In the middle-aged community sample of stroke- and dementia-free Framingham Offspring participants, we observed that clinical diabetes and various metabolic indices associated with diabetic and prediabetic states were associated with the subclinical changes of smaller brain volumes and poorer cognitive performance, especially on tests of executive function and visual memory. These findings were observed even among participants who did not have clinical diabetes, and the most consistent association was with IR, which is important in the evolution of clinical type 2 diabetes.
The relationship between diabetes and cognition was reported >85 years ago, when Miles and Root (12
) observed that patients with diabetes did not perform as well as control subjects in tests of memory, mental arithmetic, and psychomotor efficiency. Multiple studies since then have shown an adverse effect of baseline diabetes status on concomitant cognitive function and cognitive decline on follow-up. Diabetes has been associated with cognitive changes that affect learning and memory, mental speed, and mental flexibility (13
), and population-based studies have also related diabetes to the risk of incident dementia and AD (3
). The Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed an inverse relationship between glycohemoglobin levels and performance on cognitive tests; whereas, fasting plasma glucose, a measure with greater day-to-day variability, was not associated with test performance (14
). The cognitive impairment associated with diabetes may begin even before the appearance of clinical disease; compared with women with normal glucose, women with impaired fasting glucose levels had worse baseline cognitive scores and an almost twofold risk of developing cognitive impairment over a 4-year period (15
The pathophysiologic mechanisms underlying the purported relationship between diabetes, prediabetes, and dementia, thus far, remains unclear but could involve direct effects on AD neuropathology or indirectly via diabetic vasculopathy, leading to cerebrovascular brain injury. Hyperglycemia can be harmful by promoting oxidative stress, the formation of toxic advanced glycation end products, and induction for receptors for advanced glycation end products. A direct effect of insulin on cognition is supported by observations that insulin readily crosses the blood-brain barrier and the high concentration of insulin receptors on the hippocampus and medial temporal cortex (16
), areas of the brain that are primarily involved in memory and affected by AD neuropathology. At excessively high or low levels, insulin has been shown in vitro to downregulate choline acetyltransferase (17
), the enzyme that catalyzes the production of the neurotransmitter acetylcholine, which is deficient in AD. Furthermore, insulin has been implicated in τ phosphorylation and amyloid deposition, the pathophysiologic mechanisms for AD (18
Diabetes is an established risk factor for stroke and other vascular disorders, leading to an alternate hypothesis that the link between diabetes and dementia is indirect, mediated by vascular pathology (19
). In the Rotterdam Study, however, diabetes was associated with MRI markers of AD risk, including smaller hippocampus and amygdala volumes, even after accounting for vascular pathology (20
We found that, in this late adult population with a mean age of 62 years, clinical diabetes and each of the metabolic dysfunction markers of IR, hyperinsulinemia, and hyperglycemia (elevated HbA1c) were associated with signs of accelerated brain aging, as measured by MRI TCBV, and by poorer performance on tests of executive function. The association with IR and hyperinsulinemia, which are early markers of a compensated prediabetic state, were also observed in a subsample without clinical diabetes.
In addition, we found that there appear to be different patterns of association between markers of a hyperglycemic state versus measures of IR when each is related to cognitive markers of aging. Measures of IR (HOMA-IR and fasting insulin levels) were inversely associated with visual memory and executive function, whereas glycemic indices (diabetes and HbA1c
) were inversely associated only with performance on executive function. We also found a marginally significant direct association between diabetes and verbal memory, which disappeared after adjusting for all covariates. This finding is contrary to previously published studies and may be a chance artifact given our cohort’s younger average age compared with previous studies. Because it was restricted to persons on insulin supplementation, it could reflect a beneficial effect of exogenous insulin on memory (21
Our data strengthen earlier findings relating diabetes status to cognitive function, even in stroke- and dementia-free community-dwelling middle-aged men and women. Taken together, these findings suggest that the insulin resistant states seen in prediabetes and diabetes, as well as hyperglycemia, accelerate brain structural and cognitive aging, albeit in slightly different patterns, with the most robust associations being with IR.
In contrast to investigations into the association between glycemia and cognition, fewer studies have explored the possible links between insulin levels and IR, and brain structure and cognitive performance. Although hyperinsulinemia has been directly linked (22
) to AD risk, there is also accumulating evidence linking insulin levels and cognitive performance in individuals without dementia. Hyperinsulinemia has been associated with lower scores on the Mini-Mental State Examination in individuals without dementia (23
). Furthermore, IR, as measured by the HOMA-IR, has likewise been associated with poorer cognition and, more recently, with diffusely decreased cortical glucose uptake on fluorodeoxyglucose-positron emission tomography scans (24
). Our findings of inverse relationships between fasting insulin levels, HOMA-IR, and brain volume and cognitive performance—even after controlling for vascular risk factors— appear to support these findings.
One limitation of our study is that we only examined a cross-sectional association but did not examine the association of these measures with change. Another limitation is the primarily white ethnicity of the Framingham study sample; hence, these associations need to be examined among community-dwelling individuals of other ethnicities. Our results do support ongoing studies to examine whether early detection and management of diabetes and metabolic dysfunction, particularly IR, would be able to delay the clinical onset of cognitive disorders.
Diabetic and prediabetic states characterized by IR, hyperinsulinemia, and hyperglycemia, when present in late middle age, are related to decreased brain volume and lower cognitive performance on executive function and memory tasks. These results extend the body of evidence linking metabolic dysfunction to the risk of dementia and AD in late life. These results suggest that clinical trials attempting to delay cognitive and structural brain loss by controlling metabolic dysfunction, even in individuals free of clinical diabetes and as early as the 7th decade, might be warranted.