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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-1325
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 11 4306-4312
Copyright © 2006 by The Endocrine Society

Midlife Plasma Insulin-Like Growth Factor I and Cognitive Function in Older Men

Olivia I. Okereke, Jae H. Kang, Jing Ma, J. Michael Gaziano and Francine Grodstein

Division of Aging (O.I.O., J.M.G., F.G.) and Channing Laboratory (O.I.O., J.H.K., J.M., F.G.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, and the Department of Epidemiology (F.G.), Harvard School of Public Health, Boston, Massachusetts 02115; and the Veterans Affairs Boston Healthcare System (J.M.G.), Jamaica Plain, Massachusetts 02130

Address all correspondence and requests for reprints to: Dr. Olivia Okereke, Channing Laboratory, 3rd Floor, 181 Longwood Avenue, Boston, Massachusetts 02115. E-mail: ookereke{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Emerging biological and epidemiological evidence suggests possible benefits of higher IGF-I levels in cognitive aging.

Objective: The objective of the study was to examine the relation of midlife plasma IGF-I levels to late-life cognition.

Design, Setting, and Participants: We conducted a secondary analysis from the Physicians’ Health Study II, a prospective cohort of U.S. male physicians. Participants provided blood samples from 1982 to 1984 (mean age 57 yr). Using stored samples, we measured free IGF-I in 376 men and total IGF-I and IGF binding protein-3 in 460 men. Starting in 2001, we administered telephone-based tests of general cognition [the Telephone Interview of Cognitive Status (TICS)], verbal memory, and category fluency. We estimated multivariable-adjusted mean differences in cognitive performance across levels of free IGF-I and IGF-I to IGF binding protein-3 molar ratio.

Main Outcome Measures: Global score (averaging performance across all individual cognitive tests), the TICS, and a verbal memory score were measured.

Results: Each SD increment in free IGF-I was associated with a multivariable-adjusted increase of 0.08 U (P = 0.02) on the global score. This mean difference was equivalent to that observed between men 2 yr apart in age: i.e. each SD increase in free IGF-I appeared cognitively equivalent to staying 2 yr younger. No significant mean differences in TICS scores were observed across free IGF-I levels. For verbal memory, each SD increment in free IGF-I was associated with an adjusted mean difference of 0.08 U (P = 0.03). Results appeared consistent for the molar ratio but were not statistically significant.

Conclusion: Higher midlife free IGF-I may be associated with better late-life cognition.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AS THE PROPORTION of older persons continues to rise, reducing the burden of age-related conditions, such as cognitive decline and Alzheimer’s disease (AD), takes on increasing importance. Successful prevention of cognitive decline requires understanding the mechanisms whereby changes in cognitive function may occur, especially those that are important at the very earliest stages of this process and may be most amenable to intervention.

Recent literature has addressed the role of growth factors in relation to a variety of neurological diseases, including AD (1, 2, 3). In particular, IGF-I has been a focus of both biological and epidemiological study regarding its potential protective role in neurodegenerative diseases (4). Raising blood IGF-I levels via parenteral IGF-I infusions has been shown to reduce brain amyloid-ß (Aß) (the toxic peptide in AD plaques) in rodents (5, 6) and improve learning and memory of transgenic mice expressing the AD phenotype (5). In addition, limited epidemiological data, largely from small-scale studies, suggest that higher total IGF-I levels may be associated with better cognitive performance (7, 8, 9, 10, 11) and lower risk of cognitive decline (12, 13) in older individuals. Nevertheless, bioavailable IGF-I seems most likely to impact cognition (IGF-I binds to brain IGF receptors in its free, or unbound, form) (14); thus, free IGF-I levels, or perhaps the molar ratio of total IGF-I to its principal binding protein [IGF binding protein (IGFBP)-3], are likely important in determining the full impact of IGF-I. Only one previous study has explored the association between free IGF-I and cognitive function (13); none have specifically assessed the role of midlife free IGF-I levels, although a large body of evidence indicates that cognitive decline takes decades to develop and thus factors earlier in life may have the most significant impact (15, 16, 17). To explore these issues further, we examined the relation between IGF-I levels, using measures of both free IGF-I as well as IGF-I to IGFBP-3 molar ratio, and cognition in a cohort of community-dwelling male participants of the Physicians’ Health Study (PHS) II.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
PHS II

The original PHS was a randomized, double-blind, factorial trial of aspirin and ß-carotene in the primary prevention of cardiovascular disease and cancer among 22,071 U.S. male physicians, who were aged 40–84 yr and had no history of cancer or cardiovascular disease at study baseline in 1982 (18, 19). The PHS II began in 1995 and is an extension of the PHS, examining treatment with vitamin supplements (20). Of the original PHS participants, 7641 enrolled in PHS II and continue to be followed up with annual questionnaires that update information on health status and lifestyle variables; to date, overall follow-up of the PHS II trial is 97%. Cognitive testing via telephone interviews began in 2001 among PHS participants who had continued into PHS II and were aged 65 yr or older as of January 2001; we achieved 88% participation among the 4602 men eligible for cognitive testing.

Blood collection

Between 1982 and 1984, 68% of PHS participants agreed to provide blood samples (21). Before randomization, the men were mailed venipuncture kits with detailed instructions. Participants had their blood drawn into EDTA Vacutainer tubes, fractionated the blood by centrifugation, and returned the samples (in cryopreservation vials with cold packs) by overnight courier to the laboratory, where they were divided into aliquots and stored at –82 C; the vast majority of samples arrived within 26 h of being drawn, and precautions were taken to prevent thawing of specimens during storage (22, 23).

Ascertainment of IGF-I measures

As part of nested case-control studies of colon and prostate cancers, we measured free IGF-I and total IGF-I and IGFBP-3 by ELISA in the laboratory of Dr. Michael Pollak (McGill University, Montréal, Québec, Canada) using reagents provided by Diagnostic Systems Laboratory (Webster, TX). Blinded quality control specimens were used to calculate coefficients of variation (CVs). For free IGF-I, our intraassay CVs were 5.4 and 10.1% (n = 2 batches); for total IGF-I and IGFBP-3, intraassay CVs ranged from 2.9–4.8% and 2.5–8.9%, respectively (n = 5 batches). Details of the assay methods have been published previously (24, 25).

Using a single blood sample to represent plasma IGF levels

Because we used results from a single blood collection at midlife, it was important to establish that these samples accurately represent participants’ IGF-I levels during midlife. First, IGF-I and IGFBP-3 levels appear stable after long-term frozen storage at –80 C (26). Second, the concentration of IGF-I does not undergo diurnal variation (27), and there is no evidence of seasonal variation in IGF-I (28). In addition, we found that total IGF-I and IGFBP-3 measures obtained twice over 5 yr were highly correlated (r = 0.70 to 0.75) in a sample of 49 PHS participants (Pollack, M., J. Ma, unpublished results cited in Ref. 22). Thus, there is strong evidence that our one-time measures of IGF-I and IGFBP-3 should reasonably represent participants’ midlife levels. The free IGF-I measure likely is similarly representative; however, the assay was only recently developed (24), and we lack comparable reliability data for free IGF-I.

Finally, one of the best arguments for validity of a single sample is its ability to predict disease risk over many years. After 14 yr of follow-up, PHS participants with higher baseline plasma IGFBP-3 levels had substantially lower risk of colorectal cancer [relative risk (RR) 0.28; 95% confidence interval (CI) 0.12–0.66, comparing extreme quintiles] (23). In another case-control study within the prospective DAN-MONICA (DANish MONItoring trends and determinants in CArdiovascular disease) I cohort, Juul and coworkers used frozen samples to identify significant associations between low circulating IGF-I and high IGFBP-3 levels and increased risk of ischemic heart disease over 15 yr of follow-up [RR of 1.94 (95% CI 1.03–3.66) and 2.16 (95% CI 1.18–3.95), respectively, comparing extreme quartiles] (30).

Cognitive function assessment

In the cognitive interview, we used the Telephone Interview of Cognitive Status (TICS) (31), a telephone adaptation of the Mini-Mental State Examination (MMSE) (32). Extensive studies of the TICS have established its high reliability and high sensitivity and specificity for detecting cognitive impairment (31). We also included four other cognitive tests: immediate and delayed recalls of the East Boston Memory Test (EBMT) (33); delayed recall of the TICS 10-word list for assessment of verbal memory; and a category fluency test, in which men were asked to name as many different animals as they could in 1 min.

Reliability and validity of telephone assessments

We conducted reliability and validity studies of our cognitive instruments in a sample of similarly highly educated, high-functioning health professionals. In tests of interinterviewer reliability (interviewers all scored the same cognitive assessment), we found correlations 0.95 or greater across interviewers on each test. Furthermore, we observed excellent test-retest reliability (r = 0.70) of TICS scores for subjects tested twice, 31 d apart. Lastly, we found a Pearson correlation of 0.81 comparing overall performance on our telephone interview with overall performance on an in-person cognitive battery, establishing validity of our telephone method.

Population for analysis

Of participants in the cognitive study, 413 men had also been participants in case-control studies of cancers and thus had free IGF-I measurements. We excluded the small number of men older than 65 yr at blood draw because our objective was to assess midlife levels. We also excluded those with diagnosed diabetes at the time of blood draw because IGF-I may be related to type 2 diabetes (34), and diabetes may elevate risk of cognitive impairment (35). Thus, analyses of free IGF-I were based on 376 participants (Fig. 1Go). For analyses of the IGF-I to IGFBP-3 molar ratio, there were 568 cognitive study participants who had measures of total IGF-I and IGFBP-3 available. We applied the same exclusion criteria as for free IGF-I; thus, analyses of molar ratio were based on 460 participants.


Figure 1
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  		FIG. 1. Determination of population for analysis of free IGF-I and cognitive function.

 
Characteristics of the 376 men in our sample with free IGF-I measures and the 460 men in our sample with total IGF-I and IGFBP-3 measures were quite similar to those of participants in the entire cognitive study. For example, for all three groups, mean age at PHS randomization was 56 yr, mean body mass index was 25 kg/m2, and mean TICS score was 34.3 points. For both the 376 men with free IGF-I values and the 460 men with total IGF-I and IGFBP-3 measures, the proportion of current smokers was 8%; in the entire cognitive study, 9% were current smokers. Among the 376 men with free IGF-I measures, 21.9% had hypertension and 12.8% had dyslipidemia, and those proportions were 21.2 and 12.0%, respectively, among the 460 men with total IGF-I and IGFBP-3 measures; in the entire cognitive study, 21.3% had hypertension and 12.5% had dyslipidemia. Thus, despite using a convenience sample for these analyses, we found low likelihood of any meaningful bias.

This study was approved by the Human Subjects Committee/Institutional Review Board of Brigham and Women’s Hospital (Boston, MA).

Statistical analysis

Because it is a measure of readily bioavailable IGF-I, we analyzed free IGF-I as our primary variable of interest. In addition, we analyzed the total IGF-I to IGFBP-3 molar ratio because this value may also reflect the amount of unbound and potentially biologically active IGF-I (23, 36).

The two primary outcomes for this study were general cognition and verbal memory because studies have established that verbal memory is a strong predictor of AD development (37, 38). For examining general cognition, we considered the TICS as well as a global score that we calculated by averaging the z-scores for each of the five cognitive tests. For verbal memory, we calculated a composite score by averaging the z-scores from the immediate and delayed recalls of the EBMT and 10-word list. Composite scores are regularly used in cognitive research (39, 40) because they integrate information from a variety of sources and provide a more stable representation of cognition than a single test.

In analyses, we examined free IGF-I and IGF-I to IGFBP-3 molar ratio as continuous variables of 1 SD units; we also created tertiles to address possible threshold associations, which have been observed in previous studies of IGF-I and cognitive function (12) as well as other conditions in older persons (41, 42). Although there was no evidence of batch-to-batch variation in measures of free IGF-I, there was evidence of laboratory drift across batches of total IGF-I and IGFBP-3; therefore, we created batch-specific z-scores (for continuous analyses) and tertiles of the molar ratio and total IGF-I (22).

We used linear regression models to evaluate the mean differences in cognition across levels of IGF-I. In regression models, we adjusted for a variety of covariates that may influence IGF-I and cognition (43). We included the following potential confounders: age at cognitive assessment, history of hypertension, history of dyslipidemia, cigarette smoking, alcohol intake, body mass index, and history of depression as of cognitive assessment. All models were adjusted for cancer case/control status in the case-control investigations of IGFs and cancer. Apart from age and depression, information on all potential confounders was obtained as of the time of blood collection; specifically, for age and depression, we believed that status proximate to the cognitive assessment was most relevant.

Secondary analyses were also conducted. First, we added physical activity to the model because this has been modestly associated with IGF-I levels (44) and may also affect cognitive function (45). Second, we adjusted multivariable models for fasting status (≥8 h since last meal: yes, no; ~20% of our samples were fasting), although this may be less important for IGF-I and IGFBP-3 than IGFBP-1 (46). Third, although we excluded men with type 2 diabetes as of blood draw, we also considered the possible influence of diabetes status over the nearly 20 yr of follow-up after blood draw; thus, we conducted a separate analysis excluding all men who developed type 2 diabetes between blood draw and cognitive assessment. Fourth, to evaluate the influence of potential confounders during the lengthy follow-up, we conducted an analysis in which information on potential confounders was updated through the time of the cognitive interview rather than at blood draw. We also conducted a separate analysis excluding all cancer cases from the nested case-control studies of prostate and colon cancers to ensure that findings were not biased by the disproportionate number of cancer cases in the analytical population. Finally, given previous reports suggesting a relation to cognitive performance, we considered levels of total IGF-I itself and further adjusted for the presence of IGFBP-3 in addition to the other covariates.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
There was a broad distribution of free IGF-I levels (Table 1Go); median free IGF-I level in the top tertile was more than twice that in the bottom tertile. Participants with higher free IGF-I tended to be healthier at blood draw: for example, they had lower prevalence of hypertension, current smoking, dyslipidemia, and depression; thus, we adjusted for all these variables.


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  		TABLE 1. Characteristics of the study population at blood draw, according to tertiles of plasma free IGF-I levels1

 
After adjustment for age, we found significant differences on the global and verbal memory scores for those with higher vs. lower levels of free IGF-I (Table 2Go). On the global score, men in the bottom tertile scored –0.18 standard units (95% CI –0.35, – 0.02) lower than those in the top tertile. There was a significant trend of better performance on the global score with each SD increment of free IGF-I (P-trend = 0.01). To help interpret these mean differences, we compared the effect estimates for the relation of free IGF-I and cognition to the effect estimates we observed for the relation of age and cognition: the mean difference in global score with each SD increase in free IGF-I was equivalent to that observed on the global score between men 2 yr apart in age. Similarly, on verbal memory, the age-adjusted mean difference between the bottom and top tertiles of free IGF-I was –0.18 U (95% CI –0.36, – 0.01), and there was a significant trend of better performance with increasing free IGF-I (P-trend = 0.01). Estimates for global score and verbal memory were highly consistent after multivariable adjustment. On the TICS, there were no significant mean differences across levels of free IGF-I. When we examined the IGF-I to IGFBP-3 molar ratio, we found generally lower mean cognitive performance among men in the lower tertiles of molar ratio (Table 3Go); however, results were not statistically significant.


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  		TABLE 2. Adjusted mean differences in cognitive performance across levels of free IGF-I

 

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  		TABLE 3. Adjusted mean differences in cognitive performance across levels of IGF-I to IGFBP-3 molar ratio

 
In a secondary analysis of total IGF-I, mean scores were lower in the first and second tertiles, compared with the top tertile (data not shown in table); however, findings were not statistically significant. For example, the multivariable-adjusted mean differences in verbal memory were –0.15 U (95% CI –0.34, 0.05) and –0.15 U (95% CI –0.32, 0.01) in the first and second total tertiles, respectively.

We conducted several secondary analyses to test the robustness of the findings for free IGF-I. In a secondary analysis of the relation of free IGF-I levels to cognitive performance with additional adjustment for physical activity, results were identical; for example, on both the global and verbal memory scores, each SD increment in free IGF-I was significantly associated with a multivariable-adjusted mean increase of 0.08 U. Results were also highly similar after additional adjustment for fasting status. When we evaluated whether eventual development of diabetes might partly explain our findings, results remained unchanged after excluding men newly diagnosed with diabetes between blood collection and cognitive testing (n = 352 after excluding additional diabetes cases). In analyses that both excluded new diabetes cases during follow-up and updated covariate status through the cognitive interview, we again obtained similar results: for example, with each SD increment of free IGF-I, there was a statistically significant mean increase of 0.08 U on both the global and verbal memory scores. Lastly, after excluding all men who were cancer cases in the nested case-control studies for which IGF measures were obtained (n = 229 participants after excluding cancer cases), estimates remained consistent: e.g. each SD increment in free IGF-I was associated with a multivariable-adjusted mean difference on the global score of 0.08 U (95% CI –0.01, 0.17).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We found that midlife levels of free IGF-I were positively related to cognitive performance an average 18 yr later in these older men. Specifically we observed significant linear trends of better performance on the global and verbal memory scores with each SD increment in free IGF-I. The mean difference in cognitive performance that we found with each SD increment in free IGF-I was equivalent to the mean difference in performance observed between men 2 yr apart in age; thus, each 1 SD higher level of free IGF-I appeared cognitively equivalent to remaining 2 yr younger. Findings persisted after adjustment for a variety of potential confounders, including health and lifestyle factors. Importantly, our results add to the growing interest in midlife predictors of cognitive impairment: free IGF-I levels measured when the men were middle aged were associated with their cognitive performance nearly 20 yr later, indicating that variables that influence cognitive function may begin acting fairly early in life.

We found a suggestion of a relation between the total IGF-I and the IGF-I to IGFBP-3 molar ratio and cognitive performance, but results did not achieve statistical significance. Of note, the molar ratio is thought to reflect bioavailable IGF-I, and thus may be considered as comparable to free IGF-I levels. However, ascertainment of the molar ratio requires measurement of both total IGF-I and IGFBP-3; thus, there are two sources of measurement error, as opposed to one for the single measure of free IGF-I. Another complicating factor was laboratory drift over time for the assays of both total IGF-I and IGFBP-3. Together, these extra sources of variability may have rendered it more difficult to detect relations to cognition, especially with a modest sample size. Nevertheless, although statistically nonsignificant, the pattern of lower mean scores in the first and second tertiles of molar ratio and total IGF-I was consistent with those observed across tertiles of free IGF-I.

Growing biological evidence supports our finding of a relation between free IGF-I and cognition. IGF-I plays a significant part in human development, including brain development and function (6); accumulating data emphasize its potential role in cognitive aging. IGF-I is produced locally in the brain and also passes from circulation into the brain via the blood-brain barrier (4, 47). IGF-I in its free form binds IGF-I receptors, which are distributed differentially in the brain, with the highest density of receptors in the hippocampus and parahippocampal structures (48), a brain region essential for memory and particularly associated with cognitive deficits in dementia. IGF-I has been shown to increase hippocampal neurogenesis (49); also, IGF-I treatment of cultured rat neurons has been shown both to decrease amyloid-induced toxicity and reverse early indicators of degeneration in cells pretreated with harmful Aß fragments (50). Biological evidence for a neuroprotective role of IGF-I extends beyond direct treatment of brain cells: elevating blood IGF-I levels via parenteral IGF-I injections has been shown to reduce brain Aß burden in mice (5) and rats (6) and reverse spatial learning and memory deficits in transgenic mice with Alzheimer pathology (5).

There are limited larger-scale epidemiological data (12, 29) on the role of IGF-I in late-life cognition, and findings are somewhat mixed (perhaps due to the lack of data on bioavailable IGF-I); nevertheless, the literature suggests an association of higher IGF-I levels with better cognition (7, 8, 9, 11). For example, in the largest investigation, Dik et al. (12) observed the relation of total IGF-I (IGFBPs were not measured) to 3-yr cognitive decline among 1318 men and women aged 65–88 yr. They identified a threshold effect, with a significantly increased risk of decline in information processing speed among those in the bottom quintile, compared with those in quintiles II-V (RR 1.78; 95% CI 1.19–2.68); interestingly, total IGF-I was not related to decline in other cognitive tests, including the MMSE and immediate and delayed verbal recall.

Few studies additionally adjusted for the presence of binding protein, examined the IGF-I to IGFBP-3 molar ratio (10, 13, 29) or directly measured free IGF-I (13). However, Kalmijn et al. (13) reported that each SD increase in total IGF-I and IGF-I to IGFBP-3 molar ratio yielded 35 and 41% RR reductions for decline, respectively, on the MMSE among 186 older adults. In a cohort of 590 older, female health professionals, Okereke et al. (29) found a significant relation between general cognitive performance and both the molar ratio and total IGF-I controlled for IGFBP-3. In the only previous examination of free IGF-I (13), Kalmijn et al. (13) did not observe an association between free IGF-I levels and decline on the MMSE among 186 older men and women; midlife levels were not obtained. Overall, data are clearly limited but suggest the need for further research into the relation of free IGF-I and cognition, especially IGF-I levels at midlife, when cognitive decline may be most amenable to intervention.

Several limitations of our study should be considered. As in any observational study, confounding is an important concern. Thus, we collected detailed data on potential confounders 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 uncontrolled confounding could completely explain the significantly worse cognitive performance we observed among those with the lowest free IGF-I levels. In addition, the relative homogeneity of the cohort reduces the potential influence of some unmeasured confounders (e.g. access to health care, health knowledge). Misclassification of both IGF-I levels and cognitive performance should also be considered. In particular, the IGF-I to IGFBP-3 molar ratio was susceptible to random misclassification of IGF status: there was more batch-to-batch variation observed for the molar ratio (compared with free IGF-I), and the molar ratio is composed of two different measurements, which would also tend to increase measurement error; such random misclassification could bias results toward the null. Random misclassification may also have influenced measurement of cognitive function. However, our use of composite scores likely reduces such error by averaging performance across several tests: e.g. although the TICS and global score both serve as measures of general cognition, findings for the relation between free IGF-I and cognition were stronger on the global score than the TICS.

Overall, this report provides evidence that circulating IGF-I levels at midlife may be related to late-life cognition. Additional work is required to further understand this association, discern the possible differential impact of total vs. free IGF-I, and better elucidate the mechanisms by which IGF-I may influence cognitive aging.


   Footnotes
 
This work was supported by Grants AG15933, AG24215, CA97193, and CA42182 from the National Institutes of Health. O.I.O. is supported by an R01 Minority Supplement to Grant AG24215.

Disclosure summary: O.I.O., J.H.K., J.M., and F.G. have nothing to declare. J.M.G. has received investigator-initiated grants from BASF, DMS Pharmaceuticals, Wyeth Pharmaceuticals, McNeil Consumer Products, and Pliva. J.M.G. consults for McNeil Consumer Products, Wyeth Pharmaceuticals, Merck, Nutraquest, and GlaxoSmithKline. J.M.G. has received honoraria from Bayer and Pfizer for speaking engagements.

First Published Online August 15, 2006

Abbreviations: Aß, Amyloid-ß; AD, Alzheimer’s disease; CI, confidence interval; CV, coefficient of variation; EBMT, East Boston Memory Test; IGFBP, IGF binding protein; MMSE, Mini-Mental State Examination; PHS, Physicians’ Health Study; RR, relative risk; TICS, Telephone Interview of Cognitive Status.

Received June 21, 2006.

Accepted August 9, 2006.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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