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Diabetes-Related Risk Factors and Cognitive Aging: Page 2 of 3

Diabetes-Related Risk Factors and Cognitive Aging: Page 2 of 3

An emerging epidemiological literature has addressed the independent relationship of insulin resistance and chronic hyperinsulinemia (ie, in the absence of diabetes) to the risk of cognitive decline and dementia. Overall, it appears that the biologically compelling hypothesized relationship of insulin resistance to adverse brain health outcomes is being demonstrated in prospective, large-scale epidemiological studies. One example comes from the Washington Heights-Inwood Columbia Aging Project. Luchsinger and colleagues25 identified a doubling of risk for AD (RR, 2.3; 95% confidence interval, 1.5 - 3.6), with higher versus lower plasma fasting insulin levels among 531 elderly adults without diabetes.

Our research group recently followed up earlier cross-sectional investigations that identified significant associations between midlife elevated insulin secretion and risk of late-life cognitive impairment among men and women from 2 large-scale epidemiological cohorts.26,27 In 2 prospective analyses involving random samples of approximately 1200 women in the Nurses’ Health Study, elevated midlife fasting insulin and C-peptide (a measure of insulin secretion) levels were both significantly associated with more rapid decline at late life on 3 serial assessments of general cognitive function and episodic memory conducted over 4 years.28,29 Among participants in a random sample of 1353 men in the Physicians’ Health Study II, both higher fasting insulin and higher C-peptide levels were significantly related to greater average decline in general cognitive performance on 2 assessments conducted an average of 2 years apart (range, 1.5 to 4 years).30

Finally, Rnnemaa and coworkers31 reported that among 2322 men of the Uppsala cohort, midlife insulin resistance and impaired insulin response were significantly related to increased risk of AD and dementia more than 30 years later.

Metabolic syndrome

The metabolic syndrome combines aspects of both obesity and insulin resistance, as well as their likely consequences. The metabolic syndrome has been variably defined but typically involves core features of obesity (particularly central adiposity), dyslipidemia, hypertension, and evidence of insulin resistance or impaired glucose tolerance. The most commonly used criteria are from the National Cholesterol Education Program: Adult Treatment Panel III (NCEP-ATP III).32 Although the literature is still relatively scant, several recent reports suggest that the metabolic syndrome may be related to increased risk of cognitive impairment and dementia.

In a prospective study of 4895 women (mean age, 66 years) followed up for 4 years, the metabolic syndrome was associated with a nearly 70% increased adjusted RR of clinically significant cognitive impairment, including mild cognitive impairment and dementia.33 Moreover, because the NCEP-ATP III criteria do not preclude the presence of clinical diabetes, researchers performed analyses of data gathered from patients who met criteria for metabolic syndrome but who did not have diabetes, and the increased risk remained unchanged. The metabolic syndrome has been associated with a significant 3-fold increased RR of AD specifically, regardless of whether patients had diabetes.34,35

There may be important interactions on cognitive outcomes that involve the metabolic syndrome and the increased systemic inflammation that often accompanies insulin resistance. In a prospective study involving more than 2600 black and white community-dwelling elderly adults, the metabolic syndrome was associated with a 20% increased risk of cognitive decline36; however, the increased likelihood of cognitive dysfunction was strongly modified by the presence of high blood levels of inflammatory markers (CRP and IL-6), which is consistent with the potential role of inflammation in the relationship between insulin resistance and cognitive decline.

Although results have been inconsistent, markers of inflammation have been associated with risk of cognitive decline and dementia. In a cross-sectional study of CRP and late-life cognitive function among 447 persons aged 40 to 85 years (mean, 63 years), Wersching and colleagues37 observed that elevated CRP levels were associated with worse executive function and brain MRI measures of white matter integrity, including in the frontal lobe. By contrast, Women’s Health Study researchers found that plasma CRP levels were not significantly associated with cross-sectional cognitive performance among 4231 women aged 60 to 90 years who were tested 2 to 3 years after blood draw.38 Similarly, Dik and colleagues39 did not find a relationship between CRP or IL-6 and 3-year cognitive decline among 1284 adults aged 62 to 85 years at baseline.


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