In women without type 2 diabetes mellitus at blood draw, we found that higher levels of fasting insulin were associated with faster rates of cognitive decline. Associations were independent of numerous potential confounding factors and persisted after the exclusion of women who were diagnosed with diabetes mellitus or stroke after the baseline cognitive interview. Although the largest point estimates for rates of cognitive decline were found in the third and not in the fourth quartile, the p trends were significant across quartiles for the TICS and verbal memory, supporting a dose-effect relationship.
Although there are very few studies of insulin levels and cognition in nondiabetics, our findings are consistent with previous studies linking higher fasting insulin levels to cognitive impairment [15
], dementia [6
] and cognitive decline [6
] in healthy subjects. For example, among 386 nondiabetic men, 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 [15
]. Luchsinger et al. [6
] reported an association between higher insulin and an increased risk of dementia in persons without diabetes (hazard ratio = 2.3, 95% CI = 1.5–3.6); an association between insulin and decline in memory-related cognitive scores was also found. Though not directly examining fasting insulin levels, other studies support the hypothesis of a role of insulin in the development of cognitive impairment. Yaffe et al. [16
] showed an elevated risk of developing cognitive impairment in women with impaired fasting glucose but without diabetes (fasting glucose level >6.1 mmol/l but <7.0 mmol/l), compared to women with a normal fasting glucose. Recently, higher glycosylated hemoglobin levels were associated with an increased risk of mild cognitive impairment and dementia in 1,983 women; these associations remained after the exclusion of women with diagnosed diabetes [17
In this NHS cohort, we previously reported an association between higher levels of C-peptide (a measure of insulin production) and cognitive impairment among 718 women [8
]; we found similar results for C-peptide among 367 men in the Physicians’ Health Study [18
]. However, in these 2 studies, complete information from cognitive testing was only available from a single examination. Thus, the current study adds substantively to the literature by showing a significant relation between higher fasting insulin levels and increased rates of decline over time on repeated assessments of cognition – in particular, a decline in verbal memory, a key predictor of dementia [12
In addition, growing biologic evidence supports a role of insulin in cognitive decline and dementia [19
]. It has been shown that peripheral insulin is actively transported across the blood-brain barrier [20
], and insulin receptors have been found throughout the brain, in particular in the hippocampus and cortex [21
]. Moreover, it has been suggested that high insulin levels in the brain may directly interfere with Aβ metabolism by inhibiting degradation of Aβ by insulin-degrading enzyme, resulting in increased deposition of Aβ in plaques [5
]. Thus, insulin may directly affect specific Alzheimer pathologies. Additionally, it is likely that part of the relation of insulin to cognition and dementia is mediated by vascular disease, although, in our study and in others, adjustment for known major vascular factors did not affect the association between insulin and cognitive decline. However, it is difficult to accurately measure the presence of subclinical vascular disease. Indeed, it seems plausible that a combination of both direct (e.g. increased brain Aβ) and indirect effects (e.g. inflammation or vascular endothelial damage) of elevated insulin may underlie the observed association with cognitive decline.
The strengths of this study include the high rate of follow-up and the breadth of information on potential confounding factors, updated every 2 years. In addition, fasting insulin levels were measured in blood collected in mid-life; since cognitive impairment appears to take many years to develop, risk factors at these younger ages may be the most important assessment.
Potential limitations of our study should be considered. First, information on cognitive decline was gathered through telephone-based testing rather than through in-person testing. However, the high validity of our telephone method has been established [8
]; furthermore, the telephone testing yields high participation and follow-up rates, enhancing the validity of results. Second, we only had a single measurement of insulin, which may have increased random measurement error; however, this would have led to an underestimation of the association between insulin and cognitive decline. Third, this is a select population of largely healthy Caucasian nurses, and the absolute levels of fasting insulin were somewhat lower than those recently reported in nondiabetic, community-dwelling women of comparable age [22
]. However, a slightly narrower distribution of fasting insulin levels would lead, if anything, to underestimating the relation between insulin and cognitive decline in the general population; indeed, the significant association we found between insulin and cognitive decline in these healthy women with relatively low levels of insulin emphasizes the potential importance of even modestly elevated insulin. Fourth, since we relied on self-reports of diabetes status to exclude diabetic women, our study sample may have included women with undiagnosed diabetes mellitus; hence, our findings may partly be explained by the association between diabetes and cognitive decline. However, as noted earlier, insulin levels in this sample were not very high, indicating a low prevalence of insulin resistance, and our results remained similar when we excluded women who were diagnosed with diabetes mellitus during follow-up, likely eliminating any women with undiagnosed diabetes mellitus at the time of blood draw. Moreover, as health professionals, virtually all our participants have access to health care, making undiagnosed diabetes mellitus less likely; indeed, in a random sample of 200 NHS participants who never reported diabetes, we found only 1 had a plasma fasting glucose or fructosamine level in the diabetic range [8
]. Finally, although we were able to adjust for many potential confounders, residual confounding should be considered, as in any observational study. The relative homogeneity of our cohort, however, reduces the potential effect of many unmeasured confounders, such as health knowledge and access.
In conclusion, data from our study suggest a role of insulin, independent of diabetes mellitus, in the development of cognitive decline. This association clearly needs further research since modulation of insulin levels may represent an effective target for prevention of cognitive decline and Alzheimer disease.