ORIGINAL INVESTIGATION

Plasma C Peptide Level and Cognitive Function

Among Older Women Without Diabetes Mellitus
Olivia Okereke, MD, SM; Susan E. Hankinson, ScD; Frank B. Hu, MD, PhD; Francine Grodstein, ScD

Background: Growing evidence suggests that type 2 diabetes mellitus and hyperinsulinemia may be related to
diminished cognition. To help differentiate between the
effects of diabetes and insulin, we examined the relation
of insulin to cognitive function among nondiabetic participants of the Nurses Health Study.
Methods: We measured the C peptide level, representing insulin secretion, in blood samples provided by 718
women from June 14, 1989, to October 4, 1990, when
they were aged 61 to 69 years. We administered telephone interviews an average of 10 years after blood collection, testing general cognition, verbal memory, category fluency, and attention; second cognitive assessments
were conducted 2 years later. The primary outcomes were
global cognitive function across all tests and verbal
memory. We used regression models to estimate multivariable-adjusted mean differences in cognitive function and cognitive decline, and odds of cognitive impairment, across C peptide levels.

Author Affiliations: Division of

Aging (Drs Okereke and
Grodstein) and Channing
Laboratory (Drs Okereke,
Hankinson, and Grodstein),
Department of Medicine,
Brigham and Womens Hospital,
Harvard Medical School,
Boston, Mass; and Departments
of Epidemiology
(Drs Hankinson and Grodstein)
and Nutrition (Dr Hu), Harvard
School of Public Health, Boston.
Financial Disclosure: None.

Results: Cognitive function was worse among women

in the fourth C peptide quartile compared with those in
the first quartile (eg, on the global score combining all
cognitive tests, the multivariable-adjusted mean difference was 1.7 standard units [95% confidence interval,
2.9 to 0.6 standard units]; P =.002); the odds of cognitive impairment (defined as the worst 10% of the distribution) were 3-fold higher among women in the fourth
vs first quartile (95% confidence interval, 1.3-7.8). On
verbal memory, women in the fourth quartile scored significantly worse than those in the first quartile; the odds
of impairment were 2.8-fold higher (95% confidence interval, 1.1-7.0). Consistent findings were observed for cognitive decline.
Conclusion: Higher insulin secretion may be related to
worse cognition, even among those without diabetes.

Arch Intern Med. 2005;165:1651-1656

ALZHEIMER
disease is a public health
priority. Identifying mutable factors in the early
stages of preclinical dementia may be critical to effective prevention.1,2 A small impairment in cognition among healthy older individuals
strongly predicts dementia development,3-5 and may be considered a marker
of preclinical dementia.
Epidemiologic studies6 have identified type 2 diabetes mellitus as an important possible risk factor for diminished cognition. Growing evidence suggests the
impact of diabetes on cognition may not
be due entirely to cerebrovascular damage that often accompanies diabetes; for
example, adjustment for vascular disease
generally has little influence on results.
Moreover, those with type 2 diabetes have
increased hippocampal atrophy (the hippocampus is the key brain region for learning and memory), independent of vascular morbidity, on magnetic resonance
imaging.7 Type 2 diabetes is initially characterized by elevated insulin levels, and
insulin receptors are concentrated in the
ECREASING

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1651

hippocampus.8 In animal and human models,9-11 an elevated insulin level increases

the amyloid (A) level; A accumulation is implicated in the pathogenesis of
Alzheimer disease.12
To explore the effects of insulin independent of diabetes, we examined the relation
of insulin in nondiabetic women in their
early 60s to cognitive function in later life.
METHODS

NURSES HEALTH STUDY

The Nurses Health Study includes 121 700 US
female nurses, aged 30 to 55 years at its inception in 1976. Participants complete biennial
mailed questionnaires updating information on
lifestyle and health. From June 1, 1988, to May
31, 1990, blood samples were requested from
participants, and one third agreed to provide
them.13 Health and lifestyle characteristics were
similar between the whole cohort and those
who returned blood samples (eg, 43% of the
entire cohort vs 46.2% who provided blood
never smoked and the mean alcohol intake was
5 g/d for both groups). Total follow-up for these
women exceeds 98.0%.

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COGNITIVE FUNCTION ASSESSMENT

From February 1995 to July 2001, Nurses Health Study subjects 70 years and older, free of diagnosed stroke, participated
in a telephone cognitive assessment. Of the 95.1% for whom
we had telephone numbers, 93.3% completed the interview
(n=19 395). A follow-up cognitive assessment began 2 years
later and is virtually complete; so far, 92.9% completed follow-up and 7.1% refused or could not be located. Of these
women, 6861 had provided a blood sample. Participation and
follow-up in the cognitive study were similar in those who had
and had not provided blood, suggesting little possibility for bias
in examining associations within those providing blood samples.
In initial interviewing, we used only the Telephone Interview for Cognitive Status (TICS),14 a telephone version of the
Mini-Mental State Examination.15
We gradually added 5 other cognitive tests; thus, the sample
size differs somewhat for each test. We administered the following: immediate and delayed recalls of the East Boston
Memory Test16 to assess verbal memory; a test of category fluency, in which women named animals during 1 minute; a delayed recall of the TICS 10-word list; and digit span backward,
in which women repeated backward increasingly long series
of digits, to evaluate attention and working memory.
The 2 primary outcomes were general cognition and verbal
memory (studies3-5 have established that verbal memory is a
strong predictor of Alzheimer disease development). For assessing general cognition, we considered the TICS, and calculated a global score combining our 6 cognitive tests. This global
score was calculated by summing the z scores for each test. We
calculated a verbal memory score by combining results of the
immediate and delayed recalls of the East Boston Memory Test
and the TICS 10-word list, using z scores. The global and verbal memory scores were only calculated for subjects who completed all component tests. Such composite scores are regularly used in cognitive research17,18 because they integrate
information from various sources and, thus, provide a more
stable representation of cognition than a single test.

VALIDITY AND RELIABILITY

OF TELEPHONE ASSESSMENTS
We found a correlation of 0.81 comparing overall performance on our brief telephone interview with overall performance measured from an in-person interview in welleducated women, establishing high validity of our telephone
method. We also found that the yearly rate of cognitive decline measured in our subjects was quite similar to that observed in a similar cohort using in-person interviews,17 indicating our measurement of decline is valid and accurate. In tests
of instrument reliability, we administered the TICS twice to 61
Nurses Health Study subjects at an interval of 1 month and found
a correlation of 0.70 (P.001).

ASCERTAINMENT OF INSULIN SECRETION

C peptide is cleaved in a 1:1 ratio in the conversion of proinsulin to insulin and provides an accurate representation of insulin secretion.19-21 Although insulin and C peptide are secreted in equimolar amounts, C peptide is not excreted by the
liver and its half-life in the circulation is 2 to 5 times longer
than insulin22; therefore, C peptide is a more stable indicator
of insulin secretion.
As part of nested case-control studies of type 2 diabetes, breast
cancer, and hypertension, C peptide levels were measured in
791 women who also were subjects in the cognitive study.
Blinded quality control specimens were included in each batch
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1652

19 395 Subjects in the Nurses Health Study

Cognitive Study
Participants 70 y
Participants With No History of Stroke

12 534 Excluded Who Did Not Provide Blood

Samples

6861 Subjects With Blood Samples

6070 Excluded Who Did Not Have Plasma C

Peptide Measured

791 Subjects With Plasma C Peptide Measured

73 Excluded Who Had Diabetes Mellitus at Blood

Draw or Were Diabetes Cases in Nested
Case-Control Studies

718 Subjects for Analysis

Figure. Determination of the population for analysis. At each step, women

who were excluded had similar characteristics compared with women who
were included.

of samples to assess variation across batches. C peptide for all

studies was assayed using reagents provided by Diagnostic Systems Laboratory, Webster, Tex. The C peptide level was measured using antiserum M1230 in an alcohol precipitation nonequilibrium assay.23 In blinded quality control tests, we found
an intra-assay coefficient of variation of 2% and an interassay
coefficient of variation of 7%.

POPULATION FOR ANALYSIS

Among women in the cognitive study who had C peptide measured in nested case-control studies of diabetes, breast cancer,
or hypertension, we excluded 73 with diabetes: women who
were cases in the diabetes case-control study and women in the
case-control studies of hypertension and breast cancer who had
been diagnosed as having diabetes as of the blood collection.
Information on diabetes was provided via the biennial mailed
questionnaires. Self-reported diabetes from these nurse participants was 98.2% accurate compared with medical records,
and in 2 random samples of subjects without diagnosed diabetes, less than 2.0% had diagnostic evidence of diabetes in their
blood sample. We did not exclude cases of breast cancer or hypertension, because neither was related to cognition in our data
and because analyses excluding these cases yielded similar results to analyses including them. Thus, analyses presented herein
are based on 718 subjects (Figure).
The characteristics of these 718 women were similar to those
of the entire cognitive study. For example, mean age at cognitive assessment was 74 years in both groups and median body
mass index (calculated as weight in kilograms divided by the
square of height in meters) was 25 in both. For educational attainment, 71.9% had an associates degree and 7.1% an advanced graduate degree among those with C peptide measured,
compared with 77.8% and 5.7%, respectively, in the overall cognitive cohort. Thus, despite using a convenience sample for these
analyses, we did not find a likelihood of any meaningful bias.

STATISTICAL ANALYSIS
In primary analyses, we examined cognition across quartiles
of C peptide. Because of batch-to-batch variation, we calcuWWW.ARCHINTERNMED.COM

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Table 1. Characteristics of the Study Population, According to Plasma C Peptide Quartile

C Peptide Quartile
Variable
Characteristics at blood draw
C peptide level, median, ng/mL
No. of participants
Age, mean, y
Those with a masters or doctorate degree*
Those with a history of hypertension*
Current smoker*
Current postmenopausal hormone use*
Vitamin E use*
Alcohol use, g/d*
0.1-4.9
5.0
Antidepressant use*
Cognitive performance approximately 10 y after blood draw
Category fluency
Digit span backward
East Boston Memory Test
Immediate recall
Delayed recall
TICS
Overall
10-Word list
Immediate recall
Delayed recall

0.60
180
63.9
6.7
16.7
9.5
34.4
25.0

1.02
178
64.1
7.9
23.0
11.2
33.7
24.2

1.44
183
63.7
6.6
33.3
15.9
20.8
10.9

2.61
177
63.9
7.3
42.9
9.6
19.8
16.9

32.2
38.3
6.7

33.7
31.5
4.5

31.1
35.0
1.6

27.7
20.9
4.5

18.1 (5.0)
7.3 (2.5)

16.6 (4.5)
6.5 (2.2)

17.3 (5.2)
7.0 (2.4)

17.1 (4.5)
6.7 (2.5)

9.6 (1.7)
9.2 (1.9)

9.4 (1.9)
8.9 (2.1)

9.6 (1.8)
9.2 (2.3)

9.3 (1.9)
8.8 (2.2)

34.3 (2.6)

33.8 (2.7)

33.9 (2.8)

33.6 (2.9)

4.9 (1.7)
2.9 (2.1)

4.6 (1.6)
2.3 (2.0)

4.7 (1.7)
2.1 (2.0)

4.5 (1.7)
2.2 (2.0)

Abbreviation: TICS, Telephone Interview for Cognitive Status.

SI conversion factor: To convert C peptide to nanomoles per liter, multiply by 0.333.
*Data are given as percentage of subjects.
Data are given as mean (SD).

lated separate quartile cut points for each assay batch. In analyses of cognitive function, we used linear regression to estimate
multivariable-adjusted mean differences in performance across
C peptide quartiles. We also calculated odds ratios of cognitive impairment using logistic regression; cognitive impairment was defined as a TICS score of less than 31 (based on a
preestablished cut point)14 or the bottom 10% of the distribution for the global and verbal memory scores. Such a populationbased 10% cut point is commonly used in cognitive research24
and has high sensitivity and specificity for cognitive impairment.25 We also examined C peptide as a continuous variable;
the unit was a batch-specific 1-SD difference in C peptide level
(average SD, 1.32 ng/mL [0.44 nmol/L]).
We also examined cognitive decline over 2 years. However, this short follow-up is in contrast to the average 10 years
between blood collection and initial cognitive testing; thus, we
likely underestimate relations between baseline C peptide level
and cognitive decline. We used linear regression to calculate
adjusted mean differences in cognitive decline across quartiles of C peptide.
In regression models, we included the following potential confounding variables: age, educational attainment, history of hypertension, postmenopausal hormone therapy, vitamin E supplementation, cigarette smoking, antidepressant use, and alcohol
intake. In analyses of cognitive decline, we also adjusted for cognitive performance at the initial interview and for the interval
between interviews. Information on potential confounding variables was determined as of the time of blood collection.
Several secondary models were constructed. In one, we adjusted for body mass index; this was not included in primary
analyses because body mass index is among the strongest determinants of insulin levels and, thus, inclusion in models would
(REPRINTED) ARCH INTERN MED/ VOL 165, JULY 25, 2005
1653

amount to partial adjustment for our exposure. In other analyses, we adjusted for fasting status at blood draw (75.4% of
samples were fasting) and excluded women diagnosed as having diabetes after the blood collection. We also constructed an
alternative model, controlling for symptoms of depression using continuous scores from a validated mental health index.26
Finally, to consider the influence of C peptide level on subsequent covariate status, we conducted an analysis updating information on potential confounding variables through the initial cognitive interview, rather than the time of blood draw.
RESULTS

There was a broad distribution of C peptide levels among

our subjects (Table 1); the median C peptide level in
the fourth quartile was more than 4 times greater than
that in the first quartile. Characteristics, including age
and educational attainment, were generally similar across
C peptide quartiles. However, the prevalence of hypertension increased with increasing C peptide level, and
women in the third and fourth quartiles of C peptide used
hormone therapy less often than those in the lower quartiles. Compared with women in the first quartile of C peptide, women in the fourth quartile had worse mean performance on all our cognitive tests.
After adjustment for age and educational attainment
(Table 2), we found statistically significantly worse performance on the verbal memory and global scores in the
second through fourth quartiles of C peptide, compared
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Table 2. Mean Differences in Cognitive Function, According to Plasma C Peptide Quartile*

C Peptide Quartile
Cognitive Test
Verbal memory (n = 574)
Age and education adjusted
Multivariable adjusted
P value for trend
TICS (n = 718)
Age and education adjusted
Multivariable adjusted
P value for trend
Global score (n = 574)
Age and education adjusted
Multivariable adjusted
P value for trend

Per SD Increase
in C Peptide

0.3 (0.5 to 0.1)

0.3 (0.5 to 0.0)
.02

0.0
0.0
NA

0.9 (1.6 to 0.3)

0.9 (1.6 to 0.3)
NA

0.7 (1.3 to 0.0)

0.6 (1.3 to 0.0)
NA

1.1 (1.8 to 0.4)

1.0 (1.7 to 0.3)
NA

0.2 (0.4 to 0.0)

0.2 (0.4 to 0.0)
.05

0.0
0.0
NA

0.5 (1.0 to 0.1)

0.5 (1.1 to 0.1)
NA

0.4 (0.9 to 0.2)

0.3 (0.9 to 0.3)
NA

0.6 (1.2 to 0.1)

0.6 (1.2 to 0.0)
NA

0.5 (0.9 to 0.1)

0.4 (0.8 to 0.0)
.03

0.0
0.0
NA

1.9 (2.9 to 0.8)

1.9 (3.0 to 0.9)
NA

1.3 (2.3 to 0.2)

1.2 (2.2 to 0.1)
NA

1.9 (3.0 to 0.9)

1.7 (2.9 to 0.6)
NA

Abbreviations: NA, data not applicable; SD, standard deviation; TICS, Telephone Interview for Cognitive Status.
*Data are given as mean difference (95% confidence interval) unless otherwise indicated.
The verbal memory score combines the results of immediate and delayed recalls of the East Boston Memory Test and the 10-word list; and the global score
combines the results of the TICS, the category fluency test, digit span backward, and immediate and delayed recalls of the East Boston Memory Test and the
10-word list.
The average SD for C peptide is 1.32 ng/mL (0.44 nmol/L).
Adjusted for age (in years), education (associates degree, bachelors degree, or masters or doctoral degree), high blood pressure (yes or no),
postmenopausal hormone therapy (current, past, or never), vitamin E use (yes or no), cigarette smoking (current, past, or never), use of antidepressants (yes or
no), and alcohol intake (in tertiles).

with the first quartile. On the TICS, findings were slightly

weaker, but mean scores among women in the fourth
quartile of C peptide were significantly lower than among
women in the first quartile. Further adjustment for various potential confounding factors had relatively little impact on results. For example, on the global score, after
multivariable adjustment, women in the fourth C peptide quartile scored 1.7 standard units lower than those
in the first quartile (P=.002). To help interpret these mean
differences, we calculated the effect of age on cognitive
performance. In our subjects, women 6 years apart in age
had a mean difference of approximately 1.5 standard units
on the global score; thus, being in the highest quartile
of C peptide seemed cognitively equivalent to aging by
6 years. Furthermore, multivariable-adjusted analyses of
C peptide as a continuous variable also indicated significant trends of worse cognition with increasing C peptide level. Each 1-SD increase in C peptide was associated with a mean difference of 0.4 standard units (P=.03
for trend) on the global score, or the approximate equivalent of aging by 2 years.
Analyses of the odds of cognitive impairment
(Table 3) suggested the potential clinical importance
of these differences in cognitive performance. Women
in the fourth C peptide quartile had statistically significant, roughly 3-fold greater odds of impairment on verbal memory and the global score, compared with women
in the first quartile. In analyses of C peptide as a continuous measure, we found significant trends of 30% to
50% increased odds of cognitive impairment with each
1-SD increase in C peptide level on the verbal memory
and global scores.
In a secondary analysis, we evaluated whether eventual development of diabetes might explain our findings. We excluded all women who developed type 2 diabetes (an additional 35 women) between blood draw and
(REPRINTED) ARCH INTERN MED/ VOL 165, JULY 25, 2005
1654

the initial cognitive assessment, although in fact most such

women were excluded in the primary analyses because
they would have been cases in the nested case-control
study of diabetes; results remained identical. In a separate analysis, we further adjusted for fasting status: C peptide measures are equally valid in fasting and nonfasting
samples, but the absolute values of nonfasting samples
may be slightly higher.27 However, these results were similar to primary findings, as were results excluding nonfasting samples. In analyses adjusted for body mass index, results were attenuated, as expected; nevertheless,
there were significant differences in cognitive performance between those in the fourth vs first C peptide quartile (eg, on the global score, the multivariable-adjusted
mean difference was 1.3 standard units [95% confidence interval, 2.4 to 0.1 standard units]). In addition, in a model further adjusting for depression using
continuous scores from the mental health index, results
were again identical. Finally, in models using covariates
updated through the initial cognitive interview, findings were unchanged.
We had a short period for measuring cognitive decline (2 years), compared with an average 10 years between blood collection and initial cognitive testing. Thus,
we likely underestimate the relation of C peptide level
to cognitive decline. However, there was a suggestion of
greater decline in performance with increasing C peptide level, generally supporting our findings from the initial cognitive testing. On the global score, after multivariable adjustment, there was a mean difference in decline
of 0.5 standard units (95% confidence interval, 1.4 to
0.4 standard units) comparing the fourth with the first
C peptide quartile, with a borderline significant trend of
worse rates of decline with increasing C peptide quartile (P =.1) (data not shown).
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Table 3. Risk of Cognitive Impairment, According to Plasma C Peptide Quartile

C Peptide Quartile
Cognitive Test*
Verbal memory (n = 574)
No. of cases of impairment
Multivariable-adjusted OR (95% CI)
P value for trend
TICS (n = 718)
No. of cases of impairment
Multivariable-adjusted OR (95% CI)
P value for trend
Global score (n = 574)
No. of cases of impairment
Multivariable-adjusted OR (95% CI)
P value for trend

Per SD Increase
in C Peptide

NA
1.3 (1.1-1.7)
.02

8
1.0
NA

14
1.9 (0.7-4.8)
NA

14
1.8 (0.7-4.6)
NA

19
2.8 (1.1-7.0)
NA

NA
1.1 (0.9-1.4)
.40

13
1.0
NA

21
1.7 (0.8-3.5)
NA

14
1.0 (0.4-2.2)
NA

17
1.2 (0.5-2.7)
NA

NA
1.5 (1.2-1.8)
.001

8
1.0
NA

17
2.3 (0.9-5.6)
NA

11
1.3 (0.5-3.4)
NA

22
3.2 (1.3-7.8)
NA

Abbreviations: CI, confidence interval; NA, data not applicable; OR, odds ratio; SD, standard deviation; TICS, Telephone Interview for Cognitive Status.
*The verbal memory score combines the results of the immediate and delayed recalls of the East Boston Memory Test and the 10-word list; and the global
score combines the results of the TICS, the category fluency test, digit span backward, and immediate and delayed recalls of the East Boston Memory Test and the
10-word list.
The average SD for C peptide is 1.32 ng/mL (0.44 nmol/L).
Adjusted for age (in years), education (associates degree, bachelors degree, or masters or doctoral degree), high blood pressure (yes or no),
postmenopausal hormone therapy (current, past, or never), vitamin E use (yes or no), cigarette smoking (current, past, or never), use of antidepressants (yes or
no), and alcohol intake (in tertiles).

COMMENT

Among women without diabetes, we found significantly

worse cognitive function for those with higher compared
with lower levels of C peptide. These findings persisted after adjustment for covariates, at blood draw and subsequent to blood draw, and persisted after exclusion of women
who developed diabetes during the average 10 years between blood draw and cognitive testing. Specifically, being
in the highest C peptide quartile seemed cognitively equivalent to aging by 6 years, and was associated with up to a
3-fold increased odds of cognitive impairment.
There are several possible explanations for these findings. An elevated insulin level and diminished cognition
may share some common underlying cause, rather than
having a direct relation to each other. Alternatively, higher
insulin secretion, even before the development of diabetes, may lead to vascular damage and, thus, be an indirect
source of cognitive impairment. However, accumulating
evidence suggests a direct link between insulin level and
cognition. A high insulin level may inhibit neuron firing28 and decrease the activity of choline acetyltransferase,29 an enzyme involved in forming neurotransmitters
regulating memory and learning. In vitro studies11 indicate insulin causes a 3- to 4-fold increase in extracellular
A levels. The insulin-degrading enzyme provides a further possible link between insulin and A levels. The
insulin-degrading enzyme is primarily responsible for insulin degradation,30 but also degrades A.31,32 In mice,
insulin-degrading enzyme deficiency was associated with
greater than 50% reduction in A degradation, and cerebral A accumulation was increased by up to 64% (the mice
also developed a diabetic phenotype).10 Insulin binds more
readily to insulin-degrading enzyme30 than other substrates, and is a competitive inhibitor of A degradation;
a recent investigation of 16 healthy older adults9 found that,
(REPRINTED) ARCH INTERN MED/ VOL 165, JULY 25, 2005
1655

on infusion of insulin, cerebrospinal fluid A levels increased by 15% (P=.02).

Although relatively few large-scale epidemiologic studies have addressed this issue, existing data are consistent with our finding of a relation of elevated insulin level
to cognition in nondiabetic persons.33-38 In a prospective cohort, 297 prediabetic women (fasting glucose level,
110 but 126 mg/dL [6.1 but 7.0 mmol/L]) had a
significantly elevated risk of developing cognitive impairment (odds ratio, 1.64; 95% confidence interval, 1.032.61) compared with women with a normal glucose level.38
Among 386 nondiabetic men,33 those in the highest quartile of fasting insulin level had 25% more errors on the
Mini-Mental State Examination compared with those in
the lowest quartile (95% confidence interval, 4%-50%;
P =.02 for trend across quartiles). Stolk and colleagues34
observed a steady and significant decrease in mean MiniMental State Examination score with increasing postload serum insulin level among 3278 women without dementia; results remained similar after excluding diabetic
persons. Among 1897 older women without diabetes,
there was a 30% increased risk of developing cognitive
impairment with each 1% increase in glycosylated hemoglobin level,35 a measure of glucose control.
Several limitations of our study should be considered.
We used self-reports to exclude those with diabetes and,
consequently, may have included women with undiagnosed diabetes; thus, our findings could be driven in part
by the association between diabetes and cognition. However, undiagnosed diabetes is likely rare in these health
professionals; virtually all our participants have access to
health care. In a random sample of 200 participants who
never reported diabetes, we found only 1 had a plasma fasting glucose or fructosamine level in the diabetic range; in
another such test, only 1.8% had elevated levels of glycosylated hemoglobin. In addition, we found strong relaWWW.ARCHINTERNMED.COM

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tions of C peptide level to cognition in analyses excluding anyone reporting diabetes in the 10 years subsequent
to blood draw, likely eliminating most women who may
have had undiagnosed diabetes at blood draw.
An additional weakness was the brief period for assessing change in cognition. Nevertheless, our findings on cognitive decline, although nonsignificant, generally supported results from the initial cognitive testing, and
suggested adverse cognitive effects of elevated C peptide
level. Moreover, C peptide measures were taken among
young-old womenan average 10 years before initial cognitive testingand follow-up of the blood cohort was more
than 98.0% complete; thus, analyses of the initial cognitive scores can be considered a reasonable representation
of change in cognition since blood draw.
Finally, confounding is an important concern. However,
we collected detailed data on potential confounding factors
over many years, and adjusted for a wide array of covariates. Multivariable adjustment had relatively little impact
on effect estimates, rendering it less likely that residual or
uncontrolledconfoundingcouldcompletelyexplainthesubstantially worse cognitive performance we observed with
higher C peptide levels. In addition, the relative homogeneity of the cohort reduces the potential influence of some
unmeasured confounders (eg, access to health care or health
knowledge). Finally, random misclassification of cognitive
performance is possible. However, we have established high
validity of our telephone instrument. Furthermore, composite scores (averaging several cognitive test results) help
reduce random misclassification. Nevertheless, findings for
the TICS, our only primary outcome that was not a composite, may underestimate effects of C peptide.
Overall, increasing evidence suggests that insulin level
may have a direct effect on cognitive function. Further research is clearly necessary to confirm findings in our study
and others, and to establish whether the apparent effects
ofinsulinoncognitionareindeeddirect.Suchresearchcould
have a large influence on public health, especially given the
growing epidemic of obesity, which is often accompanied
by insulin resistance and increased insulin levels.
Accepted for Publication: March 24, 2005.
Correspondence: Olivia Okereke, MD, SM, Channing
Laboratory, 181 Longwood Ave, Third Floor, Boston, MA
02115 (ookereke@partners.org).
Funding/Support: This study was supported by grants
AG15424, CA49449, and CA40356 from the National Institutes of Health, Bethesda, Md.
Role of the Sponsor: The funding body had no role in data
extraction and analyses, in the writing of the manuscript,
or in the decision to submit the manuscript for publication.
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