BMJ  2004;328:548 (6 March), doi:10.1136/bmj.37977.495729.EE (published 23 February 2004)

Paper

Prospective study of type 2 diabetes and cognitive decline in women aged 70-81 years

¹ Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA, ² Channing Lab, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

Abstract

Objective To examine the association of type 2 diabetes with baseline cognitive function and cognitive decline over two years of follow up, focusing on women living in the community and on the effects of treatments for diabetes.

Design Nurses' health study in the United States. Two cognitive interviews were by carried out by telephone during 1995-2003.

Participants 18 999 women aged 70-81 years who had been registered nurses completed the baseline interview; to date, 16 596 participants have completed follow up interviews after two years.

Main outcome measures Cognitive assessments included telephone interview of cognitive status, immediate and delayed recalls of the East Boston memory test, test of verbal fluency, delayed recall of 10 word list, and digit span backwards. Global scores were calculated by averaging the results of all tests with z scores.

Results After multivariate adjustment, women with type 2 diabetes performed worse on all cognitive tests than women without diabetes at baseline. For example, women with diabetes were at 25-35% increased odds of poor baseline score (defined as bottom 10% of the distribution) compared with women without diabetes on the telephone interview of cognitive status and the global composite score (odds ratios 1.34, 95% confidence interval 1.14 to 1.57, and 1.26, 1.06 to 1.51, respectively). Odds of poor cognition were particularly high for women who had had diabetes for a long time (1.52, 1.15 to 1.99, and 1.49, 1.11 to 2.00, respectively, for 15 years' duration). In contrast, women with diabetes who were on oral hypoglycaemic agents performed similarly to women without diabetes (1.06 and 0.99), while women not using any medication had the greatest odds of poor performance (1.71, 1.28 to 2.281, and 1.45, 1.04 to 2.02) compared with women without diabetes. There was also a modest increase in odds of poor cognition among women using insulin treatment. All findings were similar when cognitive decline was examined over time.

Conclusions Women with type 2 diabetes had increased odds of poor cognitive function and substantial cognitive decline. Use of oral hypoglycaemic therapy, however, may ameliorate risk.

Introduction

Many investigations have examined diabetes in relation to early cognitive decline, but only one large prospective study has focused on women.¹ Type 2 diabetes disproportionately affects older women and is a stronger risk factor for cardiovascular disease in women than in men.² Cardiovascular disease is also an independent risk factor for cognitive decline. Moreover, few studies have evaluated the influence of different treatments for diabetes on the association between type 2 diabetes and cognition.

We assessed the associations between type 2 diabetes, different treatments for diabetes, and cognitive function in more than 16 000 women.

Methods

The nurses' health study is a prospective cohort of 121 700 US female registered nurses who were aged 30-55 years in 1976, when the study began. From 1995-2001, participants aged 70 years and older who had not had a stroke were given baseline cognitive assessments by telephone. Overall, 93% completed the interview. Interviewers were blinded to participants' health status (including diabetes). For the baseline analyses of cognitive function, we included 18 999 women with complete information on education and without type 1 diabetes, gestational diabetes, or unconfirmed diabetes.

The follow up cognitive assessment began about two years after the baseline interview. For analyses of cognitive decline, we included 16 596 participants who completed both assessments, excluding women who had died, refused, or were unreachable or in whom diabetes had been newly diagnosed between the baseline and second interviews.

Assessment of cognitive function
Our cognitive assessment has been previously described and has high reliability and validity.³ Briefly, we initially administered only the telephone interview for cognitive status (TICS)⁴ but gradually added more tests: immediate and delayed recalls of the East Boston memory test, test of verbal fluency, digit span backwards, and delayed recall of a 10 word list. To summarise performance, we calculated a global score averaging results of the six tests using z scores (16 563 women completed all six tests).

Ascertainment of type 2 diabetes
We identified women who reported that diabetes had been diagnosed by a physician before the baseline cognitive interview. We then confirmed reports based on responses to a supplementary questionnaire including complications, diagnostic tests, and treatment. Validation studies found 98% concordance of participants' reports of type 2 diabetes with medical records.⁵ We estimated duration of diabetes by subtracting date of diagnosis from date of baseline cognitive interview. We obtained information on recent drug treatment for diabetes from the biennial questionnaire of the nurses' health study before the baseline interview.

Statistical analyses
Baseline analyses—We examined the relation between type 2 diabetes and cognitive performance by comparing "poor scorers" to remaining women. "Poor scorers" on the TICS were those who scored < 31 points (a pre-established cut-off point³); on other tests, we defined poor scorers as those below the lowest 10th centile. Multivariate adjusted odds ratios of a poor score and 95% confidence intervals were calculated with logistic regression models. We also analysed scores continuously using multiple linear regression to obtain adjusted differences in mean score between women with and without diabetes.

Analyses of cognitive decline—We used logistic regression to calculate odds ratios of "substantial decline," defined as the worst 10% of the distribution of change from the baseline to the second interview. We also used linear regression to estimate adjusted mean differences in decline by diabetes status.

Potential confounding factors—Potential confounders were identified from information provided from the questionnaire immediately before the baseline cognitive assessment. All potential confounding variables were selected a priori based on risk factors for cognitive function in the existing literature. In analyses of cognitive decline, we adjusted for baseline performance.⁶

Results

At baseline interview 7.3% (n = 1394) of the women had type 2 diabetes, with a mean duration of 12 years since diagnosis. Of the 1248 women with diabetes who completed the most recent questionnaire, 901 reported recent medication for management of diabetes (294 (33%) insulin, 607 (67%) oral hypoglycaemic agents). As expected, women with diabetes had higher prevalence of several comorbid conditions (hypertension, high cholesterol, heart disease, obesity, depression) than women without diabetes, and used hormone therapy less and drank less alcohol. On every cognitive test, mean baseline scores were lower for women with diabetes.

We focused analyses on two measures of general cognitive function: the TICS and the global score (table). After we adjusted for potential confounding factors, women with diabetes were at 25-35% increased odds of poor baseline score compared with women without diabetes. Findings were consistent when we examined mean differences in scores. For those with diabetes for 15 years the odds of poor cognitive performance were 50% higher than for women without diabetes.

View this table: [in this window] [in a new window]   Diabetes, duration of diabetes, and use of medication for diabetes in women aged 70-81 in relation to baseline cognitive function

 

Compared with the odds in women without diabetes, we found high odds of poor performance for women with diabetes who did not report pharmaceutical treatment. Those taking insulin also had modestly increased odds of poor cognition. In the more powerful analyses of mean differences, the worst performance was among women using insulin. In contrast, those taking oral medications had similar odds of poor cognitive performance as those without diabetes and had the smallest mean difference in score.

As cognitive impairment may be a cause rather than a consequence of not taking medications, we also examined use of medication at time of diagnosis (average of 12 years before cognitive assessment). Results were similar: the odds ratios for poor score were 1.61, 1.19 to 2.16, and 1.43, 1.02 to 2.00, respectively, for women with diabetes who were not taking medication at diagnosis compared with women without diabetes.

In addition, as duration of diabetes, medication use, and level of control are correlated we conducted additional analyses to try to assess their independent effects. The results were largely similar after we did so.

Finally, we restricted analyses to participants who did not report any difficulty with hearing (n = 12 099) to reduce confounding by hearing status. The results were similar when we compared women with and without diabetes (1.45, 1.18 to 1.78, and 1.37, 1.10 to 1.71, respectively).

What is already known on this topic Many epidemiological studies have shown that type 2 diabetes increases the risk of cognitive decline, though most studies have been in men Type 2 diabetes is associated with greater risk of cardiovascular disease in women than in men, and cardiovascular disease may increase the risk of cognitive decline What this study adds Women with type 2 diabetes have about 30% greater odds of poor cognitive function than those without diabetes, with a 50% increase after 15 years' of diabetes Women with diabetes who did not report medical treatment had the highest risk of poor cognitive function and substantial cognitive decline Women with diabetes who reported taking oral medication had a similar risk of cognitive decline as women without diabetes

Prospective analyses of decline
We observed a significantly increased odds of substantial decline over the two year period on the TICS (1.26, 1.03 to 1.54) for women with, compared with women without, type 2 diabetes (see bmj.com). However, we observed little overall relation between diabetes and decline on the global score (1.11, 0.90 to 1.37). Similarly, mean decline was greater among women with diabetes by -0.17 points (-0.33 to -0.01) on the TICS but was comparable in the two groups on the global score (mean difference in decline -0.01, -0.04 to 0.03). In addition, qualitative relations with longer duration diabetes and use of medication were generally similar to those observed with baseline cognitive function.

Discussion

This large prospective study of women aged 70-81 years with type 2 diabetes found marginally worse baseline cognitive performance and greater cognitive decline than women without diabetes. Longer duration of diabetes resulted in larger associations. Women who said they were on hypoglycaemic treatment seemed to have a similar likelihood of poor cognition as women without diabetes, while women not taking medication for diabetes or those taking insulin had worse performance.

A major strength of our study is the large sample size, the prospective assessment of diabetes and potential confounders over 25 years of follow up and the relative homogeneity of the sample in terms of education and access to health care.

Limitations
We relied on self reported diabetes status, so we may have included some women with undiagnosed diabetes in the reference group. However, this was probably rare in these nurses; plasma samples from a random sample of those with no reported diabetes, indicated just 2% had diagnostic signs of type 2 diabetes.

As in all studies of cognitive decline, there is regression to the mean on the repeat cognitive assessment. As women with type 2 diabetes had worse cognitive performance at baseline, regression to the mean would probably have attenuated the true magnitude of cognitive decline associated with diabetes.

Participants who were not taking any treatment for diabetes probably included a heterogeneous group of women with untreated diabetes and diabetes controlled through diet. Diabetes that can be controlled through diet may not be associated with poor cognition.⁷ Thus, we have probably underestimated the effect of untreated diabetes. However, the increased odds of poor cognition associated with no treatment was similar across those with shorter and longer duration of diabetes (and duration is probably a good indicator of prevalence of dietary control), suggesting that our underestimate may be minimal.

There is growing evidence directly linking insulin to cognitive impairment: chronic hyperinsulinaemia⁸ and incremental increases in serum insulin concentration after a glucose load⁹ predict diminished cognition in the absence of diabetes or glucose intolerance. Moreover, insulin degrading enzyme regulates concentrations of both insulin and amyloid in the brain¹⁰ and infusion of insulin into healthy humans increases amyloid concentrations in the cerebrospinal fluid,¹¹ further supporting a direct association between insulin and cognition.

Other studies have also found less cognitive decline in those with medical treatment for their diabetes than those without.^{12 13} Thus, although physicians may avoid prescribing oral therapy for diabetes in older people, it may be important to their cognitive health.

Conclusions
We found worse cognitive function and accelerated cognitive decline among women with type 2 diabetes, which seemed to be ameliorated with oral hypoglycaemic treatment. Studies have established that, in apparently healthy people, even modest differences in cognition result in substantially increased risks of dementia over several years.¹⁴ Prevention and control of type 2 diabetes in women could have critically important public health consequences.

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This is the abridged version of an article that was posted on bmj.com on 23 February 2004: http://bmj.com/cgi/doi/10.1136/bmj.37977.495729.EE

Contributors: See bmj.com

Funding: Grants AG15424 and CA87969 from the National Institutes of Health. FG is partially supported by a New Scholars in Aging award from the Ellison Medical Foundation.

Competing interests: During the last five years GL has received honorariums for lectures from Pfeizer and Lilly Pharmaceutical. During the past five years FG has received honorariums or temporary consulting fees from Novo Nordisk, Schering-Plough, Novartis, Orion Pharma, and Wyeth Ayerst.

Ethical approval: This study was approved by the Institutional Review Board of Brigham and Women's Hospital, Boston, MA.

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(Accepted 27 November 2003)

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