in a population-based sample of the oldest old: Impact of
comorbid dementia. Aging Neuropsychol Cognit 2003; 10:
99107.
9. Bourdel-Marchasson I, Dubroca B, Manciet G, Decamps A,
Emeriau JP, Dartigues JF. Prevalence of diabetes and effect on
359
L. B. Hassing et al.
quality of life in older French living in the community: the
PAQUID Epidemiological Survey. J Am Geriatr Soc 1997; 45:
295301.
10. Breteler MM, Claus JJ, Grobbee DE, Hofman A. Cardiovas-
cular disease and distribution of cognitive function in elderly
people: the Rotterdam Study. Br Med J 1994; 308: 16048.
11. Waldstein SR. Health effects on cognitive aging. In Carstensen
LL ed. The Aging Mind: Opportunities in Cognitive Research.
Washington DC: National Academy Press, 2001.
12. Elias MF, Wolf PA, DAgostino RB, Cobb J, White LR.
Untreated blood pressure level is inversely related to cognitive
functioning: the Framingham Study. Am J Epidemiol 1993;
138: 35364.
13. Cervilla JA, Prince M, Joels S, Lovestone S, Mann A. Long-
term predictors of cognitive outcome in a cohort of older peo-
ple with hypertension. Br J Psychiatry 2000; 177: 6671.
14. Glynn RJ, Beckett LA, Hebert LE, Morris MC, Scherr PA,
Evans DA. Current and remote blood pressure and cognitive
decline. JAMA 1999; 281: 43845.
15. Posner HB, Tang MX, Luchsinger J, Lantigua R, Stern Y,
Mayeus R. The relationship of hypertension in the elderly to
AD, vascular dementia, and cognitive function. Neurology
2002; 58: 117581.
16. Elias PK, Elias MF, DAgostino RB et al. NIDDM and blood
pressure as risk factors for poor cognitive performance. The
Framingham Study. Diabetes Care 1997; 20: 138895.
17. Kuusisto J, Koivisto K, Mykkanen L et al. Essential hyperten-
sion and cognitive function. The role of hyperinsulinemia.
Hypertension 1993; 22: 7719.
18. Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A
practical method for grading the cognitive state of patients for
the clinician. J Psychiatr Res 1975; 12: 18998.
19. McClearn GE, Johansson B, Berg S et al. Substantial genetic
influence on cognitive abilities in twins 80 or more years old.
Science 1997; 276: 5603.
20. Nilsson SE, Johansson B, Berg S, Karlsson D, McClearn GE.
A comparison of diagnosis capture from medical records, self-
360
reports, and drug registrations: a study in individuals 80 years
and older. Aging Clin Exp Res 2002; 14: 17884.
21. WHO Expert Committee on Diabetes Mellitus: second report.
World Health Organ Tech Rep Ser 1980; 646: 180.
22. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A,
Breteler MM. Diabetes mellitus and the risk of dementia: The
Rotterdam Study. Neurology 1999; 53: 193742.
23. Hassing LB, Johansson B, Nilsson SE et al. Diabetes mellitus is
a risk factor for vascular dementia, but not for Alzheimers
disease: A population-based study of the oldest old. Int Psy-
chogeriatr 2002; 14: 23948.
24. Blumenthal JA, Madden DJ, Pierce TW, Siegel WC, Appelbaum M.
Hypertension affects neurobehavioral functioning. Psycho-
som Med 1993; 55: 4450.
25. Kilander L, Nyman H, Boberg M, Hansson L, Lithell H.
Hypertension is related to cognitive impairment: a 20-year follow
up of 999 men. Hypertension 1998; 31: 7806.
26. Wallace RB, Lemke JH, Morris MC, Goodenberger M,
Kohout F, Hinrichs JV. Relationship of free-recall memory to
hypertension in the elderly. The Iowa 65+ Rural Health Study.
J Chronic Dis 1985; 38: 47581.
27. Waldstein SR. Hypertension and neuropsychological function:
a lifespan perspective. Exp Aging Res 1995; 21: 32152.
28. Kumari M, Brunner E, Fuhrer R. Minireview: Mechanisms by
which the matabolic syndrome and diabetes impair memory.
J Gerontol A Biol Sci Med Sci 2000; 55: B228232.
29. Welsh B, Wecker L. Effects of streptozotocin-induced diabetes
on acetylcholine metabolism in rat brain. Neurochem Res
1991; 16: 45360.
30. Breteler MM, van Swieten JC, Bots ML et al. Cerebral white
matter lesions, vascular risk factors, and cognitive function in
a population based study: the Rotterdam Study. Neurology
1994; 44: 124652.
Received 13 June 2003; accepted in revised form 29 December 2003

Appendix A
Baseline Model
proc mixed method = ml noitprint covtest noclprint;
class id id2; *where zyg = 1;
model mmse = year0/s;
random intercept/sub = id type = un group = zyg; *Level 3
Variance Component;
random intercept year0/sub = id2 (id) type = un gcorr
group = zyg;
repeated/sub = id2 (id) group = zyg;
title MZ Twins: Stacked No covariates;
run;
Model A
proc mixed method = ml noitprint covtest noclprint;
class id id2; *where zyg = 1;
model mmse = year0 age educ sex smok mi ap chf stke
tia hyper hyper*year0/s;
random intercept/sub = id type = un group = zyg; *Level 3
Variance Component;
random intercept year0/sub = id2 (id) type = un gcorr
group = zyg;
repeated/sub = id2 (id) group = zyg;
title MZ Twins: Stacked fixed effects age, education,
sex, smoking, miocardial infarction, angina pectoris,
congestive heart failure, stroke, TIA, hypertension;
run;
Diabetes, hypertension, and cognitive decline
Model B
proc mixed method = ml noitprint covtest noclprint;
class id id2; *where zyg = 1;
model mmse = year0 age educ sex smok mi ap chf stke
tia diab diab*year0/s;
random intercept/sub = id type = un group = zyg; *Level 3
Variance Component;
random intercept year0/sub = id2 (id) type = un gcorr
group = zyg;
repeated/sub = id2 (id) group = zyg;
title MZ Twins: Stacked fixed effects age, education,
sex, smoking, miocardial infarction, angina pectoris,
congestive heart failure, stroke, TIA, diabetes;
run;
Model C
proc mixed method = ml noitprint covtest noclprint;
class id id2; *where zyg = 1;
model mmse = year0 age educ sex smok mi ap chf stke
tia diab*hyper diab*hyper*year0/s;
random intercept/sub = id type = un group = zyg; *Level 3
Variance Component;
random intercept year0/sub = id2 (id) type = un gcorr
group = zyg;
repeated/sub = id2 (id) group = zyg;
title MZ Twins: Stacked fixed effects age, education,
sex, smoking, miocardial infarction, angina pectoris,
congestive heart failure, stroke, TIA, diabetes and
hypertension;
run;
361